Diabetic retinopathy is the most common ocular complication of diabetes and a cause of vision loss in adults. Diabetic retinopathy screening leading to early identification of the disease followed by timely treatment, can prevent vision loss in people living with diabetes. A key barrier to the implementation of screening services in low- and middle-income countries is the low number of ophthalmologists per million population. Interventions that shift screening to non-ophthalmology cadres have been implemented in programmes in low- and middle-income countries and are routinely used in high-income countries. The aim of this rapid review is to summarise the published literature reporting the effectiveness of task-shifting interventions for the detection of diabetic retinopathy by non-ophthalmologists in low- and middle-income countries.We will search MEDLINE, Embase, Global Health and Cochrane Register of Studies for studies reporting task-shifting interventions for diabetic retinopathy detection. The review will include studies published in the last 10 years in the English language. We will include any interventional or observational comparative study measuring outcomes in terms of participation or access to diabetic retinopathy detection services (uptake) and quality of diabetic retinopathy detection services . For included studies, cost-effectiveness of the task-shifting intervention will also be presented. Two reviewers will screen search results independently. The risk of bias assessment and data extraction will be carried out by one reviewer with verification of 10% of the papers by a second reviewer. The results will be synthesised narratively.Differences in health systems organization, structure and resources will determine the need and success of task-shifting interventions for DR screening. The review will examine how these interventions have been used and/or tested in LMICs. The results will be of interest to policy makers and programme managers tasked with designing and implementing services to prevent and manage diabetes and its complications in similar settings.https://osf.io/dfhg6/.OSF:  Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes and a significant cause of vision loss in adults . Vision DR screening has been shown to be cost-effective when compared to no screening or opportunistic screening , 6, 7. HA crucial limitation to deliver DR screening in LMICs is the low availability of ophthalmologists, particularly in sub-Saharan Africa (SSA), where the mean ophthalmologist density per million population is 3.7 . In thisThere are several factors that can potentially affect the effectiveness of task-shifting interventions for DR screening. Firstly, the choice, level and training of the cadre performing the screening is a key consideration and is likely to be different depending on the composition and competencies of the health workforce in a particular country. The quality of the screening is measured by the diagnostic test accuracy (DTA) of the method of choice in the hands of non-ophthalmologists . It is rSecondly, the screening technique used can also affect the DTA. The recommended technique is photography-based screening which adds the possibility of quality assurance . DR screThirdly, the use of mydriasis can improve the effectiveness of task-shifting by increasing the number of gradable images . HoweverFinally, an important consideration in LMICS is the need to reach rural and remote populations with difficult access to eye health services. Outreach services delivered by non-ophthalmologists can be an answer to this problem, but must ensure that DTA is maintained , 20. EviThis rapid review aims to identify and synthesise the peer reviewed literature on the effectiveness of task-shifting for the detection of DR in LMICs. It is an important topic given the predicted epidemic of diabetes mellitus which will disproportionally affect LMICs which will require major prevention strategies to prevent the corresponding increase in blindness caused by diabetic retinopathy. There is a body of evidence to support the effectiveness of task-shifting in DR screening in high-income settings which suggests that this may be a viable strategy in LMICs. However, given the differences in structure, organization and resourcing in health systems in LMICs, evidence from HICs may not be generalizable to these settings. The aim of this rapid review is to summarise the published literature reporting the effectiveness of task-shifting interventions for the detection of diabetic retinopathy by non-ophthalmologists low- and middle-income countries.Can task-shifting improve the detection of diabetic retinopathy (DR) compared with eye examination done by ophthalmologists among adults with diabetes in LMICs?A rapid review was chosen as it is an effective methodology to support health programme decision-making through quality evidence in a timely and cost-effective manner. These rapid review methods were informed by the WHO practical guide on rapid reviews and we used the STARR (Selecting Approaches for Rapid Reviews) Decision Tool to carefully take into account the possible limitations introduced by the choice of methodology , 28. We The review will focus on adults only as they represent the larger population group at risk of DR and are the target of population-based screening programmes. We will include any study that measures any of the uptake and quality outcomes described in the above table. For included studies, we will also collect data on cost-effectiveness of the task-shifting intervention where available.We will only include peer-reviewed publications reporting studies conducted in LMICs, as classified by the World Bank  in the lThe following exclusion criteria will be applied: firstly, reviews, editorials, case studies, conference abstracts; secondly, studies involving health education, training programmes or qualitative studies and thirdly, studies conducted in high income settings.Following guideline of the STARR Decision tool, we consulted the review commissioners (FHF) and conducted scoping searches on PubMed to inform the decision on which information sources to include, balancing the scope and time available to do the review . The CocSearch strategy is included in Additional file www.covidence.org). Any conflicts will be discussed and resolved. Two reviewers will independently screen the full text articles of potentially relevant studies against the inclusion and exclusion criteria and any will discuss any differences to reach consensus. A summary of the study selection process will be presented in a PRISMA flow diagram.Two reviewers will independently review each title and abstract using the online review management software  to assess the risk of bias for included studies. This will be presented in narrative form with the review findings.One reviewer will use SING critical appraisal checklists (We will develop an Excel data extraction form which will be tested by two reviewers on three papers. One reviewer will conduct data extraction and a second reviewer will check 10% of the studies for accuracy. If more than 1% errors are found, another 10% will be checked Table .Table 2As we anticipate to find heterogeneity in study design, interventions, methods and outcome reporting, we will summarise data narratively following the SWiM reporting guidance: Synthesis Without Meta-analysis reporting items . We willDifferences in health systems organization, structure and resources will determine the need and success of task-shifting interventions for DR screening. The review will examine how these interventions have been used and/or tested in LMICs. This rapid review will provide context-specific evidence to inform policy makers and programme managers tasked with designing and implementing services to prevent and manage diabetes and its complications in low- and middle- income settings.In balancing the time demands of a rapid review methodology, we have prioritized the peer-reviewed literature as we considered the more robust evidence for effectiveness will be found in published scientific journals. We acknowledge that the limits in searches and time may potentially miss some evidence which could have been published before the period included and in the grey literature.Additional file 1. Reporting standards – PRISMA-P Checklist.Additional file 2. Registration OSF: https://osf.io/h5wgr/Additional file 3. Search strategy.


Tracking outcomes is integral to assessing effectiveness of health systems. Multimodal training was offered in the use of a contextually appropriate, patient-centered outcome measure in a low-resource setting. Results offer insights for designing future capacity-building programs. Ninety-two percent of respondents stated that they felt either “quite” or “very” confident in their abilities to establish functional goals.Seventy percent of respondents stated that they continue to use patient-reported outcome measures either “a lot” or “quite a bit” 26 months after the close of the grant.After completing the training:Targeting stakeholders from a range of health system levels to facilitate systemic and institutional support of practice changes as well as maximize adoption, penetration, and sustainability of new skills and conceptsAdopting culturally appropriate outcome measure toolsUsing multimodal strategies for capacity buildingProgram managers should consider: Patient-reported outcome measures (PROMs) assess disability and progress toward functional goals while promoting patient-centered practice. They can be used by health professionals in any specialty and in a multitude of settings. This study reviews implementation strategies and lessons learned in a capacity-building program that took place with pediatric physiotherapists in Rwanda.Use of PROMs and patient-centered practice were integrated into 4 consecutive continuing professional development courses offered to 164 participants in Rwanda. We sought to identify a simple generic measure with proven validity in cross-cultural settings. The Patient-Specific Functional Scale was chosen due to its ease of use and ability to measure change in a wide range of patient conditions. Didactic classroom training and clinical site visits were 2 essential pedagogical elements of the capacity-building strategy. Site visits allowed for evaluation of skill levels and facilitation of knowledge transfer to patient care settings. Unique pairs of Rwandan colleagues were trained to serve as coteachers in each course to maximize sustainability of new techniques. This study presents data on a subset of 65 participants who completed a 48-hour pediatric rehabilitation course.After classroom instruction, 78% of participants were observed independently determining functional limitations with their patients. Additionally, pre- and post-tests indicated that therapists substantially increased their understanding of patient-centered practice after attending courses. Interviews conducted 26 months after the conclusion of the project revealed mixed success in sustainability of the use of PROMs, although