{"text": "Eucalyptus. Eucalyptus leaves can alter soil chemistry and negatively affect underground macro- and microbial communities. Amphibians serve as excellent models to evaluate the effect of Eucalyptus invasion on ground-dwelling species as they predate on soil arthropods and incorporate soil microbes into their microbiotas. The skin microbiota is particularly important to amphibian health, suggesting that invasive plant species could ultimately affect amphibian populations. To investigate the potential for invasive vegetation to induce changes in microbial communities, we sampled microbial communities in the soil and on the skin of local amphibians. Specifically, we compared Batrachoseps attenuatus skin microbiomes in both Eucalyptus globulus (Myrtaceae) and native Quercus agriflolia (Fagaceae) dominated forests in the San Francisco Bay Area. We determined whether changes in microbial diversity and composition in both soil and Batrachoseps attenuatus skin were associated with dominant vegetation type. To evaluate animal health across vegetation types, we compared Batrachoseps attenuatus body condition and the presence/absence of the amphibian skin pathogen Batrachochytrium dendrobatidis. We found that Eucalyptus invasion had no measurable effect on soil microbial community diversity and a relatively small effect (compared to the effect of site identity) on community structure in the microhabitats sampled. In contrast, our results show that Batrachoseps attenuatus skin microbiota diversity was greater in Quercus dominated habitats. One amplicon sequence variant identified in the family Chlamydiaceae was observed in higher relative abundance among salamanders sampled in Eucalyptus dominated habitats. We also observed that Batrachoseps attenuatus body condition was higher in Quercus dominated habitats. Incidence of Batrachochytrium dendrobatidis across all individuals was very low . The effect on body condition demonstrates that although Eucalyptus may not always decrease amphibian abundance or diversity, it can potentially have cryptic negative effects. Our findings prompt further work to determine the mechanisms that lead to changes in the health and microbiome of native species post-plant invasion.Invasive plants are major drivers of habitat modification and the scale of their impact is increasing globally as anthropogenic activities facilitate their spread. In California, an invasive plant genus of great concern is Anthropogenic habitat modification has dramatic direct and indirect effects on wild animal populations . InvasivOne way that invasive plants impact native animal populations is by altering their microbial commensals. Plant invasions could influence the microbial community structure of native fauna by changing microbial communities that hosts are exposed to, by altering host physiology, or both . InvasioEucalyptus sp. resulting in changes in soil microbial communities and native Quercus agrifolia (Fagaceae) dominated forests in the San Francisco Bay Area. Specifically, we determined whether changes in microbial composition, diversity and stability in both soil and Batrachoseps attenuatus skin were associated with Eucalyptus or Quercus dominated habitat. To evaluate animal health across Eucalyptus and Quercus dominated habitats, we also measured and compared Batrachoseps attenuatus body condition and the presence/absence of the amphibian chytrid fungus Batrachochytrium dendrobatidis, which causes the lethal amphibian disease chytridiomycosis. Our results illustrate a decline in the richness of skin associated microbiota and a decrease in salamander body condition in Eucalyptus forest, illustrating that plant invasions may have consequences for native species.To investigate potential changes induced by invasive vegetation on environmental and host-associated microbial communities, we sampled microhabitat soil and Eucalyptus invasions on native fauna and their microbiotas. The Bay Area is home to numerous seed-producing stands of E. globulus, E. pulchella, and E. viminalis among a mosaic of mixed native evergreen forests and coastal scrublands. The discrete\u2014yet interspersed\u2014distribution of invasive and native vegetation types in the Bay Area make it an ideal location to evaluate vegetation effects on resident host-associated microbiotas while controlling for geography. In addition, multiple ground dwelling amphibians are distributed throughout the Bay Area and may be sensitive to effects of invasive Eucalyptus on the skin microbiome because of their highly-limited dispersal as it has been eroded by a nearby stream, and instead chose a new site with similar characteristics.The San Francisco Bay Area (Bay Area) provides an opportunity to test the effect of crobiome . One ampy campus . To miniBatrachoseps attenuatus skin swabs from Quercus and 28 from Eucalyptus dominated habitats . Access to off-campus sampling sites was granted by East Bay Regional Parks under permit # 965. We collected salamanders by hand using gloves through log flip surveys within ~100 m of the location coordinates. New gloves were donned between the handling of each salamander. To avoid resampling individuals and ensure that salamanders were later returned to their original capture site, we marked each capture log with the individual(s) identification number. We rinsed each salamander with 250 mL of sterile water and swabbed the dorsum with a sterile cotton swab 30 times. Following microbiota sampling, we measured each salamanders\u2019 total body length and mass. All salamanders were returned to their location of capture immediately after sampling. To characterize the microhabitat microbiota, we collected ~20 mg of soil or soil swabs directly from under the logs where each salamander was captured after releasing each individual. We collected 22 habitats . All samWe isolated DNA from skin swab samples using the DNeasy PowerSoil DNA Isolation Kit following the modifications to the manufacturer\u2019s protocol described in We performed a second PCR on microbiota amplicons to ligate dual-index barcodes paired with Illumina sequencing adaptors to the eBatrachochytrium dendrobatidis infection in our swabbed individuals, we performed real-time quantitative PCR (qPCR) reactions in duplicate following Batrachochytrium dendrobatidis zoospore standard dilution ranging from 100,000 to 0.1 genomic equivalents. These zoospore standards were prepared using the Bd-GPL strain CJB7\u2013originally isolated from Kings Canyon, CA. At least three reactions per 96-well plate were designated as negative controls, with each receiving five \u00b5L of water in lieu of template DNA. To reduce the risk of laboratory contamination we set up qPCR reactions in a laminar flow hood. We ran all qPCR reactions on an Applied Biosystems StepOnePlus Real-Time PCR System , and used the manufacturer\u2019s software for standard curve analysis. We considered an average qPCR quantification of less than one genomic equivalent per swab to be negative for Batrachochytrium dendrobatidis infection.To detect and quantify We processed raw sequencing reads using Trimmomatic to removPRJNA574188).Our microbiota sequence analysis consisted of established sequence read processing pipelines to filter erroneous reads, generate an amplicon sequence variant table, create a representative sequence phylogeny and assign taxonomy to ASVs. We chose to use ASVs rather than operational taxonomic units (OTUs), because ASVs provide greater resolution in amplicon differentiation . ASV varvegan and picante: community richness , evenness and phylogenetic diversity . We calculated these metrics in order to evaluate differences in the number of ASVs (community richness), distribution of ASV frequencies within samples (Shannon diversity index), and phylogenetic representation (Faith\u2019s phylogenetic diversity) across sample groups. To assess differences in community composition across samples, we applied the R packages GuniFrac and vegan to calculate three separate beta diversity metrics: pairwise unweighted/weighted UniFrac distances and Bray\u2013Curtis dissimilarities. We chose to include these beta diversity metrics as they account for differences in presence/absence of phylogenetic lineages among samples (unweighted UniFrac), abundance-based differences in phylogenetic lineages among samples (weighted UniFrac), and non-phylogenetic abundance-based differences among samples (Bray\u2013Curtis). In addition, we computed the core microbiomes of Eucalyptus soil, Eucalyptus salamander skin, Quercus soil and Quercus salamander skin samples.We transferred the rarefied ASV table and Newick phylogeny to R (version 3.5.1) for further analyses. A Shapiro\u2013Wilk test in R was implemented on all univariate dependent variables to evaluate normality prior to statistical model selection. We calculated three distinct alpha diversity metrics using the R packages Effects of Eucalyptus invasion on soil bacterial composition, diversity, and stability: We evaluated differences in soil community diversity, composition and community homogeneity between Quercus and Eucalyptus dominated habitats. To evaluate differences in alpha diversity between soil communities sampled in Quercus and Eucalyptus dominated habitats, we implemented community richness, Shannon diversity