perceived confidence remained high.Challenges in long-term sustainability of new practices call attention to the need to target not only clinicians when introducing new methodologies, but also the Ministry of Health, hospital administration, and university faculty. Lessons learned from this study may be useful to other medical professionals planning capacity-building programs in low- and middle-income countries. Historically, the data have been based on medical tests of body function and structureStandardized and validated instruments to measure outcomes are utilized to both guide treatment and determine its functional impact.The Advancement of Rwandan Rehabilitation Services Project (ARRSP) was a 27-month program funded by the United States Agency for International Development and implemented by Health Volunteers Overseas from March 2013 until May 2015. Key goals of the program were to upgrade rehabilitation standards in Rwanda and improve the quality of services provided. This aim was in alignment with Rwanda’s Third Health Sector Strategic Plan, July 2012–June 2018, in which one of the strategies listed was to “train health workers on control, prevention, and treatment of injuries and disabilities.”Key goals of the ARRSP were to upgrade rehabilitation standards in Rwanda and improve the quality of services provided.The ARRSP offered successive continuing professional development courses to practicing physiotherapists. Content specialists were recruited from the United States to teach a series of courses on topics that had been selected by a steering committee made up of Rwandan rehabilitation professionals. The committee also chose 2 different Rwandan physiotherapists to be co-instructors for each course. Preference was given to physiotherapy faculty members so that they could integrate new concepts and practices into their teaching of students at the university. During the grant period, there were 4 physiotherapy faculty members in the country, and all participated in the courses. Rwandan co-instructors received intensive training on PROMs, course content, and patient-centered practice. This study focuses on the participants of the pediatric rehabilitation course since a follow-up assessment was conducted on this subgroup 26 months after the conclusion of the grant to determine sustainability of introduced skills and concepts.Courses ranged from 36 to 48 hours in length and were offered to 2 or 3 cohorts at a frequency of one weekend class session per month per cohort. By the last class session each month, Rwandan co-instructors were responsible for the majority of teaching. At the time the courses were given, records from the Rwanda Allied Health Professionals Council indicated that there were 142 registered physiotherapists employed in direct patient care in the country. One hundred sixty-four therapists attended at least one of the courses included in this study, with most participants attending 2 or 3 continuing professional development offerings . This inAll courses incorporated didactic classroom teaching as well as training in clinical settings. An essential element in both environments was the use of PROMs and patient-centered clinical decision making to facilitate patients’ return to optimal function. To achieve this, we set out to select a contextually appropriate, generic PROM that could be used across all courses.,–Since the use of outcome measures has been identified as an essential component of best practices in physical therapy,The use of outcome measures was a new concept among the majority of physiotherapists in Rwanda.,Studies have demonstrated that consideration of local, contextual factors is often essential to the long-term success of a project.–An additional strength of the PSFS is its inherent patient-centeredness. Rather than using predefined activities that might lack a local context, the PSFS calls on patients to identify and assign a rating to activities that they have difficulty completing as a result of their impairment. In this manner, the scale is tailored toward activities that are relevant to each patient and a separate pediatric version is not necessary. For infants, toddlers, and nonverbal children, functional deficits and goals can be determined by a proxy, such as parents. The measure has demonstrated reliability and validity for use in impairments of the lower extremity, upper extremity, and the cervical and lumbar spine.The ARRSP sought to build capacity through training clinicians and rehabilitation faculty in PROMs and patient-centered practice. Once we determined that the PSFS would be the PROM of choice, the course instructors and project coordinator began an iterative process of refining implementation techniques for capacity building in both use of the measure and improvement of patient-centered practice. Because 4 unique instructor teams each taught successive courses covering a different topic in rehabilitation, capacity building evolved as the unique needs of each cohort became apparent. A 3-pronged approach was used to maximize acceptance, adoption, penetration, feasibility, and sustainability of the measure.The ARRSP sought to build capacity through training clinicians and rehabilitation faculty in PROMs and patient-centered practice.1.Course instructors used the World Health Organization’s International Classification of Functioning, Disability and Health (ICF)2.In an attempt to maximize adoption and feasibility of the PSFS, a booklet was drafted and distributed to participants that included instructions and rationale for its use. The booklet also contained a completed sample PSFS and 3 blank forms. PSFS data collected via site visits and booklets were presented in the classroom to facilitate discussions on how results can be used to assess and progress treatment.3.The inclusion of clinical site visits was an integral component of the ARRSP and was thought to be essential for achieving maximal adoption and penetration of the PSFS and patient-centered practice. Site visits provided an opportunity to offer direct clinical mentoring and observation. This allowed instructors to evaluate skill levels and reinforce classroom lessons to help facilitate knowledge transfer to patient care settings. A site visit checklist was utilized to evaluate clinical reasoning, documentation of functional problems, patient-centered practices, and implementation of the PSFS. Formative feedback was offered to those who needed assistance completing the measure or had difficulty relating it to patient-centered practice. Course participants typically invited colleagues to engage in clinical visits so that the number of rehabilitation professionals influenced by the visits substantially exceeded the number formally attending classes.Pre- and post-tests for each courseClinical observationsParticipants’ written assessments of each courseEnd-of-grant written assessmentsEnd-of-grant interviews with course participantsInterviews and survey conducted 26 months after the conclusion of the ARRSPWe used 6 measures to assess the success of the project:Six measures were used to assess the success of the project, including an evaluation 26 months after the grant ended.Supplement 1 contains the full pre- and post-test questionnaire. On the pretest, 55% of the participants (N=66) selected option B, the correct answer. On the post-test, 94% (N=61) chose the correct answer, demonstrating an increased understanding of the value of the PSFS.Pre- and post-tests were a part of every course. Item analysis of the pre- and post-tests indicated that participants’ understanding of PROMs and patient-centered practice increased after attending courses. An example of a question included in the pre- and post-test of the pediatric rehabilitation course is shown . SupplemBOX.Example of Pretest/Post-test Pediatric Rehabilitation Course QuestionUsing the Patient Specific Functional Scale (PSFS) with our pediatric patients and their families can help us:Perform a standardized, norm-based assessment allowing us to compare our patient to other children his/her age.Understand and identify what activities are important to the child and his/her family.Make a diagnosis about what is wrong with the child.The information we learn from the PSFS does not really help us in our evaluation, choice of treatment or setting of goals for the child.Course instructors evaluated the participants’ ability to identify functional deficits during structured clinical observations. This skill was new and was not previously a routine part of clinical practice. In the pediatric rehabilitation course, observations were completed on 60 participants. As can be seen in Clinical observations indicated successful transfer of didactic knowledge to clinical practice.Supplement 2), participants were asked to rate their perceived competency in various indicators related to functioning . Fifty-five participants who attended at least one of the ARRSP courses completed the assessments. This represents 35% of the total number of unique course participants. As part of the assessment, they were asked to rate their perceived improvement in various aspects of patient-centered practice and clinical reasoning . Forty-three people (66%) completed the survey. As can be seen in In the summer of 2017, a postgrant evaluation was conducted 26 months after the conclusion of the last course offering. An online survey was sent to the 65 participants of the pediatric rehabilitation course (Additionally, the survey asked participants to rate their perceived competency in the same indicators related to functioning that they self-rated in the course assessment that was filled out on the last day of the course. The perceived competency 26 months after the grant end remained high, suggesting good sustainability of skills and concepts learned.In 2016, the Rwanda Ministry of Health outlined new guidelines for data collection stating that it is essential to collect accurate data to track patient outcomes.Although these changes are positive, there are still obstacles to the long-term adoption of PROMs. Interviews and clinical observations held 26 months after the conclusion of the ARRSP revealed that PROMs were not regularly completed. Two frequently cited reasons included lack of promotion of the measures by department managers and the feeling among therapists that they were too time-consuming.Two further obstacles were noted at the institutional level. Although we supplied participants with a number of PSFS booklets for use in the workplace, there were barriers to producing more. Copiers were not available in physiotherapy departments and blank sheets of paper were often in short supply. Additionally, initial evaluations were often stored centrally within hospital records and not easily accessible to therapists after the evaluation had been completed. This storage issue created an obstacle to intermittent monitoring to assess changes in function and modify treatment programs accordingly.Results indicate that the use of the PSFS reached encouraging levels of acceptability, adoption, feasibility, and