indices and phylogenetic diversity as dependent variables, habitat type as a fixed variable and site identity as a random variable in linear mixed models . The significance of the predictor variable was calculated with likelihood ratio tests (LRT). To characterize the strength and significance of soil community compositional and structural differentiation among habitat types, we implemented three PERMANOVA tests (R package vegan) using weighted UniFrac, unweighted UniFrac, and Bray\u2013Curtis dissimilarity matrices as dependent variables and site identity as a random variable. We produced NMDS plots using the three dissimilarity matrices to visualize clustering of samples by habitat and site identity using the R package phyloseq. To assess whether habitat type influenced variation in soil community structure, we performed three separate multivariate of homogeneity of group dispersions analyses (R package vegan) using the beta diversity metrics. For each beta diversity metric, we used a one-way ANOVA to test differences in point-to-centroid distances between soil samples obtained from Eucalyptus and Quercus dominated habitats. We implemented an indicator species analysis using the R package indicspecies to identify ASVs whose relative abundance differs between soil samples collected in Eucalyptus and Quercus dominated habitats.Effects of Eucalyptus invasion on Batrachoseps attenuatus bacterial composition, diversity and stability: To assess whether salamander skin microbiota sampled in Quercus or Eucalyptus dominated habitat differ in their overlap with microhabitat microbiota, we calculated average unweighted UniFrac, weighted UniFrac, and Bray\u2013Curtis dissimilarity values between every salamander skin sample and all environmental samples in its corresponding site. We used these dissimilarities as dependent variables in a generalized linear mixed model using a logit distribution with habitat type as a fixed variable and site as a random variable. We also evaluated whether skin microbial community diversity, composition and heterogeneity differed between Batrachoseps attenuatus sampled in Quercus and Eucalyptus dominated habitats. We assessed differences in community richness, Shannon diversity indices, and phylogenetic diversity between salamander skin communities sampled in Quercus and Eucalyptus dominated habitats using linear mixed models as described above. We ran PERMANOVA tests using weighted UniFrac, unweighted UniFrac, and Bray\u2013Curtis dissimilarities as dependent variables, habitat type as a fixed variable and site identity as a random variable to evaluate variation in community composition and structure. We produced NMDS plots using the three dissimilarity matrices to visualize clustering of skin samples by habitat and site identity. We also performed three separate multivariate of homogeneity of group dispersions analyses to evaluate how habitat type influenced variation in community structure among individuals in the same group. For each beta diversity metric, we used a one-way ANOVA to test differences in point-to-centroid distances between Eucalyptus and Quercus salamander skin microbial communities. We implemented an indicator species analysis using the R package indicspecies to identify ASVs whose relative abundance differs between salamander skin samples collected in Eucalyptus and Quercus dominated habitats. Lastly, we assessed patterns of isolation by distance (IBD) by comparing our three dissimilarity matrices of community composition to a Euclidean geographic distance matrix between sampling locations. We tested for significance of IBD through mantel tests using R package ade4 with site identity as a random factor. Lastly, we evaluated whether there were correlations between skin alpha diversity metrics and body condition using Pearson correlation tests.tebrates . We omitEucalyptus and Quercus dominated habitats . The core microbial communities of Eucalyptus dominated habitat soil samples (16 ASVs) were composed of ASV\u2019s characterized as Actinobacteria and Proteobacteria . In contrast, the core microbiome of Quercus dominated habitat soil samples was composed of eight ASV\u2019s characterized as Actinobacteria , Bacteroidetes , Proteobacteria , and Verrucomicrobia . The indicator species analysis identified 216 ASVs that differed significantly between habitat types with 122 associated with Eucalytpus soil samples and 94 associated with Quercus soil samples , weighted UniFrac , or Bray\u2013Curtis dissimilarities . Microbial community richness and phylogenetic diversity were significantly lower for salamanders in Eucalyptus dominated habitat compared to salamanders sampled in Quercus habitats but not for Bray\u2013Curtis dissimilarities but no patterns of IBD with both our weighted and unweighted UniFrac matrices .We did not observe differences in composition and structure between skin and corresponding soil samples among Eucalyptus dominated habitat was comprised entirely of ASVs assigned to the phylum Proteobacteria . The core microbiota of salamander skin samples collected in Quercus dominated habitat was richer in that it possessed 32 ASVs assigned to the phyla Actinobacteria , Chloroflexi , Proteobacteria , and Verrucomicrobia . As observed in the soil core microbial communities, salamander skin core ASVs consisted mostly of rare taxa . However, we found one skin ASV identified as Bordetella petrii to dominate skin communities in Eucalyptus (29.81%) and Quercus (20.45%) dominated habitats. The indicator species analysis identified 294 ASVs that differed significantly between habitat types with 36 associated with Eucalyptus salamander skin samples and 258 associated with Quercus salamander skin samples compared to individuals collected in Quercus dominated habitats .The core microbiota of salamander skin samples collected in samples . As obseEucalyptus and Quercus dominated habitats . Salamanders sampled in Quercus dominated habitat possessed higher body condition indices than those sampled from the Eucalyptus dominated habitat , Shannon diversity index , or Faith\u2019s phylogenetic diversity . One salamander (OHG-47_S202) tested positive for Batrachochytrium dendrobatidis with a low average infection load of 41.59 zoospore equivalents .Body condition indices differed significantly between salamanders sampled in habitat . We did ivalents . The preEucalyptus and Quercus dominated sites. Thus, the filter acting on microbial richness is likely operating at the host level, rather than the passive uptake of different soil microbial communities. At the individual level, we found differences in native salamander skin microbial diversity and body condition associated with Eucalyptus invasion. We also observed higher salamander skin microbial composition heterogeneity and relative abundances of an ASV identified to the family Chlamydiaceae in salamanders inhabiting Eucalyptus dominated habitats.We observed no differences in richness, little variation in community composition and structure, and similar differentiation between soil and skin samples across Eucalyptus sites. In addition, a small fraction of the variation in community composition among soil samples was explained by vegetation type. This finding is surprising given the documented shifts in soil microbiomes following plant invasions \u2013in the Eucalyptus samples. While we cannot differentiate among these two possibilities using 16S rRNA amplicon sequencing alone, this pattern could reflect microbial community changes due to environmental filters present in the Eucalyptus dominated habitat. Changes in the relative abundance of core bacteria and alpha diversity have been documented in previous studies assessing the effects of environmental changes on the skin microbiota of amphibians has not been established . Additionally, Batrachoseps attenuatus\u2019 high site fidelity, relatively short dispersal distances and association with fallen logs may decrease differences compared to surrounding leaf litter, which may show greater microbial composition differences between sites possess distinct skin microbial communities and biotic factors may have disproportionate effects on the persistence of distinct rare bacteria in these salamanders. The loss of bacterial species in salamanders inhabiting Eucalyptus habitat may vary by individual- and site-specific factors that were not measured in the current study. Heterogeneous responses of microbial communities have been demonstrated for soil microbes in response to silviculture and agricultural practices , it is possible that an increase in Chlamydiaceae in the skin of salamanders results from microbial dysbiosis than those in native Quercus woodland . Interestingly, we found differences in the skin microbial community of the native salamander Batrachoseps attenuatus, but no differences in soil microbial communities between Eucalyptus and Quercus habitats. We also found decreased body condition of this native salamander in Eucalyptus dominated habitats. Our findings prompt further experimental work to determine the mechanisms causing these microbial changes and their potential effect on the fitness of native fauna following invasion.To our knowledge, our study is the first to demonstrate changes in the microbial communities of native hosts associated with plant invasion (10.7717/peerj.8549/supp-1Supplemental Information 1Click here for additional data file."