penetration at the end of the grant period. Additionally, participants demonstrated greater understanding and utilization of patient-centered practice techniques. The postgrant evaluation found that perceived confidence in establishing functional goals; selecting functional, meaningful treatment activities; and progressing those activities remained high 26 months after the grant period ended. However, the evaluation also revealed obstacles that limited optimal sustainability of the use of PROMs. Both institutional and clinical practice challenges were cited.The use of the PSFS reached encouraging levels of acceptability, adoption, feasibility, and penetration at the end of the grant period.The challenges in achieving long-term sustainability highlight difficulties that can be encountered when introducing new methodologies in low-resource settings. There must be a solid foundation upon which to introduce new practice standards. Accomplishing this is difficult without support at every level of the health system. In this project, we used the capacity-building model illustrated in In retrospect, we think the model in Although the Rwandan steering committee requested that ARRSP courses emphasize clinical decision making, the majority of physiotherapists in Rwanda were not familiar with outcome measures and patient-centered practice. Therefore, there were uneven perceptions of need for change and motivation to change. Some therapists understood that using PROMs was an essential aspect of clinical decision making and were motivated to use them. But others did not fully integrate them into their practices.Because the end-of-grant assessment was distributed at the closing ceremonies, it was only available to those in attendance, which was approximately 35% of course participants. If we could do it over, we would send out an electronic version of the assessment to reach more participants.The postgrant assessment was performed 26 months after the grant closing and only included participants who attended the pediatric rehabilitation course. This was due to the interest, availability, and motivation of one of the Rwandan co-instructors in sampling this subset. In hindsight, we would have implemented the postgrant assessment 12 months after the final course and included participants from all ARRSP courses to assess the levels of success across all participants. Additionally, the pediatric group was challenging since many of the patients had long-term congenital conditions that do not respond quickly or completely to physical therapy interventions.We recommend that groups planning similar capacity-building endeavors consider the model presented in


The MRI revealed a strong contrast enhancement of the conus medullaris and fibers of the cauda equina, while the 18F-FDG PET/CT was without pathological findings. Examination of cerebrospinal fluid led to the definitive diagnosis of Lyme neuroborreliosis with monocytic pleocytosis and a positive intrathecal test for Borrelia burgdorferi. The patient became pain-free after 10 days of ceftriaxone, and the paralysis slowly regressed the following month. This case highlights the difficulty of the diagnosis of Lyme neuroborreliosis and discusses the relevant imaging findings.We present a case demonstrating the performance of different radiographical and nuclear medicine imaging modalities in the diagnostic work-up of a patient with Lyme neuroborreliosis. The patient presented in late summer 2019 with radicular pains followed by a foot drop and peripheral facial palsy, both right-sided. Due to a history of breast cancer, disseminated malignant disease was initially suspected. Bone metastasis was ruled out by skeletal scintigraphy. Magnetic resonance imaging (MRI) of the neuroaxis and a whole body


This work deals with molecular dynamics simulations of systems composed of telomeric dsDNA fragments, iG, and functionalized carbon nanotubes, fCNT. The iG contains 90 nucleotides in total and in its middle part the noncanonical i-motif and G-quadruplex are formed. Two chiralities of the fCNT were used, i.e.,  and  and these nanotubes were either on-tip functionalized by guanine containing functional groups or left without functionalization. We proposed a dedicated computational procedure, based on the replica exchange concept, for finding a thermodynamically optimal conformation of iG and fCNT without destroying the very fragile noncanonical parts of the iG. We found that iG forms a V-shape spatial structure with the noncanonical fragments located at the edge and the remaining dsDNA strands forming the arms of V letter. The optimal configuration of iG in reference to fCNT strongly depends on the on-tip functionalization of the fCNT. The carbon nanotube without functionalization moves freely between the dsDNA arms, while the presence of guanine residues leads to immobilization of the fCNT and preferential location of the nanotube tip near the junction between the dsDNA duplex and i-motif and G-quadruplex. We also studied how the presence of fCNT affects the stability of the i-motif at the neutral pH when the cytosine pairs are nonprotonated. We concluded that carbon nanotubes do not improve the stability of the spatial structure of i-motif also when it is a part of a bigger structure like the iG. Such an effect was described in literature in reference to carboxylated nanotubes. Our current results suggest that the stabilization of i-motif is most probably related to easy formation of semiprotonated cytosine pairs at neutral pH due to interaction with carboxylated carbon nanotubes. The noncanonical DNA forms like i-motif ,2,3, iM,Interaction of carbon nanotubes with iM has also important biological implications. It was reported that carboxylated single walled carbon nanotubes can selectively induce human telomeric iM formation . Moreovea of CC+ pairs protonation. Which of these two ways is more likely or dominant could be answered by application of dedicated theoretical studies, particularly molecular dynamics. However, until very recently there were no published results concerning the interaction of these noncanonical DNA forms with carbon nanotubes. First insights into a complex picture of an isolated iM interaction with functionalized carbon nanotubes, fCNT, were provided in our recent paper : [3′-CCC(ATTCCC)7] where in the middle of the guanine-rich strand the G-quadruplex ‘basket’ topology is formed and in the middle of the cytosine-rich strand the i-motif is formed. The analyzed here telomeric fragment of DNA is the same as already described in refs. ,23 iG moThe molecular topologies and force fields used for the iG and fCNT compounds are described thoroughly in our recent papers. Thus, details concerning the architecture of the DNA duplex, G-quadruplex, and i-motif are available in refs. ,23. The Taking into account that we consider two kinds of iG differing in protonation state of cytosines and two kinds of carbon nanotubes, differing in chirality, we have to deal with four different systems: a10, a20, n10, and n20. These are: protonated iM with  nanotube, protonated iM with  nanotube, unprotonated iM with  nanotube, and unprotonated iM with  nanotube, respectively.+ and Cl− ions in order to compensate the charge of phosphate backbones and to mimic the ionic strength of solution 0.145 mol L−1. The number of water molecules was ca. 32,600 molecules, thus the simulation boxes contained about 102,000 atoms in total. The calculations were carried out using lammps code [The simulation boxes also contained adequate amounts of Namps code  in the NThis work deals with two distinct but actually coupled important problems related to the interaction of carbon nanotubes with DNA fragments containing non-canonical DNA structures. The first problem is related to purely computational side and it was detected during attempts of determination of thermodynamically optimal configurations of fCNT and iG. It turned out that those optimal configurations are unreachable in standard unbiased calculations and application of various biasing methods, which should help to pass the energy barriers (infrequent events), destroys the fragile structures of the noncanonical iM and Gq forms.Therefore, we proposed computational procedure which allows probing configurational space of two (or more) complex bodies efficiently and, at the same time, it keeps the fragile internal structures of those bodies unaffected by the biasing factors. This can be achieved by (i) transferring the essential components of the system to a simple implicit solvent model, (ii) rescaling the potential energy landscape so that the energy barriers can be overcome by the applied biasing factor, (iii) transferring the essential components of the system into rigid bodies and running computation according to the rigid body dynamics, (iv) applying biasing factors like increasing the simulation temperature and running the replica exchange simulations. This approach, as presented in By applying the above procedure, we were able to analyze and discuss the configurations of guanine functionalized fCNT and iG. We found that preferred alignments of these compounds is when fCNT locates in the junction of Gq + iM and the duplex and with the iG immobilized on the nanotube surface. The lack of guanine functional groups on the nanotube tips leads, however, to a free motion of iG on the nanotube surface. The general and important conclusion is that the presence of guanine functional groups favors configurations with the nanotube tips close to the Gq + iM section. In other words, such type of CNT functionalization makes the nanotubes able to selectively attack the Gq + Im parts of DNA with its tip. The lack of guanine functionalization leads to nonspecific arrangement of these compounds.We did not find a stabilizing effect of CNT on the structure of iM at neutral pH being the effect of physical interaction between these two compounds. However, we found that deterioration of iM at neutral pH is at some moment hindered due to the presence of either guanine-rich supplementary strands (or Gq) or carbon nanotube. Anyway, the iM deteriorates quickly and spontaneously until it loses all hydrogen bonds in C:C Hoogsteen pairs. Afterwards the structure becomes rather static, but it cannot be called as i-motif since its characteristic factors (Hoogsteen pairs) do not exist anymore. Thus, the final conclusion related to the observed in literature stabilization of iM by carboxylated CNT is the following. Most probably it is due to proton transfer from carboxyl groups from functionalized CNT and formation of semiprotonated cytosines. Then, the iM-CNT complex becomes highly stable due to acid-base balance between carboxylated CNT and unprotonated cytosines. It is very likely that carboxylated nanotube also preferentially attack the Gq + iM part of DNA (or just cytosine-rich DNA fragments) with its tips, thus such chemical factor like proton transfer is highly possible to occur when protonated carboxyl residue approaches unprotonated cytosine. Then, stabilization or even formation of iM is very likely.


Introduction: The primary aim of this study was to determine whether the tissue type and anatomical location of intra-operative samples influences the accuracy of culture in the diagnosis of periprosthetic joint infection (PJI). The secondary aim was to create a predictive model of PJI using other known patient variables.Methods: A retrospective cohort of 3460 intra-operative samples from 887 patients was identified. The data was then analysed to compare intra-operative culture results (positive or negative) to the chosen gold standard of clinical diagnosis made by the treating team (infected or non-infected prosthetic joint). The intra-operative samples were grouped according to their labelling at the time of collection.Results: No single tissue type or anatomical location had both high sensitivity and specificity. The highest specificity for an anatomical location was hip bursa with 100%, for tissue type it was synovium with 93%. Sensitivity was highest in the anatomical locations for hip capsule (68%) and in the tissue types for pus (83%). Data analysis was performed to create a model for PJI and identified pre-operative predictors of PJI  which when used in combination with intra-operative culture results increased the sensitivity.Conclusion: Sample type and anatomical location influenced the reliability of the diagnosis of PJI however, no single sample type had higher diagnostic accuracy than samples combined thereby highlighting the necessity of obtaining multiple intra-operative samples in the diagnosis of PJI. The variation in predictive values of tissue types as well as improvement in sensitivity when combined with patient factors indicates that types of intra-operative sampling and the overall diagnostic pathway should vary depending on the individual case. Periprosthetic joint infection (PJI) is the second most common complication of joint arthroplasty In order to maximise the accuracy of periprosthetic tissue culture, research has focused on numerous factors including types of samples Regarding the specific tissue type or anatomical location of the samples, the evidence base is lacking and associated guidance is vague. Tissue samples have been shown to have superior sensitivity and specificity compared to deep intra-operative swab samples in cases where tissue samples were selected in the areas that appeared most inflamed and infected It has also been reported that adjunct investigations and patient factors can be used in combination to determine an individual's risk of having a PJI The primary aim of the current study was to examine the impact of anatomical site and tissue sample type in the diagnosis of hip and knee PJI. The secondary aim was to create a prediction model of PJI incorporating patient factors along with serum inflammatory markers and microbiology results, which have previously been used to predict the risk of PJI This was a retrospective cohort study investigating the effect of tissue type and anatomical location of intra-operative samples on the accuracy in the diagnosis of PJI. The standard for comparison was the clinical diagnosis made by the treating surgical team of an infected or non-infected prosthetic joint. A prediction model for PJI was then created using pre-operative patient factors in isolation and also in combination with intra-operative cultures. This study was conducted in collaboration with orthopaedic surgeons, microbiologists and diagnostic laboratory services at a tertiary centre.A consecutive cohort of all microbiology intra-operative periprosthetic samples taken from hips or knees between January 2010 and December 2016 was identified. The patient cohort was identified from the Laboratory Information Management System (LIMS) by using search tool Cognos Figure These 887 patient numbers were then entered into the centre's electronic records system, which contains information on laboratory results, radiological investigations, discharge letters and clinic letters. Combined with the microbiology sample information from LIMS each individual patient had data collected for: date of birth, sex, past medical history, orthopaedic history, pre-operative white blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), type of surgery performed at time of sampling, type of sample and request information (i.e. site/tissue type/method of collection), culture results, organisms identified and sensitivities , clinical diagnosis of PJI versus aseptic joint and subsequent management plans. Due to the retrospective design of the study data was not collected regarding when the specimens were collected in relation to the stage of the procedure and antibiotic administration, nor was information available regarding the surgeon's reasoning for selecting a particular sample type, for example whether the area looked clinically infected.The final cohort of 3460 samples taken from 887 patients with 1076 patient-operation pairs provided the material to test the null hypothesis that sample tissue type or anatomical location would not affect the diagnostic reliability for PJI, using the clinical diagnosis of PJI versus aseptic joint as the standard for comparison.Simple descriptive statistics were undertaken to calculate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for intra-operative samples in diagnosing PJI. The sample culture test result (positive or negative) was compared against the clinical diagnosis of PJI (yes or no).p value of <0.05 was defined as significant.Statistical analysis was performed using Statistical Package for Social Sciences version 17.0 . A Student's t-test and ANOVA were used to compare continuous variables between groups. Dichotomous variables were assessed using a Chi square test. A A logistic regression model The authors conducted a retrospective service evaluation, as such there was no additional patient contact and no requirement for formal ethical approval. The project was registered with the institutions audit department (registration number 7851) and was conducted in accordance with the Declaration of Helsinki and the guidelines for good clinical practice.The final cohort had 1815 samples taken during 557 operations from 474 patients undergoing hip surgery and 1645 samples taken during 519 operations from 416 patients undergoing knee surgery (three patients underwent both hip and knee surgery). The mean age was 68 years range 24-94), with 493 female and 394 male. 314 patients had medical co-morbidities that could increase their risk of infection  and whether the operation was a revision surgery. The best fitting model included the covariates: WBC count, whether the operation was a revision, and the sample tissue type. Age did not improve the fit of the model. Revisions  decreased the probability of infection.Adding culture results to the prediction model improved the fit considerably, and again comparison of the Bayesian information criterion (BIC) for the models gave a best model with WBC count, revision and sample tissue type and additionally, the culture result. All of these co-variants were significant with p<0.0001.Figure The key finding of this investigation is that there is a variation in diagnostic accuracy between intra-operative samples with differing tissue types and anatomical location. However, no single sample type had diagnostic accuracy comparable to previously reported rates of sensitivity, specificity and predictive values of intra-operative culture samples considered collectively One limitation of this study is the retrospective design, so data could not be collected on the surgeons' decision making in selecting the samples types and sites, nor could the accuracy of the sample labelling be controlled. However, the dataset was collected independent of any specific hypothesis therefore excluding the potential for bias. Data was not collected regarding when the specimens were collected in relation to the stage of the procedure and antibiotic administration. Trampuz et al.Staphylococcus aureus growing easily Propionibacterium acnes need one to two weeks for isolation It could also be argued that the choice of the documented clinical diagnosis of PJI as the gold standard for comparison is a limitation. The recorded diagnosis of PJI versus an aseptic joint was collected in the dataset based solely on the documentation of the treating clinical team, without reviewing or revising the basis of their diagnostic decision making. The majority of the current literature uses intra-operative culture results as one of the criterion for their gold standard but as that was the variable the current study was assessing a different standard was chosen. Furthermore, using culture results as a gold standard does have its limitations as false negative culture results have been reported with a frequency that ranges from 7-23% The majority of samples analysed in the current study had been taken from patient without a clinical diagnosis of PJI. The majority of cases also had one to three samples taken, rather than the recommended five or six samples The current study found fluid samples to have a low sensitivity but high specificity, which has previously been reported by Gallo et al.The tissue type and anatomical location of samples has been shown by the current study to have varying predictive values for PJI. For tissue type, pus had the highest PPV although there was a small sample size for this group. Capsule had the most superior NPV. For hips, bursa samples had high PPV and NPV. It is recommended that tests with high NPV be used to screen for infection and those with high PPV be used to confirm a diagnosis of PJI Using co-variates to create a predictive model for PJI showed pre-operative WBC count, type of surgery (revision versus non-revision) and sample tissue joint type (knee or hip) to be the best fit. Patients with non-revision (type of surgery) and WBC count >10 x 109 cells per litre and tissue from knee joints were found to be at increased risk of a PJI diagnosis. The finding that knee prostheses have an increased risk of PJI correlates with Pulido et al.The current study has demonstrated a variation in sensitivity, specificity and predictive values according to intra-operative sample type. Due to the variation in predictive values, the operating surgeons may wish to alter which intra-operative sample types are selected depending on their level of clinical suspicion, as well as considering pre-operative patient and joint variants in the diagnostic process.In conclusion, this study analysed intra-operative samples collected irrespective of type and presence of infection and irrespective of the surgeon's reasoning for selecting a particular sample type. Whilst this did demonstrated variation in diagnostic accuracy depending on the tissue type and anatomical location of intra-operative culture samples taken to diagnose PJI, no individual tissue or anatomical type had superior accuracy compared to all samples used collectively. However, the diagnostic reliability was increased when pre-operative inflammatory markers and surgical factors (type or joint and primary or revision arthroplasty) were incorporated into a predictive model for PJI.LCW performed the investigation, data curation and writing of the original draft manuscript and re-editing. NDC reviewed and edited the manuscript. IW performed the formal data analysis. MH supervised the project as well as reviewing the manuscript. JS helped devise the metholodology and data curation by allowing access to the necessary software. DJD devised the concept of the project and provided supervision throughout as well as reviewing and editing the manuscript.


In recent decades, consumption of psychostimulants has been significantly increased all over the world, while exact mechanisms of neurochemical effects of psychomotor stimulants remained unclear. It is assumed that the neuronal messenger nitric oxide (NO) may be involved in mechanisms of neurotoxicity evoked by psychomotor stimulants. However, possible participation of NO in various pathological states is supported mainly by indirect evidence because of its short half-life in tissues. Aim of this review is to describe the involvement of NO and the contribution of lipid peroxidation (LPO) and acetylcholine (ACH) release in neurotoxic effects of psychostimulant drugs. NO was directly determined in brain structures by electron paramagnetic resonance (EPR). Both NO generation and LPO products as well as release of ACH were increased in brain structures following four injections of amphetamine (AMPH). Pretreatment of rats with the non-selective inhibitor of NO-synthase (NOS) N-nitro-L-arginine or the neuronal NOS inhibitor 7-nitroindazole significantly reduced increase of NO generation as well as the rise of ACH release induced by AMPH. Both NOS inhibitors injected prior to AMPH had no effect on enhanced levels of LPO products. Administration of the noncompetitive NMDA receptor antagonist dizocilpine abolished increase of both NO content and concentration of LPO products induced by of the psychostimulant drug. Dizocilpine also eliminated the influence of AMPH on the ACH release. Moreover, the neurochemical and neurotoxic effects of the psychostimulant drug sydnocarb were compared with those of AMPH. Single injection of AMPH showed a more pronounced increase in NO and TBARS levels than after an equimolar concentration of sydnocarb. The findings demonstrate the crucial role of NO in the development of neurotoxicity elicited by psychostimulants and underline the key role of NOS in AMPH-induced neurotoxicity. This was the reason to call NO a retrograde messenger Amphetamine-like psychostimulants, such as amphetamine (AMPH), 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy), and methamphetamine (METH) are psychomotor stimulants that may cause addiction The precise mechanisms of AMPH-induced neurotoxicity remain unclear. Characteristic manifestations of the neurotoxic effect of AMPH and its derivatives, along with the depletion of intracellular DA and degeneration of neurons, are considered to be due to an generation of reactive oxygen species (ROS) and reactive nitrogen species . This method allows to determine NO in vivo as a paramagnetic complex in organs and tissues, e.g. liver, heart, tumor etc. We used the following two approaches to study the participation of NO in the development of neurotoxicity evoked by psychomotor stimulants.2.1.Experiments were carried out on a male Sprague-Dawley rats (280–300 g) from the vivarium of University of Innsbruck. Protocols were approved by the Bundesministerium für Wissenschaft, Forschung und Kunst, Austria, Kommission für Tierversuchsangelegenheiten. Rats were injected with AMPH  four times. The EPR signals of paramagnetic mononitrosyl MNIC–DETC complex registered in the brain cortex of rats are shown in Repeated, systemic application of AMPH elevated striatal and cortical NO content . AdminisThe interaction of NO with the neurotransmitter glutamate prompted us to study the possible role of this messenger in the pathophysiological mechanisms of AMPH-induced neurotoxicity. The inhibitor of NMDA glutamate receptors dizocilpine  was administered 30 min prior first AMPH injection. Dizocilpine abolished the rise of NO content induced by four injections of the psychostimulant  [47]. Th−level in the striatum and in the cortex was found NO might interact with other radicals, such as ROS. It is known that high doses of AMPH - like psychostimulants lead to an increase in the levels of hydroxyl radicals and LPO products in rat brain These findings are in accordance with our results carried out on the seizure models of rats 2.2.In our experiments the push-pull superfusion technique was used that makes it possible to determine quantitatively ACH released from their neurons in the synaptic cleft in distinct brain areas −1. Four injections of the vehicle did not influence the release of ACH  was found to be 25.1 ± 9.1 fmol mine of ACH , while fe of ACH  as well e of ACH  almost cVery probably, the increase in ACH release following AMPH administration is due to the activation of nNOS. Moreover, the findings point to the crucial role of nNOS in the neurotoxic effects of AMPH. It is still controversial whether NO is functioning as protective agent against neurotoxic effects of AMPH It has been suggested that glutamatergic neurotransmission is involved in neurotoxicity elicited by AMPH 3.In clinical practice, the administration of psychostimulants is limited due to a number of side effects. including their neurotoxic action. However, administration of psychostimulants is necessary for the treatment of a number of diseases of the central nervous system, especially in the case of attention deficit hyperactivity syndrome EPR technique was used to compare the effects of two psychostimulant drugs, AMPH and sydnocarb, at the equimolar doses  on the NO level in striatum and cortex of male Sprague Dawley rats (180–210 g) These findings are consistent with recent studies that AMPH has a significantly higher impact on the parameters of the stereotypical behavior of rats Taken together, these findings confirm that NO and ROS play important role in processes of neurotoxicity evoked by AMPH and sydnocarb. Furthermore, they point to the key role of neuronal NOS in AMPH- induced neurotoxicity and demonstrate the crucial role of NO in neurotoxicity induced by psychostimulant drugs.