} {"text": "Neoadjuvant therapy with conventional chemotherapies have visibly improved the prognosis of locally advanced pancreatic cancer (PCa). However, molecular targeted therapies that have provided durable responses in other tumor entities, have not yet found access into neoadjuvant therapy of PCa. In fact, due to the presence of the tumor burden serving as an antigen source for T cell priming, neoadjuvant chemotherapy may unleash a more potent antitumoral immune response than adjuvant or palliative chemotherapy. Despite tremendous efforts, successful therapy of pancreatic cancer (PCa) remains a major challenge . FindingCancer immunotherapy, led by immune checkpoint inhibitors (ICI) and cancer vaccines have shown notable long-term efficacy in many solid malignancies . The limAdoptive immunotherapy involves injecting antitumor-programmed immune cells into the patient. New directions are pointing to tumor lysate-pulsed dendritic cells , 12 or tThe failure of immunotherapy in PCa may be partly due to the exclusion of T cells by cancer-associated fibroblasts (CAF) and the impaired drug delivery caused by increased hydrostatic pressure and the poor vascularization in the highly fibrotic pancreatic stroma . Exploitin vitro and in the in vivo murine xenograft model and inhibited PCa growth [While metabolic plasticity has long been recognized as a hallmark of cancer, we have only recently started to exploit the differences between cancer cell and normal cell metabolism . Metabola growth .Our growing understanding of the PCa biology has led to the development of novel immunotherapies as well as drugs targeting key regulators of the stromal and tumor metabolism. However, the full potential of these agents has been hampered by the presence of therapeutic resistance, resulting from intrinsic compensatory signalling pathways and mutagenic evolution . Only co"} {"text": "Older residents often experience disruption in family relationships and social networks due to isolation once they move into public housing communities. While the need for social contact continues, the opportunity may diminish. Older African-American women living in one housing community attempted to cope with their personal safety fears through social isolation . Women in the study (N = 25) were survivors of one or more forms of interpersonal trauma, including childhood abuse, sexual assault and domestic violence. In contrast, a few women in the same sample spontaneously formed social networks within the community. This qualitative investigation will examine how the women adapted to an isolating and unsafe environment by developing social connections. As a social determinant of health, developing healthy social networks inside a housing community can reduce fear and improve well-being and quality of life for low-income older residents who are aging-in-place."} {"text": "Methamphetamines are commonly abused drugs for their stimulant and euphoric effects. Inhaled and intravenous use may cause damage to the respiratory system. Spontaneous pneumomediastinum is a condition where changes in intrathoracic pressure leads to alveolar rupture and dissection of air along the tracheobronchial tree. Massive subcutaneous emphysema may result from pneumomediastinum which may compromise the central airway. In this case report, we present an unusual case of spontaneous pneumomediastinum and severe subcutaneous emphysema following inhalation of methamphetamine. This case emphasizes the rising concern on the acute respiratory complications of methamphetamine use. Inhaled and intravenous use of stimulants may cause a variety of respiratory injuries. These injuries include but are not limited to nasal septum perforation, pulmonary vascular disease, pulmonary hemorrhage, thermal injury, pulmonary edema, and pneumothorax . SpontanA twenty-two-year-old previously healthy male presented to the emergency department for worsening facial and neck swelling. He noticed worsening dyspnea accompanied by facial swelling a few hours after smoking methamphetamine. Within a few minutes in the emergency room, the patient's mental status declined with more labored breathing; thus, the patient was electively intubated for airway protection. Differential diagnosis was acute allergic reaction to illicit drugs causing upper airway compromise versus acute inhalational injury. Initial chest computed tomography (CT) showed extensive pneumomediastinum with air dissecting to the peribronchovascular interstitial sheaths, interlobular septa, and visceral pleura Figures . There wMechanical ventilation was adjusted having very minimal to no positive expiratory pressure (PEEP) and prolonged expiratory phase. Placement of chest blow holes was not pursued as swelling on the face and neck improved after a few hours. The suspicion for tracheobronchial tree injury was low; thus, we did not perform bronchoscopic surveillance of the airway. Patient received empiric antibiotic treatment with ampicillin sulbactam. The patient was extubated in less than 24 hours after the improvement of peak inspiratory and plateau pressures with the positive cuff leak test. Repeat chest imaging showed decreased subcutaneous emphysema and resolution of pneumomediastinum. No dietary restriction was recommended after extubation as there was no evidence of aerodigestive organ injury. The patient was discharged after 72 hours with improved symptoms.Pulmonary complications have been reported with the use of illicit stimulants. Some recognized respiratory complications are nasal septum perforation, pulmonary vascular disease, pulmonary hemorrhage, pulmonary edema, and pneumothorax . Our casPlain chest X-ray including computed tomography (CT) is an adequate evaluation procedure after a thorough history and physical examination to exclude secondary pneumomediastinum . In one Spontaneous pneumomediastinum is often a self-limiting disease; however, due to concerns for the integrity of the aerodigestive tract, this finding usually results to unnecessary radiological investigations and antibiotic use. In one case series, spontaneous pneumomediastinum is overinvestigated and overtreated; thus, clinicians need to be more judicious with the use of hospital resources in managing patients with spontaneous pneumomediastinum . For thi"} {"text": "Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with significant mortality and morbidity. The central pathophysiological mechanisms by which repetitive cranial injury results in the neurodegeneration of CTE are poorly understood. Current well-established working models emphasize a central role for trauma-induced excessive phosphorylation and accumulation of insoluble tangles of Tau protein. In this review, we summarize recent data from preclinical animal models of CTE where a series of candidate treatments have been carefully evaluated, including kinase inhibitors, antibody therapy, and anti-inflammatory therapies. We discuss the overall translational potential of these approaches and provide recommendations for future bench-to-bedside treatment strategies. Initial symptoms manifest as non-specific cognitive and neuropsychiatric impairments, including depression and heightened aggression, and eventually progress to include a variety of motor impairments and cognitive decline . While tlistica) , it has listica) . In a relistica) . Militarlistica) . Aside fcted CTE .The initial symptoms of CTE may not occur until years or even decades after rmTBI and may affect cognitive and/or emotional domains. By one classification system, symptoms occurring in more than 50% of \u201cmild\u201d CTE (Stages 1 or 2) include impulsivity, depression, physical and verbal violence, memory loss, and suicidality. Severe CTE (Stages 3 or 4) is characterized by additional symptoms such as language impairments, visuospatial deficits, parkinsonism, and dementia-like deficits . CTE is While there remain many unknowns about the molecular and cellular pathological changes that are presumably incited by repeated cranial impact, a strong consensus has unified around the pathophysiological role of hyperphosphorylated tau (\u201cp-tau\u201d) accumulation and neurofibrillary tangle (NFT) formation . Thus, Cin vivo premortem diagnostic markers. In particular, PET imaging with radiotracers such as [F-18]FDDNP (which binds insoluble protein aggregates) has been used to identify tau and beta-amyloid patterns consistent with CTE and CTE remains somewhat enigmatic. Both tauopathies share a series of culprit tau phosphorylation sites and TBI Given the major knowledge gaps in our understanding of CTE pathogenesis, as well as limitations in available premortem diagnostic biomarkers, it is not surprising that there are currently no ongoing clinical trials for the treatment of CTE. However, in light of the proposed pathophysiological overlaps between AD and CTE, several therapies that have demonstrated preclinical success in AD models have now been applied to CTE models. This review summarizes key recent findings within this body of literature which have focused on accumulations of hyperphosphorylated tau aggregates as both a direct mediator of neuronal injury and a histological biomarker of disease