During the last few years graphene has emerged as a potential candidate for electronics and optoelectronics applications due to its several salient features. Graphene is a smart material that responds to any physical change in its surrounding environment. Graphene has a very low intrinsic electronic noise and it can detect even a single gas molecule in its proximity. This property of graphene makes is a suitable and promising candidate to detect a large variety of organic/inorganic chemicals and gases. Typical solid state gas sensors usually requires high operating temperature and they cannot detect very low concentrations of gases efficiently due to intrinsic noise caused by thermal motion of charge carriers at high temperatures. They also have low resolution and stability issues of their constituent materials  in harsh environments. It accelerates the need of development of robust, highly sensitive and efficient gas sensor with low operating temperature. Graphene and its derivatives could be a prospective replacement of these solid-state sensors due to their better electronic attributes for moderate temperature applications. The presence of extremely low intrinsic noise in graphene makes it highly suitable to detect a very low concentration of organic/inorganic compounds (even a single molecule ca be detected with graphene). In this article, we simulated a novel graphene nanoribbon based field effect transistor (FET) and used it to detect propane and butane gases. These are flammable household/industrial gases that must be detected to avoid serious accidents. The effects of atmospheric oxygen and humidity have also been studied by mixing oxygen and water molecules with desired target gases (propane and butane). The change in source-to-drain current of FET in the proximity of the target gases has been used as a detection signal. Our simulated FET device showed a noticeable change in density of states and IV-characteristics in the presence of target gas molecules. Nanoscale simulations of FET based gas sensor have been done in Quantumwise Atomistix Toolkit (ATK). ATK is a commercially available nanoscale semiconductor device simulator that is used to model a large variety of nanoscale devices. Our proposed device can be converted into a physical device to get a low cost and small sized integrated gas sensor. Gas sensing has been a critical subject for wide range of applications such as medical, industrial environment, military and aerospace applications. The presence of hazardous and toxic gases may lead to some serious accidents in industrial as well as household environments. There must be some tool to detect the presence of these gases effectively ,2. The uAlthough, with an increase in the demand of gas sensors, still there is a need to develop robust, highly sensitive and reversible sensors that work at low temperatures. Gas sensors based on conventional semiconductor materials usually require high operating temperatures. In order to cope with these issues, several efforts are being made to modify the shape and orientations of such materials . NanomatGraphene based gas and inorganic/organic molecule detectors detect the presence of these molecules with different mechanisms. The most popular detection mechanisms are the resistive method, field effect transistors (FET) method and micro-electromechanical system (MEMS) based method. In the resistive method, the change in electrical conductivity in the presence of target molecules is used as a detection signal . In FET Graphene based field effect transistor (FET) can be a potential candidate to detect the presence of a wide range of chemicals, toxic compounds, biomolecules and gases with better sensitivity compared to that of solid-state sensors. The sensitivity range of these graphene based FETs usually range from parts per billion (ppb) to parts per million (ppm) ,22,23. TMoreover, propane and butane are the most commonly used fuel for household/industrial environments . These aIn this article, we simulated a novel FET device based on graphene nanoribbons with nanoscale semiconductor device simulator, Quantumwise Atomistix Toolkit (ATK). This simulated device has been used to detect the presence of propane and butane gases. The change in electric current through FET device at different gate voltages in the presence of these gases has been used as a detection mechanism. To the best of our knowledge, this type of device has not been reported in the literature for the detection of propone and butane gases.The simulations of GNR based FET for the detection of propane and butane gases have been carried out with Quantumwise Atomistix Toolkit (ATK) software package. Graphical user interface of ATK is called Virtual Nano Lab (VNL). ATK-VNL allows atomic scale modeling of nano-systems. This software uses several in-built calculators to solve and calculate transportation properties of quantum systems. Density functional theory (DFT) calculator has been used for the simulations of our proposed device in ATK-VNL. The work flow and mathematical formalism used by ATK-DFT has been given in . All theThe constituent materials of simulated graphene field effect transistor are armchair graphene nanoribbons (AGNR) and zigzag graphene nanoribbons (ZGNR). The termination pattern of the edge of these structures defines the type of nanoribbon either armchair edge or zigzag edge, as shown in Furthermore, the two probe model of GNR based FET has been simulated by using AGNR and ZGNR in ATK-VNL. The builder tool of ATK-VNL is used to simulate FET. All the details have been given in next lines. First of all, the central region of the device have been simulated. The central region of FET consists of AGNR. AGNR with width of four atoms has been created using Nanoribbon Plugin Tool of ATK Software. Afterwards, this GNR has been extended 5 times along C-axis (the repetition pattern) as shown in εo and a very thin metallic layer has been deposited on it to form a gate electrode of field effect transistor. The lengths of source and drain electrodes are approximately 7 Å. In next step, three molecules of propane, three molecules of butane and both propane & butane (four molecules of butane and one molecule of propane) have been exposed to the FET device in three different experiments, as shown in After that, the next step is to join the central region  with theX, Y, Z coordinates) the target molecules with respect to the simulated FET device. The position and geometry of each butane molecule along with X, Y, Z axis have been shown as an example in Furthermore, an in-built Merger Tool of ATK-VNL has been used to expose the target molecules  to the simulated FET device d. ATK-VNIn this section, the results obtained from simulations have been presented and discussed in detail. The DOS and IV-characteristics of simulated FET based sensor have been calculated. A significant and distinct change in the DOS of FET device have been observed in the presence of different target gas molecules. A comparison of DOS of simulated FET device in the absence of any target gas molecules and in the presence of three propane gas molecules has been shown in Furthermore, the presence of three butane gas molecules affected DOS of FET differently compared to that of propane gas molecules, as shown in dsI) and voltage (dsV) curves of simulated FET have been calculated for different applied gate voltages. The simulated device (in absence of any target gas molecules) showed depletion mode MOSFET like behavior. A decrease in dsI versus dsV has been observed with an increase in negative gate to source voltage (gsV), as shown in Drain to source current (dsV), but also on gate voltage. The adsorbed target gas molecules act as donors or acceptors of charge carriers for the graphene. If they act as donors, they change (increase) the concentration of charge carriers in graphene. Consequently, the electric current through the graphene based device increases in the presence of adsorbed target molecules under same bias condition. When the foreign target molecules behave like acceptors of charge carriers, they decrease the current through the graphene based device [dsV on the IV-characteristics of FET based sensor.In our previously published work , we usedd device . In resigateV = −0.1 V and at a fixed dsV, shown with a solid black line in dsI has been observed in the presence of propane as a target gas, at gateV = −0.1 V, as shown with orange dotted line in dsI in presence of butane gas molecules compared to that of reference device. The range of the dsI is between −26 nA to −134 nA approximately in the presence of butane gas, shown with blue color dashed line in dsI has been observed when FET device is exposed to four butane and one propane gas molecules simultaneously. The range of dsI in this case is between −93 nA to −167 nA at gateV = −0.1 V, which is quite high compared to that of the reference device. This high amount of current through the device may be due to the donor like dominated effect of four butane molecules compared to that of one propane molecule (acceptor like behavior), which are exposed to the device simultaneously. This curve has been shown with a dotted-dashed green colored line in Furthermore, our simulated device exhibited a considerable change in IV-characteristics in the presence of the target gases. The reference FET device showed a current range between −24 nA to −66 nA at dsI through reference FET, as it is a depletion mode n-channel FET. A similar trend of increase and decrease in dsI at gateV = −0.3 V for the same dsV has been observed with respect to the reference FET device, as shown in dsI at this gateV has been observed compared to that of reference FET. The range of dsI in this case is between −20 nA to −57 nA, approximately. Whereas butane gas increased the dsI compared to that of reference FET and the range of current is between −18 nA to −106 nA. The simultaneous presence of both gases increased the dsI in similar manner that is observed in previous cases. The range of electric current under this bias condition is between −187 nA to −220 nA, which is quite high compared to that of the device at gateV = −0.1 V, as shown in gateV = −0.5 V, as shown in However, an increase in negative bias gate voltage reduced the overall gateV = −0.1 and fixed dsV have been calculated. A slight decrease in dsI of the simulated FET has been observed in the presence of two oxygen molecules, as shown in dsI has been observed, when water and oxygen molecules are mixed with propane gas molecules, as shown in dsI, as shown in dsI has been observed in the presence of mixture of butane and oxygen molecules, as shown in In The presence of both oxygen and water molecules degraded the device performance in terms of reduction of detectable current for propane and butane gases. A careful calibration of such physical sensor is required to nullify the environmental effects on the actual reading of the device in the presence of desired target molecules. The presence of oxygen content in the atmosphere has a strong influence on the electrical properties of graphene. The oxygen content of the air strongly affects the electrical resistance of graphene which depends on the exposure time. The electrical conductance of graphene reduces with passage of time at its exposure to the oxygen content of the air. Therefore, the