severity.By definition, the vast majority of CTE diagnoses occur in individuals with a self-reported or witnessed history of contact-sport-related head injuries or military-related blast exposure . AccordiThis approach does have drawbacks: secondary injuries such as cranial fracture or intracranial hemorrhage do occur at some measurable rate . AdditioWhile the more nuanced aspects of CTE-related cellular and molecular derangements remain an active area of research, most agree that a valid preclinical model of CTE should demonstrate evidence of a phosphorylated tauopathy in response to rmTBI. In this regard, insights into CTE pathophysiology may be borrowed from transgenic Alzheimer\u2019s disease models such as TauP301L and 3xTg-AD, with the caveat that these mice develop amyloid and tau pathology even in the absence of rmTBI . Other myears of participation in a contact sport and include individuals who have only received sub-concussive impacts permeability is one of the main factors limiting the efficacy of antibody treatment in CTE and other neurological diseases. Recent advances in ultrasound technology may be used to aid immune response or drug delivery across the BBB. Unilateral focused ultrasound (FUS) has been a candidate method used to increase BBB permeability by producing transient openings in endothelial tight junctions . Recentl the BBB . In an A the BBB . In conjrvention . While trvention . Low-intrvention and AD are also involved in pathological tau hyperphosphorylation. The potent CDK inhibitor roscovitine has been studied in models of TBI and demonstrated attenuation of neurodegeneration in a model of controlled cortical impact in mice . CombiniBeyond tau hyperphosphorylation, the progression of CTE is thought to include a complex cascade of secondary inflammatory and metabolic changes that may also represent potential targets for therapeutic intervention . Ionic iThe production of reactive oxidative species and mitochondrial stress likely plays a key role in driving neuronal ischemia in CTE . These pSadly, despite increasing recognition among athletes and military personnel, there are currently no available treatments for CTE or practical clinical diagnostic markers to identify at-risk individuals. Fortunately, with a detailed neuropathological description from postmortem samples combined with preclinical models that have been inspired by the Alzheimer\u2019s field, we are closer to obtaining a comprehensive pathophysiological understanding of CTE. Like AD, CTE is a progressive neurodegenerative disease that appears to propagate via tau phosphorylation and subsequent aggregation into neurofibrillary tangles. At the same time, trauma-induced changes in circuit function may borrow from prior research in severe traumatic brain injury. While research on these related conditions may shed light on CTE pathology, it also warns of potential pitfalls. In particular, both AD and severe TBI have suftrans to pathogenic cis form has driven the development of isoform-specific phosphorylated tau monoclonal antibodies. The use of immunotherapy is one of the most promising strategies to treat CTE and other neurodegenerative diseases but suffers from poor translational efficiency. Techniques such as FUS/LIPUS may be used in conjunction with antibody treatment to improve the delivery of cis p-tau antibodies and immune agents across the blood\u2013brain barrier.Perhaps the most intuitive way to halt the progress of CTE is to inhibit processes directly affecting tau phosphorylation and aggregation. Given tau\u2019s multiple physiological functions, therapies must selectively inhibit formation and spreading of pathogenic tau. A profile of kinases directly phosphorylating tau in CTE has been developed and opened the door to a number of kinase inhibitors such as roscovitine and lithium which have shown promising preclinical results. The recent finding that tau is converted from a functional As these candidate therapies move forward to clinical phases, researchers should note the failure of dementia research to produce successful clinical trials . Why do PB and VK played significant roles in the initial manuscript drafts and subsequent revisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "The potential importance of germline genetic variation for identifying men at increased risk of prostate cancer has become increasingly recognised in recent years. We present an extensive review of the major developments in the identification of genetic loci, genes and individual variants associated with greater risk of prostate cancer, and what is currently known regarding whether these heritable prostate cancer risk factors can also inform likelihood of experiencing clinically significant rather than indolent forms of the disease. We finally discuss how these research discoveries might serve to inform clinical germline genetic testing guidelines and treatment options for prostate cancer in the future.Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine. Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in Europe and North America and second most common worldwide, with over 1.4 million diagnoses recorded in 2020 ,4.Although several promising molecular and genomic biomarkers for PrCa diagnosis or management have been identified in recent years , prostatNo consistent, consensus definition of aggressive PrCa has thus far been adopted within the research or clinical settings, which can hinder comparability of studies to identify risk factors and uniformity of clinical treatment application. Prior to the advent of PSA testing, aggressive PrCa had been considered to encompass only cancers which had advanced beyond the prostate itself . More reThe most clearly established risk factors for PrCa are increased age, ethnicity and family history of PrCa and certain other cancers. Familial aggregation of PrCa is one of the strongest risk factors, and provided support for the likely existence of genetic risk factors shared among families. Men with one male first-degree relative diagnosed with PrCa themselves have an estimated relative risk of approximately 2.5, and risk of diagnosis with PrCa further increases for men with multiple affected FDRs and lower ages at their diagnoses ,14,15. REvidence has also been presented for clustering of aggressive clinical presentation of PrCa within families, suggestive for heritability of aggressive PrCa phenotypes. A number of studies from the Swedish population have demonstrated increased risk of high grade PrCa observed among brothers of cases with high grade disease , with grBRCA1 and BRCA2 genes, whilst Lynch syndrome is categorised by germline mutations in DNA mismatch repair genes. A strong family history of PrCa remains a more effective indicator of PrCa risk than family history of other cancer types however, especially with respect to early-onset and lethal disease . This is consistent with previous reports that the KLK3 GWAS SNP rs2735839 is associated with Gleason score in addition to overall disease risk or remained associated with aggressive status among only patients with low PSA levels from two separate ancestral populations [KLK3 variation in PrCa susceptibility, risk of aggressive disease and serum PSA levels may therefore warrant more extensive investigation, especially in prospective or PSA na\u00efve cohorts, and may have the potential to enable the identification of a subset of individuals at lower risk of poor prognosis disease who could benefit from less interventionist treatment options.Case-only GWAS have to date reported at a genome-wide significant threshold two loci associated with Gleason score , one wit of PrCa , whilst of PrCa ,242. Thease risk ,246,247.ulations . The fulWhilst these initial case-only reports imply that caution is warranted regarding the potential for GWAS loci to be able to accurately stratify PrCa patients more likely to develop clinically significant disease, increasing evidence supports the improving ability of genetic risk scores incorporating ever larger numbers of established susceptibility variants to identify a population subset at greater lifetime risk of diagnosis with PrCa of any severity ,256,257.Although the ability of GRS to predict disease status within cohort studies has been demonstrated for various traits, their potential clinical utility to inform screening decisions for individual members of the population does however largely remain to be established at this point in time. Their potential consideration for implementation as a prospective risk-profiling tool prior to screening for PrCa may, however, soon become warranted. A polygenic hazard score (PHS) has demonstrated initial promise for the detection of clinically significant PrCa at younger age among higher PHS percentiles ,264, incAlthough many common loci have been identified which contribute substantially towards PrCa risk, rare variation is also estimated to play an important role in PrCa heritability , especiaBRCA2 gene, confirming earlier observations linking BRCA2 mutation carriers to more aggressive phenotypes through other approaches [ATM, BRCA1 and PALB2 and HOXB13. The latest National Comprehensive Cancer Network (NCCN) guidelines for germline testing also propose screening CHEK2 and PALB2 as part of their minimum recommended predisposition gene panel [TP53 plus additional DNA repair genes including BRIP1 and NBN have also been proposed for inclusion on screening panels, but await more definitive evidence to achieve consensus of utility [ATM, BRCA1, BRCA2 and potentially other DNA repair genes may inform response to PARP inhibitors [BRCA1, BRCA2 and other DNA repair genes sensitivity to platinum chemotherapy [Germline testing for rare moderate penetrance pathogenic variants in specific genes is becoming an increasingly important focus of PrCa management and treatment, with the additional promise of guiding tailored therapeutic interventions appropriate for targeting specific molecular vulnerabilities in individual patients\u2019 tumours. Although few genes have been conclusively identified to date in which rare variants confer higher risk of developing aggressive PrCa, as further larger, cross population sequencing studies and meta-analyses are performed, additional genes for which mutation carriers experience greater risk of aggressive disease and/or more favourable response to particular treatment options are likely to be established . At presne panel . The tum utility . In patihibitors ,305,306,otherapy ,308, andotherapy ,310. InvAlthough family history of the disease is usually the main reason for genetic testing of men without a diagnosis of PrCa, an appreciable proportion of PrCa patients without a family history sufficient to meet NCCN guidelines for germline genetic testing have also been demonstrated to carry rare germline putative PrCa susceptibility variants . Even grThe majority of samples included in studies investigating risk factors for PrCa to date have been from populations of European ancestry. However, given differing allelic architecture and frequencies of both rare and common variants between populations, in addition to the higher incidence and poorer prognosis of PrCa among men of African descent, reducing under-representation of additional ethnicities in PrCa research remains an unmet requirement in order to ensure applicability of discoveries across populations and pan-ethnic access to healthcare improvements ,312,313."} {"text": "On July 28, the correctional officer had multiplebrief encounters with six incarcerated or detained persons (IDPs)Subsequently, VDH and facility staff members reviewed July 28 quarantine unit videosurveillance footage and standard correctional officer shift duty responsibilities toapproximate the frequency and duration of interactions between the correctional officerand infectious IDPs during the work shift . AlthougThe correctional officer reported no other known close contact exposures to persons withCOVID-19 outside work and no travel outside Vermont during the 14 days preceding illnessonset. COVID-19 cumulative incidence in his county of residence and where thecorrectional facility is located was relatively low at the time of the investigation , suggesting that his most likely exposures occurred in thecorrectional facility through multiple brief encounters with IDPs who later received apositive SARS-CoV-2 test result.Among seven employees with exposures to the infectious IDPs that did meet the VDH closecontact definition, one person received a positive test result. Among thirteen employees with exposures to the infectious IDPs that did notmeet the VDH close contact definition during contact tracing, only the correctionalofficer received a positive SARS-CoV-2 test result.Data are limited to precisely define \u201cclose contact\u201d; however, 15 minutesof close exposure is used as an operational definition for contact tracinginvestigations in many settings. Additional factors to consider when defining closecontact include proximity, the duration of exposure, whether the infected person hassymptoms, whether the infected person was likely to generate respiratory aerosols, andenvironmental factors such as adequacy of ventilation and crowding. A primary purpose ofcontact tracing is to identify persons with higher risk exposures and therefore higherprobabilities of developing infection, which can guide decisions on quarantining andwork restrictions. Although the initial assessment did not suggest that the officer hadclose contact exposures, detailed review of video footage identified that the cumulativeduration of exposures exceeded 15 minutes. In correctional settings, frequent encountersof \u22646 feet between IDPs and facility staff members are necessary; public healthofficials should consider transmission-risk implications of cumulative exposure timewithin such settings."} {"text": "With advancing age, the incidence rate of Alzheimer\u2019s disease and dementia gradually increases, and mortality from either Alzheimer\u2019s disease or dementia has increased in recent decades . RecentlPostmenopausal women experience a dramatic decrease in circulating estrogen level. Due to the cardio-protective effect of estrogen, premenopausal women are exposed to a lower risk of cardiovascular disease compared to postmenopausal women. Elastic conduit arteries including the aorta are more vulnerable to either internal or external stimulation than smaller muscular vasculatures because of their anatomical characteristics. Thus, central artery stiffness measures such as pulse wave analysis (augmentation index) and aortic pulse wave velocity are used as validated surrogate markers to predict future cardiovascular morbidity and mortality. Elastic central arteries in postmenopausal women older than 60 yr of age are in particular stiffer than pre- or postmenopausal women under 60 yr of age . In a reRegular physical activity including aerobic and resistance exercise is recommended for postmenopausal women to improve not only musculoskeletal and cardiovascular function, but also cognitive function. Three months of combined circuit exercise reduce arterial stiffness and other cardiovascular disease risks in hypertensive postmenopausal women. FurtherCompared to continuous exercise, high-intensity interval exercise can be more beneficial in enhancing cognitive function via not only decreased central artery stiffness but also facilitated neurotrophic factors production and increased neurotrophic factor bioavailability in postmenopausal women. The hypoxia state in high-intensity aerobic exercise increases VEGF production. In particular, intermittent hypoxia for high-intensity interval exercise facilitates the generation of BDNF, the most important neuroplasticity marker, in the cerebrovascular endothelium. Furthermore, lactate, a byproduct of high-intensity exercise, can be used to facilitate BDNF and VEGF generation in peripheral tissues and is an additional energy resource for brain neuron activity. Both the BDNF and VEGF produced in peripheral tissues can directly facilitate neuroplasticity in the central nervous system after passing through the blood brain barrier.Future studies are warranted to comprehensively investigate the effects of high-intensity interval training on central artery stiffness, neuroplasticity, and cognitive function, and elucidate the associated physiological mechanisms in postmenopausal women, the population most vulnerable to cardiovascular events and cognitive impairment."} {"text": "TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions , carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions . Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT) promoter mutations occur in 60\u201380% of all urothelial bladder cancers (UBC) independent of tumor stage and grading thus, represent the most frequent alteration in this tumor entity [TERT [TERT promoter mutations in UBC are found in 99% of tissue samples at position \u2212124 and \u2212146 base pairs upstream from the ATG transcriptional start site position and are responsible for aberrant telomerase activity [TERT mutational incidence rates in UBC several studies proposed a possible role implementing these alterations in urinary testing and as a follow-up diagnostic tool [Telomerase reverse transcriptase and CIS as well as the tumor mass [Archival material of the Institute of Pathology, Erlangen was retrospectively evaluated and available bladder cancer specimens diagnosed as MIBC were screened for mor mass . All themor mass . A schemmor mass . PatholoTERT promoter mutated tumor associated normal urothelium as well as non-invasive urothelial lesions from the whole-organ mapping bladder specimens were immunohistochemically evaluated for CK20, CD44, TP53 and MIB1 staining. CK20 and CD44 were chosen as differentiation markers, which show distinct staining patterns among normal urothelium as well as for non-invasive urothelial lesions thus, are used for routine diagnostic evaluation. P53 evaluation as well as MIB1 staining is also used for evaluation of distinguishing normal urothelium as well as for non-invasive urothelial lesions [TERT promoter mutations and used for immunohistochemistry as preformed with a Ventana BenchMark Ultra and a Dako Link 48 autostainer accreditated by the German Accreditation Office (DAKKs) according to DIN EN ISO/IEC 17020. Detail information of the used antibodies are displayed in All lesions . Whole t\u00ae 16 System, Promega, Mannheim, Germany) according to the manufacturer\u2019s instructions. The tissue component from each tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC was manually microdissected from marked areas on each consecutive tissue slide derived from its corresponding tissue block in order to achieve at least 80% purity. DNA isolation was performed using the DNA preparation kit . The usage of labelled dideoxynucleotides enables the identification of the nucleotide base at the site of interest . After a denaturation step at 90 \u00b0C for five minutes the detection was performed with capillary electrophoresis using an ABI 3500 Genetic analyzer .The digestion of the remaining primers and free deoxynucleotides after PCR amplification was performed with alkaline phosphatase and an exonuclease . . The mulinterest . Two difTelomere length was analyzed by Relative Human Telomere Length Quantification qPCR Assay Kit according to the Manufacturer\u2019s instruction. Telomere length is recognized and amplified by comparing samples to reference genomic DNA containing a 100-base pair (bp) telomere sequence located on human chromosome 17. The total as well as the average telomere length was then calculated. p-Values < 0.05 represented statistical significance.Descriptive statistical analysis was used to characterize the nominal variables in terms of frequency and percentages. A non-parametric Wilcoxon rank-sum test was used for comparison between continuous variables. All analysis was performed by GraphPad Prism 7.2 and JMP SAS 13.4 (SAS). TERT promoter mutated regions were identified. TERT promoter mutations identified among the different tissue regions within the whole-organ mapping bladder tumor specimens. Results showed that the percentages of mutated samples generally increased in a step-wise manner from 17.24% among tumor associated normal urothelium, 33.3% in hyperplasia, 14.3% in dysplasia to 46.1% of CIS specimens and 100% of all MIBC regions. Representative images of mutated tumor associated normal urothelium as well as CIS are shown in From 149 available tissue samples, 75 (50.33%) TERT promoter mutations within the whole-organ mapping bladder cancer specimens. As shown in TERT promoter mutation compared to the MIBC. Interestingly, in Bladder #9 the CIS housed a TERT \u2212124 mutation, which was also different to the MIBC (\u2212146). Detailed information of the tissue histologies as well as the mutational status for the TERT promoter for the polyclonal events are displayed in TERT promoter mutation compared to the MIBC.One objective of this study was to test for clonality events of TERT promoter mutations and total telomere length, some TERT mutated and wild type tissues as well as TERT mutated MIBC samples were analyzed. None of the determined telomere lengths were significantly different between mutated and wild type tissue samples (data not shown). To determine if there was an association between TERT promoter gene mutations throughout nine whole-organ mapping bladder cancer specimens thus, representing a full spectrum of tumorigenesis. Our results demonstrate that adjacent and non-adjacent tumor associated urothelium, non-invasive urothelium lesions as well as CIS surrounding the tumors are TERT mutated. Additionally, detection of mono- as well as polyclonal mutated specimens with identification of one or several TERT promoter mutations strengthen both clonality hypotheses. In this study, we evaluated the role of TERT promoter mutations have been identified in the vast majority of bladder tumors independent of pathological characteristics. The hot spot mutations detected in UBC and identified among this cohort locate at \u221257, \u2212124 and \u2212146 base pairs upstream from the ATG site of the TERT gene and generate novel transcription factor binding sites. Similar to the first descriptions of these mutations by Allory et al. the hot spot mutation at the \u2212124 nucleotide position was the most frequent substitution identified in our whole-organ mapping bladder cancer cohort [TERT promoter mutations in systematically collected normal urotheliums locating adjacent to non-invasive bladder tumor tissue. Additionally, even when the tumor was not mutated the associated normal urothelium showed a TERT promoter mutation. Moreover, if TERT mutations were initially observed, positive associations with bladder recurrence after therapy were shown indicating a potential use of TERT promoter gene mutations as a biomarker [TERT promoter mutations in tumor associated normal urothelium but also in non-invasive urothelial lesions adjacent to or non-adjacent to muscle invasive tumors. Considering TERT mutations in bladder tumors, it is interesting to note that we found in contrast to non-invasive tumors described above, all MIBC tissues presented with a specific mutation within a whole-organ mapping bladder specimen. Additionally, this observation also strengthens the fact that TERT promoter mutations seem to be an early and crucial event during bladder tumorigenesis and importantly are independent of pathological, histological and clinical characteristics [Evolution of especially epithelial cancers can be demonstrated by identifying distinct histologies including dysplasia or CIS sharing both mutational backgrounds with the tumor ,10. Due iomarker . In lineeristics ,15. TERT promoter gene were identified. Interestingly, all MIBC samples within its respective bladder specimen showed the same hot spot mutation. However, in contrast to MIBC polyclonal TERT mutations within the same bladder specimens were identified in tumor associated normal urothelium and non-invasive urothelial lesions. This finding supports the widely accepted idea that carcinogens in the urine could damage the urothelial layer and therefore mutational backgrounds could differ. On the other hand, four out of nine analyzed whole-organ mapping bladder tumors were monoclonal for TERT promoter mutations pointing to the fact of a possible seeding or migration of the cells [TERT promoter mutations and how they affect follow-up diagnostic tools has to be investigated in the future [Clonality is widely discussed regarding bladder tumorigenesis with poly- as well as monoclonal observations. In detail, whether the process of tumor formation is due to monoclonal events within the urothelium spreading through the bladder wall or by polyclonal, events resulting in several independent tumor clones is still under debate. Findings for both theories exist and with recent advances in molecular subtyping multifocal tumors and tumor heterogeneity will even be more important in terms of planning neoadjuvant treatment regimens for patients . We demohe cells . To whice future .TERT gene is to maintain and protect the ends of human chromosomes however, as we age they become shorter [TERT promoter mutation, functional investigations are still ongoing. In the study by Borah et al. [TERT mutated as well as wild type urothelial cell lines and observed an increased mRNA level of TERT transcripts, however neither the protein level nor the telomere length showed significant differences thus supporting non-translated mRNA. Additionally, Allory et al. [TERT between mutation carriers and wild types. These observations described above are comparable with our findings where there was no differences in telomere lengths. One further explanation could be that activation of the telomerase via mutations of the TERT promoter could also lead to other functions independent of telomere lengthening. These independent functions could affect many biological processes, including cell survival and apoptosis, DNA damage repair, mitochondrial function and stem cell activity. In addition, evidence exists that activating telomerase could also enable cells to acquire tumor-initiating mutations [TERT promoter mutations ultimately affect the urothelial tumor cells and additionally, implementing TERT promoter mutations as a diagnostic tool needs further investigation. Moreover, it was recently shown that cell lines from solid tumors with somatic TERT promoter mutations showed a significantly shorter telomere length compared to cell lines with a wild type TERT promoter [TERT promoter mutations compared to tumor associated urothelium and non-invasive urothelium as well as CIS possibly indicating a complex interplay between TERT mutational activation, telomere length variation and other cellular processes. The normal function of telomerase encoded by the shorter . With aph et al. the authy et al. observedutations . How TERpromoter . AlthougTERT promoter gene have been analyzed and thereby other TERT promoter alterations could have been missed. Limitations of our study is the retrospective nature as well as the limited, partly heterogenous sampling of the bladder cancer specimens. In addition, only hot spot mutations of the TERT promoter gene mutations occur in tumor associated urothelium, non-invasive urothelial lesions and CIS thus, highlighting a crucial and important role of the TERT gene in the development of bladder tumors. Moreover, the evaluation of distinct promoter mutant positions strengthens both theories of a mono- as well as a polyclonal development of bladder tumors. To our knowledge, we demonstrate for the first time in tissues from whole-organ mapping bladder tumor specimens containing MIBC,"} {"text": "Contrast induced neurotoxicity (CIN) is a rare complication of cardiac catheterization and re-exposure