change in device performance may be expected as exposure time increases . Similar2) and carbon dioxide (CO2) on the electrical conduction properties of graphene based sensors are negligible. Whereas, water molecules have strong influence on the conductivity of graphene. The considerable response of graphene to the water molecules makes it highly suitable for humidity sensor applications [2 and CO2 gases have not been considered in these simulations. The purpose of these simulations is to investigate the feasibility of simulated FET device for the detection of solely propane and butane molecules for household and industrial environments. However, the concentration of methane (CH4) gas is increasing day by day due to green house effect. Several efforts have been done for the development of CH4 gas sensors [4 with our proposed device for climatic and household applications can be considered as future work. These simulation results are convincing in terms of the ranges of detectable electric current values. In our previous work [Moreover, in ambient atmospheric conditions, the effect of nitrogen (Nications . Therefo sensors ,56,57,58ous work , the difous work . The phyThe goal of the work that has been presented in this article is to access the potential of graphene nanoribbon based FET for the detection of propane and butane gases. Armchair graphene nanoribbons and zigzag nanoribbon have been used to develop FET device. In the absence of any target gas molecules, the IV-characteristics of the simulated device are similar to n-channel depletion mode FET. In the proximity of target gas molecules, a change in source-to-drain current of FET at different gate voltages has been observed. This change is distinct for each specific target gas i.e., propane and butane. Our simulated FET device also exhibited a noticeable change in the density of states in the proximately of these target gases. The change in source-to-drain current of FET in the presence of target gas molecules has been used as a detection signal for the leakage detection of these gases. The influence of atmospheric factors like the presence of water and oxygen molecules on the proposed device have also been investigated. It has been observed that the presence of these molecules also affected the IV-characteristics of the device. A careful calibration of such physically fabricated device is required to nullify the effect of atmospheric factors and get the correct reading for desired target gases. Our proposed device could be a promising candidate to replace conventional solid-state gas sensors due to its exceptional electronic properties and compact size. Theoretically, it is possible to simulate such type of FET sensors. However, the physical fabrication of these kind of device could be a challenge due to extremely small dimensions of graphene nanoribbons that make it difficult to handle at atomic levels. Moreover, during physical fabrication of our proposed FET, there is a need of some suitable substrate like SiC or Si for the deposition of graphene. Our nearest future intension is to develop graphene based FET device for the detection of propane and butane gases.


Obesity has been shown to intensify the decline of physical function and lead to frailty. Nutrition is an important method in managing obesity and frailty, while seldom reviews have ever explored the effects of nutritional education interventions. We conducted a systematic review (PROSPERO: CRD42019142403) to explore the effectiveness of nutritional education interventions in managing body composition and physio-psychosocial parameters related to frailty. Randomized controlled trials and quasi-experimental studies were searched in CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, PubMed and Scopus from 2001 to 2019. Hand search for the reference lists of included papers was conducted as well. We assessed the quality of included studies by Cochrane risk of bias tool. Meta-analyses and narrative synthesis were used to analyse the data. Two studies with low risk of bias were screened from 180 articles, which involved 177 older people with an average age of 69.69±4.08 years old. The results showed that nutritional education was significantly effective in reducing body weight and fat mass than exercises, and it was beneficial to enhancing physical function and psychosocial well-being. But the effects of nutritional education in increasing muscle strength were not better than exercises. The combined effects of nutritional education and exercises were superior than either exercises or nutritional education interventions solely in preventing the loss of lean mass and bone marrow density, and in improving physical function. Due to limited numbers of relevant studies, the strong evidence of effectiveness of nutritional education interventions on reversing frailty is still lacking.


We report here the case of a patient admitted for management of posterior fossa cerebral hemangioblastoma. A 16-year-old male patient with a history of intracranial hypertension syndrome consisting of progressively worsening headache, vomiting, especially morning and jet vomiting, and decreased visual acuity. The patient's symptomatology worsened a few days later with the appearance of a disturbance of balance with enlargement of the sustentation polygon. The patient initially benefited from a brain computed tomography (CT) scan that objectified a solidocystic process of the posterior brain fossa. The patient then underwent a surgical excision that was considered partial and the diagnosis of hemangioblastoma was made on the surgical specimen. Since the surgical removal was partial the patient was referred to our training where he received external radiotherapy on his hemangioblastoma of the posterior brain fossa. The patient was examined one month after the end of irradiation; he presented a spectacular improvement in his neurological symptomatology with a clear regression of balance disorders. The standard treatment for cerebellar hemangioblastoma is complete microsurgical removal, but our results show a high level of efficacy for fractional photon radiotherapy after partial surgery of this benign tumour. Hemangioblastomas (HB) are benign tumors that comprise 2% of all intracranial tumors and 3-4% of all spinal tumors . They arA 16-year-old male patient who presented, 2 months before his consultation, with rapidly progressive worsening headaches that became increasingly resistant to the usual analgesics, These headaches were accompanied by nausea, morning jet vomiting and decreased visual acuity. Several days later, disturbances of balance appeared in the patient. He denied any notion of fever, fatigue, altered general condition or seizures. At the time of questioning there was no notion of a similar case among first-degree relatives of the patient or other family members. Physical examination on admission found a conscious patient with a Glasgow score of 15/15, well-developed and well-nourished. At the neurological examination the patient presented a balance disorder with widening of the sustentation polygon, walking was impossible without help and was heeling, standing was also impossible without help, there was no sensory or motor deficit or cognitive impairment in the patient. On ophthalmological examination, the patient's visual acuity was 8/10 and the fundus was normal. Laboratory evaluations including complete blood count, electrolytes and basic metabolic profile were normal. The patient was investigated by a brain CT scan that showed a cerebellar tumour process with two components; a fleshy component and a cystic component, measuring 70 mm in diameter; this process compresses the 4th ventricle and leads to significant tri-ventricular hydrocephalus with signs of trans-ependymal resorption of cerebrospinal fluid . The expThe term HB was introduced in 1928 by Cushing and Bailey  to definOur case is an example of HB which is quite rare since it is sporadic and does not fit into the framework of the VHL disease unlike the majority of cerebellar HB which occurs most often in the framework of the VHL syndrome. The result of radiotherapy treatment in cases where surgery is not possible is encouraging.


The first line approach for subclavian steal syndrome is PTA-stenting of subclavian artery. When the ipsilateral vertebral artery origin is involved or in closed proximity of the atherosclerotic lesion in the subclavian artery PTA-stenting is at risk of ipsilateral vertebral artery coverage. Herein we report our experience with DEB to address lesions involving the subclavian artery and the origin of the ipsilateral vertebral artery. From January 2017 to February 2019, patients presenting subclavian artery lesion involving the origin of the ipsilateral vertebral artery and treated using primary DEB, were included. Three patients, with left subclavian steal syndrome, were identified. The perioperative mortality and morbidity were outcomes evaluated. Freedom from occlusion, secondary patency, amputation rate was registered. A total of 3  patients were included in the study. No complication, symptoms recurrence, restenosis or occlusion were reported at duplex scan during 12-month follow-up. Indication for stenting was arterial dissection. In our limited experience, the use of DEB in association to embolic protection device in the treatment of atherosclerotic subclavian lesion involving the origin of the vertebral artery was safe and technically feasible. The first line approach of subclavian steal syndrome is PTA-stenting of subclavian artery. When the ipsilateral vertebral artery origin is involved or close to the atherosclerotic lesion in the subclavian artery, PTA-stenting is at risk of ipsilateral vertebral artery coverage: in this case, the open surgical treatment is indicated. However, applying the knowledge gained by use of Drug eluting balloon (DEB) in peripheral artery disease, we think it’s possible to extend the endovascular treatment also in vertebral artery involving cases. Herein we report our experience with DEB to treat lesions involving the subclavian artery and the origin of the ipsilateral vertebral artery.A retrospective analysis of patients with subclavian steal syndrome, addressed with endovascular procedures, was conducted. From January 2017 to February 2019, were included patients presenting subclavian artery lesion involving the origin of the ipsilateral vertebral artery and treated using primary DEB . Three pA total of 3  patients with a mean age of 66 years were included in the study. Technical success was achieved in all cases . After tTraditional open surgical revascularization treatments have shown excellent long-term durability for supra-aortic vessels. Neurological manifestations such as dizziness, visual disturbances, and stroke indicate failure perfusion of the central nervous system, which is a significant predictor of mortalityIn our limited experience, the use of DEB in association to embolic protection device in the treatment of atherosclerotic subclavian lesion involving the origin of the vertebral artery was safe and technically feasible. The use of DEB represents an additional tool for patients with complex subclavian lesions involving the vertebral artery origin that are unfit for conventional surgery or when standard PTA stenting is at high risk of vertebral artery coverage.