to contrast medium carries the risk of recurrent CIN. We report a case of successful contrast re-challenge in a 60-year-old female patient who developed CIN after her first procedure of coronary angiography (CAG) which resulted in symptoms of disorientation, amnesia and cortical blindness. A non-contrast enhanced CT performed four hours after the CAG was normal, however, her MRI brain scan showed scattered tiny hyper intensities in posterior occipito-temporal and parietal regions suggesting CIN. Patient\u2019s symptoms resolved completely after 72 hours. Two months later, because of persistent exertional angina, patient was successfully re-challenged with lesser amount of contrast medium with administration of hydrocortisone prior to procedure, and PCI to LAD was completed without recurrence of CIN. Contrast induced neurotoxicity in form of fits, confusion, cortical blindness and encephalopathy is very rare complication after angiography of coronary arteries and bypass grafts.A-60-year old woman with history of hypertension, dyslipidemia and paroxysmal AF admitted for acute coronary syndrome and underwent CAG. Her CAG was performed through right radial access with 5F Judkins diagnostic catheters. There was significant tortuosity in her brachiocephalic trunk which resulted in difficult engagement of both left and right coronary systems, hence larger volume (300 ml) of contrast media (Iohexol) was administered during her coronary angiography. Patient did not have a previous history of any procedure with contrast agent exposure. Her CAG showed significant 70% & 90% tubular lesions in proximal and mid segments (respectively) of left anterior descending coronary artery (LAD) requiring intervention. However, patient started to become confused, aggressive and later developed amnesia and cortical blindness. Her neurological examination did not reveal any cranial, sensory or motor nerves abnormality. A non-contrast computerized tomography (CT) scan performed four hours after the start of symptoms showed no acute pathological findings. Her brain magnetic resonance imaging (MRI) demonstrated tiny hyperdensities in the posterior occipito-temporal and parietal regions suggesting contrast induced neurotoxicity . PatientContrast induced neurotoxicity (CIN) following cardiac catheterization is a rare but devastating complication. Its clinical presentation varies from mild symptoms of headache and vomiting to more serious presentation with seizures, hemiparesis, encephalopathy and cortical blindness.The exact mechanism of contrast induced CIN remains unknown. Disruption of blood brain barrier and direct contrast neuronal toxicity mainly in the occipital region of brain haven been postulated as a possible mechanism in many reports.8Contrast media re-challenge has not been widely reported in literature. We identified only three cases where re-challenge of contrast media did not result in recurrence of cortical blindness.9Herein, we propose that re-challenge with minimal amount of contrast medium after pre-treatment with intravenous corticosteroids can be considered in patients with previous history CIN if: i) a second procedure is mandated as was the case in our patient to have persistent angina despite optimal anti-anginal medical therapy ii) CIN resolves completely after the first contrast exposure and iii) larger volume of contrast is associated with CIN.CIN following coronary angiography is an extremely rare but usually reversible complication. Re-exposure of contrast media to patients with history of CIN carries the risk of recurrent CIN, hence it is not well documented. We successfully re-challenged contrast medium in our patient and proposed that contrast rechallenge may be considered in some patients if certain conditions are fulfilled However, it is difficult to conclude whether or not CIN will recur with contrast re-challenge but we are reassured with the fact that CIN is usually transient and resolves completely.MAS & MWA did manuscript writing. MMS edited the manuscriptSKN reviewed the manuscript. HAB gave final approval. MAS responsible and accountable for the accuracy or integrity of this study."} {"text": "The purpose of this study was to explore demographic differences in health personality. Data consisted of 3,907 participants, 65 years and older. Multivariate analysis of variance with post-hoc testing revealed that women had higher health neuroticism scores than men, but men had higher health extraversion scores than women. Those married reported higher health agreeableness than those not married and young-old participants had higher health extraversion and health openness compared to other age groups. Regional differences included Midwest participants reporting higher health openness but lower health conscientiousness scores when compared to participants from other regions. There were also significant interactions. For example, individuals from geographic areas with predominately White Midwest residents were significantly higher on health neuroticism when compared to Northwest, South, and West regions. The results are helpful for healthcare providers who can tailor intervention approaches to specific populations."} {"text": "Gs), net assimilation rate (A), and LOX and methanol emissions to varying MeJA concentrations (0.2\u201350 mM) in cucumber (Cucumis sativus) leaves with partly open stomata and in leaves with reduced Gs due to drought and darkness. Exposure to MeJA led to initial opening of stomata due to an osmotic shock, followed by MeJA concentration-dependent reduction in Gs, whereas A initially decreased, followed by recovery for lower MeJA concentrations and time-dependent decline for higher MeJA concentrations. Methanol and LOX emissions were elicited in a MeJA concentration-dependent manner, whereas the peak methanol emissions (15\u201320 min after MeJA application) preceded LOX emissions (20\u201360 min after application). Furthermore, peak methanol emissions occurred earlier in treatments with higher MeJA concentration, while the opposite was observed for LOX emissions. This difference reflected the circumstance where the rise of methanol release partly coincided with MeJA-dependent stomatal opening, while stronger stomatal closure at higher MeJA concentrations progressively delayed peak LOX emissions. We further observed that drought-dependent reduction in Gs ameliorated MeJA effects on foliage physiological characteristics, underscoring that MeJA primarily penetrates through the stomata. However, despite reduced Gs, dark pretreatment amplified stress-volatile release upon MeJA treatment, suggesting that increased leaf oxidative status due to sudden illumination can potentiate the MeJA response. Taken together, these results collectively demonstrate that the MeJA dose response of volatile emission is controlled by stomata that alter MeJA uptake and volatile release kinetics and by leaf oxidative status in a complex manner. Treatment by volatile plant hormone methyl jasmonate (MeJA) leads to release of methanol and volatiles of lipoxygenase pathway (LOX volatiles) in a dose-dependent manner, but how the dose dependence is affected by stomatal openness is poorly known. We studied the rapid (0\u201360 min after treatment) response of stomatal conductance ( Thexenals . The emi\u03a6M) and the total volatile emission bursts after (IT) during a period of 60 min after MeJA treatment were calculated as our previous report [To study the quantitative emission characteristics of LOX compounds and methanol, the emission maxima and all statistical effects were considered significant at p < 0.05.All experiments were replicated at least three times with different plants and all data shown are averages \u00b1 SE. Effects of MeJA dose on foliage photosynthetic and emission traits were studied by linear or non-linear regressions depending on the shape of the response. Effects of abiotic factors combined with MeJA treatment on Gs that controls MeJA entry into the leaf. This implies that environmental stresses that reduce Gs are expected to reduce the plant sensitivity to airborne MeJA as was confirmed in our study for drought stress. Furthermore, changes in Gs alter the dynamics of water-soluble stress-volatile release from the plants, and this can have significant implications for stress propagation and signaling. A model of the relationships between rapid constitutive emission of volatiles and the role of stomata and cuticle by MeJA treatment interacting with light condition was put forwarded (Our experiments demonstrate that the response to MeJA strongly depends on orwarded . On the"} {"text": "Sadness is often thought of as unpleasant and dysfunctional. Yet, evolutionary-functionalist approaches and discrete emotional aging frameworks suggest that sadness is an emotion that helps us deal with loss and thus may become particularly salient and adaptive in late life. This talk presents findings from a multi-study, multi-method research program using age-diverse samples and experimental and longitudinal study designs. Findings show (1) intact or elevated levels of sadness responding in late life . Moreover, (2) higher levels of sadness responding are linked to adaptive outcomes in late life with some effects generalizing across age groups . Implications for future research are discussed."