COVID-19 started in Wuhan province of china and spread in a faster rate covering all continents in the world. The pandemic has affected the socio-economic, political fabric of all countries, and exacerbated undernutrition and food insecurity problems of Low and Middle Income Countries (LMICs). COVID-19 has also disrupted the health system, resulted in low level utilization of essential services, such as childhood immunization, labor and childbirth, and treatment for children with serious illness. Unless the spread of the COVID-19 pandemic slows down, Ethiopia and other low income countries are at the verge of losing all the progresses made in health and wellbeing over the last two decades. The novel corona virus disease 2019 (COVID-19) which originated in Wuhan, China, in December 2019, spread rapidly around the world and became a pandemic . In EthiThe sudden increase of COVID-19 cases after 53 days of reporting of the index case was perhaps the result of the government´s inability to sustain its initial mitigation strategies. Citizens coming from high caseload neighboring countries have entered to Ethiopia without proper vetting as the government has loosened its restrictions on in-land transportations. As time went, local governments failed to apply other mitigation strategies as well. In countries such as Ethiopia, stay at home prevention measure is difficult to apply for a prolonged time as significant numbers of people are deployed in the informal sector. It is barely possible to force these citizens to stay at home without providing food and other essential items. Furthermore, low level awareness among the public about the risk of acquiring the virus and its mode of transmission was an exacerbating factor. The Ethiopian healthcare system lacks adequate resources to manage severe cases unless the spread of the virus is slowed down  reduced In order to curb the spread of the pandemic, Ethiopia should ramp up its mitigation strategies at borders with a huge influx of refugees. The country should establish examination and testing centers at borders with Kenya, Djibouti and Somalia as the number of reported COVID-19 cases are steadily increasing in these countries. The Addis Ababa-Djibouti transport corridor is also warranted a strong mitigation strategy as there are a huge influx of traders and long truck drivers. Unless the spread of the COVID-19 pandemic slows down, Ethiopia and other low income countries are at the verge of losing all the progresses in health and wellbeing. This is the great setback of the health system in low income countries with significant reversal of gains made over the last two decades.The authors declare no competing interests.


Multimodality imaging is of imperative value for the planning and guidance of transcatheter mitral valve interventions. This review employs the value of different imaging modalities and future implications for clinical practice. Transcatheter mitral interventions (TMVI) have exceeded the expectations oftechnical progress over the last decade. The recent explosion of technological advances that allows the personalized management of every patient with mitral valve disease, highlights the pivotal role of multimodality imaging in the decision making process. Specific challenges include the large spectrum of underlying pathology, the multidimensional feature of mitral annulus, the interaction with the left ventricle and its outflow tract, the constantly raising number of different devices which are available on the market, and the prevention of thromboembolism. Despite multiple challenges, the tremendous value of TMVI is offering a solution to these patients who almost a decade ago would be considered inoperable , 2.There are 5 different categories of TMVI: balloon valvotomy, mitral valve leaflet repair , transcatheter mitral valve replacement, mitral annuloplasty, and paravalvular leak closure.There has been a vast development of transcatheter valves which managed to address the issue of durability . Most imAt the latest AHA/ACC guidelines on valvular heart disease , it is cTransthoracic (TTE) and 3D transesophageal (TEE) echocardiography are the first line imaging tools for the assessment of mitral valve. For the purposes of this review, we will separate echocardiographic imaging into 3 parts: (i) pre-procedural, (ii) intra-procedural, and (iii) post-procedural.(i) Pre-proceduralThe role of the imager in guiding further management, in close collaboration with the interventionist and surgeon, is crucial. TTE as well as 3D TEE will identify the etiology and mechanisms of mitral pathology . It is iTechnical considerations when obtaining the basic measurements for mitral valve assessment, such as the appropriate alignment of continuous wave Doppler with the jet and the appropriate settings for proximal isovelocity surface area (PISA) /EROA/regurgitant volume assessment, should be applied .In addition, assessment of interatrial septum and the best anatomical position for transeptal puncture will facilitate the operator during TMVI. An incidental finding of a patent foramen ovale is of no hemodynamic significance. On the contrary, it may act in favor of the interventionist during the advancement of the guiding catheter.For balloon valvotomy, the most common imaging tool for mitral stenosis assessment is the Wilkins score which consists of scoringleaflet mobility, valve and subvalvular thickening as well as calcification. A score of ≤ 8 predicts a more favorable procedural, short, intermediate and long-term outcome . Other important predictors of procedural success and long-term outcome include commissural calcification or fusion, pre-procedure mitral regurgitation >2+, post-procedure mitral regurgitation >3+, age, prior surgical commissurotomy, NYHA functional class IV, and higher post-procedure pulmonary artery pressure .For mixed MVD or pure mitral regurgitation, the development of 3D TEE has allowed us the reconstruction of the mitral valve in a similar way as the surgeon would view this in the operating room . Another(ii) Intra-procedural echocardiographyCare should be taken in the evaluation of MR during general anesthesia as the degree of regurgitation as well as Doppler values may be underestimated. The echocardiographic views differ depending on the intervention which is taking place.COAPT trial , 12 and For edge to edge repair, the bicaval view is important for the advancement of the steerable guide catheter while all TEE planes focusing on the mitral valve are important for the advancement of MitraClip in the left ventricle and the grasping of the leaflets. It is recommended to initially close the MitraClip only up to 60–90° and aim for a full closure of the Clip only after determination of proper leaflet insertion and demonstration of MR reduction. For assessment of proper leaflet insertion into the MitraClip multiple planes are useful. The insertion of the posterior leaflet is commonly best seen in the LVOT view, and the insertion of the anterior leaflet in the four-chamber view. The intercommissural view can add information such as entrapped chordae tendinae which may be visible at the free edges. Once the leaflets appear securely inserted and well-positioned in between the Clip arms and the grippers and some reduction in mitral regurgitation is documented, the MitraClip can be fully closed. An example of preprocedural imaging for MitraClip is demonstrated on After MitraClip positioning, the evaluation of residual mitral regurgitation is important in deciding the number of clips to be employed. With implantation of a second MitraClip, the orientation of the second Clip should be optimized by 2D and 3D echocardiography in the left atrium. During advancement of the MitraClip from the left atrium into the left ventricle, the Clip should be closed to avoid any interference or entanglement with the chordae tendinae then re-opened in the ventricle. In general, fluoroscopy is more helpful than TEE for the positioning of a second MitraClip which should be aligned as parallel as possible to the first Clip. Folding of leaflet tissue between two MitraClips should be avoided as this may cause irreparable residual mitral regurgitation.For color quantification , 18, theTranscatheter mitral valve replacement may be performed either trans- septal or trans-apical. TEE guidance to ensure the guide wire and device delivery system are centrally located (between A2 and P2) is important to avoid chordal rupture as well as to avoid interference with the anterior mitral leaflet and acute severe MR. After deployment of the device, multiplane 2D and 3D TEE are fundamental for device positioning, stability and function . The imager should carefully identify central MR jets through the bioprosthesis due to cusp malfunction, which would be assessed with correct alignment of the continuous wave Doppler. Paravalvular leak  may resuAnother important part of TMVR is to avoid LVOT obstruction. 3D TEE and CT software simulations add invaluable information in procedure planning, predicting the risk of post-operative LVOT obstruction. The LVOT size, aorta- LVOT angulation, the length of anterior mitral valve leaflet as well as the distance between the aorto-mitral continuity and basal ventricular septum should be monitored at all times during the mitral valve positioning and deployment procedure.Each native valve has its own anatomical and physiological characteristics therefore, an individualized approach should be adopted . Color DAs a summary of the echocardiographic assessment post-procedurally, Dr. Zoghbi et al.  suggesteComputed tomography (CT) and cardiac magnetic resonance (CMR) are complementary tools to echocardiography that provide valuable information on mitral valvular structure, function, and associated chamber volumes , 22. CT Multidetector CT adds precision to planning the optimal intervention by determining annular size, landing zone characteristics, and predicting the risk of post-operative LVOT obstruction . Left ve2 had the greatest discriminatory value for predicting LVOT obstruction post TMVR  . Surgeryost TMVR . Furtherost TMVR .Patients not suitable for completely interventional TMVI in MAC, can be treated with the adoption of a hybrid technique, where a trans-catheter aortic valve is implanted in mitral position during open heart surgery. The advantages in this setting would be multiple. An extensive annular decalcification will not be needed, with the consequent reduction of the surgical risk; the trans-catheter valve will allow a greater EROA even in small mitral valve annuli with good hemodynamic results; the technique will be easily reproducible also in a minimally invasive setting. Most importantly, the possibility of surgically removing the anterior mitral leaflet during an open operation reduces drastically the risk of LVOT obstruction which is still matter of significant concern.Complications due to mitral valve intervention are also well-suited for assessment by CT and CMR. CT has the advantage of increased spatial resolution and is less prone to artifact from metal and prosthesis artifact . FurtherCoronary CT is valuable for preoperative planning in young patients. In this category of patients, the etiology of mitral valve disease is often myxomatous in nature and associated with mitral regurgitation secondary to valve prolapse. In this setting, coronary CT allows for pre-operative, non-invasive visualization of coronary arteries in low-risk patients .CMR provides valuable functional data and allows accurate quantification of chamber volumes. It is particularly helpful in quantifying MR  Figures, 9. CMR In cases of severe MR, CMR can provide guidance on the optimal time to intervene . CMR is While CMR has good concordance with echocardiography to localize leaflet pathology in mitral valve prolapse, an important limitation is the suboptimal assessment of small structures such as chordae or vegetations due to the partial volume effect from limited CMR resolution of finer voxels .As a conclusion, while echocardiography remains the cornerstone imaging methodology, integrated CT and CMR are increasingly becoming the standard of care in mitral valve assessment prior to intervention. This provides operators with the best chance of procedural success.The future of imaging lays on hybrid imaging which fuses the advantages and overcomes the disadvantages of all the above mentioned imaging modalities. Pascual et al.  describeAs CT and CMR gain more wide-spread use, it will be important to standardize protocols and evaluate the most reliable measurements. To this end, Garg et al. recently published a consensus statement supporting a standardized CMR protocol which includes the assessment of MR . Future While CT assessment provides a high degree of precision, it comes at the cost of radiation and risk of contrast injury. Decreasing the radiation associated with CT and the time required for obtaining the optimal image are future directions of research which will allow us to more safely provide CT assessment of mitral valve pathology. Moreover, contrast-associated renal injury remains an important concern given its association with increased mortality, so further studies in reducing contrast injury are needed .Finally, an exciting area of research is in the hybrid modality approach . For exaTranscatheter mitral valve interventions have overcome multiple limitations and have a bright future: the future is standing on the rapid development of imaging and the greater application of hybrid modalities. Furthermore, transcatheter procedures will expand in areas beyond the current guidelines such as in dilated left ventricles, . We alsoAs a conclusion, TMVI multimodality imaging is expanding fast and in all dimensions. New valves and devices, but also large studies with long term results of the existing one, will shed light in the management of mitral valve pathology.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 American Congress of Rehabilitation Medicine (ACRM) in 2010 called for more head injury research on gender disparities to bridge the gender gap for the short-and long-term effects of TBI, including sexual and reproductive outcomes. In this paper, we review the state of the literature before and after the ACRM announcement, and evaluate how research teams have considered females and mildly injured TBI(mTBI)/concussion groups in post-TBI-related changes in sexual functioning.The research question for this scoping review was “what is the state of the literature in the evaluation of post-TBI sexual changes for women, and individuals with mTBI?” Using the 2010 ACRM call for action as a line of demarcation, we compared our findings before and after the 2010 announcement.We identified 9 research studies that addressed sexual functioning changes in females and mTBI/concussion groups. Four of the nine were published before the 2010 ACRM announcement, and five were published after. The representation of female research participants increased steadily over the 28-year timespan. The proportion of individuals with mTBI included in the post-2010 era was higher than the earlier time period. Consistently, women with mTBI reported more adverse sexual outcomes compared to male cohorts, orthopaedic, and non-injured comparison groups. This observation persisted regardless of recruitment site (rehabilitation center/Emergency Department (ED)/Community) or time of outcome assessment (acute versus chronic). The findings also remained despite the heterogeneity of survey questionnaires used to evaluate sexual functioning outcomes. Excluding the most recent 2019 study, none of the research groups compared the findings by TBI severity, making it difficult to fully understand how concussion-related sexual changes compare to more severe forms of the head injury. The long term impacts of the sexual changes, such as infertility and relationship discord were also absent across all studies; even though most evaluated outcomes chronically (some as far out as 20 years post injury).The number of publications in the era before the ACRM call for action and afterwards were almost identical. In order to tailor interventions for the appropriate groups of TBI patients, more neurosexuality research is needed to increase awareness of the importance of sexuality as a health outcome for individuals with neurodisabilities. Nature’s Body (Schiebinger 2013).“At least since Aristotle, natural historians [have] given preference to the study of male bodies, or more precisely, the bodies of male citizens. Woman, considered a monstrous error of nature, was studied for her deviation from this male norm” ~Londa Schiebinger’s Since the origins of science and medicine, the “woman” has been considered negligible. Historically, it was believed that the female form was simply a male ‘turned outside in’  in all clinical research Clayton . RecogniHuman sexuality, according to the World Health Organization (WHO), is an essential aspect of health  or concussion, a bump, blow or jolt to the head that disrupts the normal function of the brain , the first author (MAO) initiated a comprehensive search of bibliographic databases (with citation tracking). We used the three largest and most comprehensive library databases for this purpose: Pubmed, Embase and Web of Science. Our librarian team member (LH) worked with MAO to select appropriate search terms . The seaprimary research papers thatevaluate sexual functioning as the outcomeinclude females in the study populationinclude mTBI or concussion in the TBI groupfocus on human participants, and not animal modelsStudies were extracted and managed in the EndNote bibliographical software  , proportion of female and male study participants, proportion of mTBI research participants, where patients were recruited from , measures used to evaluate concussion-related sexual outcomes and the study design. We then grouped studies into those published in 2010 and before, and those published after the ACRM call for action. KT initially charted the studies, and MAO reviewed them to ensure accuracy. A final review was conducted by EvW.We worked as a team to synthetize the findings in an iterative manner. In particular, MAO and EvW took the responsibility to appraise the quality of the studies reviewed on the basis of the information on study population, study design, outcome assessment and analysis. KT and MAO then engaged in a series of interactive discussions about the relevance of the retained studies to the overarching research question and project goals. We used descriptive and frequency tables to aggregate the data, distinguishing the two publication time periods as previously noted, starting with the first year we could identify a relevant article, which was 1991.The initial search identified 798 records from the three databases Fig. . After tRanging from publication dates of 1991 to 2019, the 9 articles Table , Canada All four pre-2010 studies provided gender specific details on the effects of the head injury on sexual outcomes; though O’Carroll (1991) and Kreuter (1998) focused exclusively on male study participants and provided no insights on the sexual changes for the head injured women enrolled in their study. In contrast, Hibbard (2000) provided not only details on TBI and female sexuality, but elaborated on the sexual domains impacted, and the endocrinological and psychological predictors of the observed adverse outcomes. Gaudet followed suit in 2001, but with interestingly positive findings regarding the association between TBI and sexual dysfunction. Compared to male study participants, the team observed that females with TBI reported more positive feelings about their sexuality.p = 0.03), though no evaluation of sexual domains was conducted.In the post-2010 period, two studies failed to provide gender-stratified findings (Moreno 2014 and 2015) while all others provided necessary details. Similar to Hibbard’s 2001 findings, Golding (2014) and Downing (2018) reported worse post-TBI sexual changes for women compared to men. Golding reported statistically significant differences in sexual frequency and the importance of sexuality for injured women compared to men, noting that these differences were not seen in the comparison groups. Downing reported on the effects of the injury on the lubrication sub-scale of the Derogatis Interview for Sexual Function-Self Report (DISF-SR). Comparing outcomes in all injured female research study participants, findings by Anto-Ocrah et al. (2019) echoed these earlier results and revealed that compared to extremity injured groups, women with mTBI have 70% greater risk of reporting sexual changes , the remaining 8 studies focused on chronic changes (1 to 20 plus years after injury). Study participants were recruited from a mix of community, rehabilitation and hospital settings, and outcomes were assessed with a heterogeneous array of sexuality questionnaires, including the Brain Injury Questionnaire for Sexuality (BIQS)  (Downing and Ponsford One of the limitations of our review is that not all injuries studied across the 9 included studies were mTBI/concussions. Thus using these mixed-severity studies to address the outcomes of mTBI/concussions exclusively, could be potentially biased.In order to tailor interventions for the appropriate group of TBI patients, cohort studies and other epidemiologic research in neurosexuality are needed to better understand the effects of concussions, the most common form of TBI on the sexual health of women, one of the most rapidly growing and vulnerable subgroups within the head injured population. The long term effects of the sexual changes, such as infertility and relationship discord should also be evaluated to better understand the longitudinal impact of the injury. Consideration should be given to the sexuality of lesbian and transgender women with mTBI, the sexuality of older women with mTBI, and other such under-represented subgroups within the TBI population, who are often over-looked across the literature. Research funds are needed to overcome some of the unique challenges associated with engaging such under-represented groups in research, in order to advance the field. Fiscal and logistical limitations however, should not deter the scientific community from actively engaging women and other under-represented populations in such epidemiological endeavors. Such research is necessary to inform policy and advocate for the allocation of fiscal resources to further train rehabilitation professionals, neuroscientists, sex therapists and other mental health providers, to further integrate neurosexual outcomes for the diverse spectrum of patients who may be seeking neuro-rehabilitative care.Women with TBI have been historically under-presented in clinical research. Compared to the sexuality of women with neurodisabilities, male sexual problems and treatments are better documented (Latella et al.