} {"text": "Leishmania genus protozoan parasites. Inoculation by infected Phlebotamine sandflies results in asymptomatic infection or a diverse range of clinical manifestations. Leishmaniasis can present with tegumentary lesions or visceral disease with parasite dissemination and high mortality [Leishmania species cause this spectrum of human disease [Leishmaniasis is a vector-born disease, caused by ortality . The spe disease . HoweverLeishmania parasites encounter diverse environments, genetic adaptations may result in positive or negative trade-offs in other life-cycle stages. In addition, as humans are not the primary vertebrate reservoir, protective or pathologic immune responses may alter disease outcome but not parasite fitness. Thus, understanding how Leishmania genetics influences outcomes of human leishmaniasis requires consideration of selective pressures across life-cycle stages (Leishmania parasites to navigate its evolutionary landscape.Evolutionary biology can be applied to understand the genetic differences among parasites with different disease manifestations. Because e stages . For insLeishmania evolution provide challenges to investigating host range and parasite virulence, they also present opportunities to understand human susceptibility. The range of leishmaniasis is limited by interactions between vectors and animal reservoirs. As their habitat is altered due to climate change and social conflict, ecologic studies informed by evolutionary dynamics could predict changes in leishmaniasis distribution. Human pathogenesis varies with the infecting Leishmania species; however, infection with the same species can result in an appropriate immune response with resolution, impaired response with parasite proliferation, or excessive inflammation with immunopathology [Leishmania parasites encode mechanisms to influence host immunity, understanding molecular pathogenesis requires studies using a diverse collection of parasites. Synthesis of these approaches is needed to understand variation in leishmaniasis outcomes and improve human health.While the complex pressures shaping athology . To elucPlasmodium parasites by treating mosquito nets with anti-malarial compounds [This evolutionary complexity may prove advantageous in developing novel treatments. For example, targeting parasites in vectors and reservoirs can decrease transmission and minimize human toxicity. This strategy has shown promise against ompounds . Furtherompounds uniquely"} {"text": "Multisite medical data sharing is critical in modern clinical practice and medical research. The challenge is to conduct data sharing that preserves individual privacy and data utility. The shortcomings of traditional privacy-enhancing technologies mean that institutions rely upon bespoke data sharing contracts. The lengthy process and administration induced by these contracts increases the inefficiency of data sharing and may disincentivize important clinical treatment and medical research. This paper provides a synthesis between 2 novel advanced privacy-enhancing technologies\u2014homomorphic encryption and secure multiparty computation (defined together as multiparty homomorphic encryption). These privacy-enhancing technologies provide a mathematical guarantee of privacy, with multiparty homomorphic encryption providing a performance advantage over separately using homomorphic encryption or secure multiparty computation. We argue multiparty homomorphic encryption fulfills legal requirements for medical data sharing under the European Union\u2019s General Data Protection Regulation which has set a global benchmark for data protection. Specifically, the data processed and shared using multiparty homomorphic encryption can be considered anonymized data. We explain how multiparty homomorphic encryption can reduce the reliance upon customized contractual measures between institutions. The proposed approach can accelerate the pace of medical research while offering additional incentives for health care and research institutes to employ common data interoperability standards. The current biomedical research paradigm has been characterized by a shift from intrainstitutional research toward multiple collaborating institutions operating at an interinstitutional, national or international level for multisite research projects; however, despite the apparent breakdown of research barriers, there remain differences between ethical and legal requirements at all jurisdictional levels . There aFor example, the International Cancer Genome Consortium endeavors to amass cancer genomes paired with noncancerous sequences in a cloud environment, known as pancancer analysis of whole genomes. The International Cancer Genome Consortium\u2019s data access compliance office was unable to establish an international cloud under the Pancancer Analysis of Whole Genomes Project because of conflicts between United States and European Union data privacy laws . These cIn this paper, we describe how traditional data-sharing approaches relying upon conventional privacy-enhancing technologies are limited by various regulations governing medical use and data sharing. We describe two novel privacy-enhancing technologies, homomorphic encryption and secure multiparty computation, that extend the capacity of researchers to conduct privacy-preserving multisite research. We then turn to analyze the effects of regulation on using these novel privacy-enhancing technologies for medical and research data sharing. In particular, we argue these privacy-enhancing technologies guarantee anonymity as defined under the EU GDPR and are, therefore, key enablers for medical data sharing. We focus on the GDPR, as it currently represents a global benchmark in data protection regulations. We argue that using these technologies can reduce the reliance upon customized data-sharing contracts. The use of standardized agreements for multiparty processing of data in concert with privacy-enhancing technologies can reduce the bottleneck on research. Finally, we turn to address how these novel privacy-enhancing technologies can be integrated within existing regulatory frameworks to encourage increased data sharing while preserving data privacy.Before examining novel privacy-enhancing technologies, it is necessary to examine the main models for exchanging medical data for research purposes and the limitations of conventional privacy protection mechanisms that are currently used to reduce the risk of reidentification. We synthesize the data-sharing models into three categories and analyze their main technological issues .The centralized model requires medical sites that are willing to share data with each other to pool their individual-level patient data into a single repository. The data repository is usually hosted by one medical site or by an external third party , playing the trusted dealer role. The main advantage of this model is that the trusted dealer enables authorized investigators to access all the patient-level information needed for data cleaning and for conducting statistical analysis. Moreover, such a data-sharing model minimizes infrastructure costs at medical sites, as data storage and computation are outsourced. However, from a data privacy perspective the centralized model is often difficult to realize, especially when medical and genetic data should be exchanged across different jurisdictions. The central site hosting the data repository represents a single point of failure in the data-sharing process. All participating sites must trust such single entity for protecting their patient-level data .k-anonymity privacy model . Although homomorphic encryption and secure multiparty computation offer privacy guarantees, there is still an orthogonal risk of reidentifying individuals from aggregate-level results that are eventually decrypted and can be exploited by inference attacks [Nevertheless, any standards will need to be continually updated to respond to new technological changes. For example, one of the most significant drawbacks of fully homomorphic encryption is the complexity of computation. This computational complexity makes it hard to predict running times, particularly for low-power devices such as wearables and smartphones. For the foreseeable future, this may limit the devices upon which fully homomorphic encryption can be used . Therefo attacks ,21,27,74A final consideration relates to ethical issues that exist beyond whether homomorphic encryption, multiparty computation, and multiparty homomorphic encryption involve processing anonymized or personal data. First, the act of encrypting personal data constitutes further processing of those data under data protection law. Therefore, health care and research institutions must seek informed consent from patients or research participants . InstituMedical data sharing is essential for modern clinical practice and medical research. However, traditional privacy-preserving technologies based on data perturbation, along with centralized and decentralized data-sharing models, carry inherent privacy risks and may have high impact on data utility. These shortcomings mean that research and health care institutions combine these traditional privacy-preserving technologies with contractual mechanisms to govern data sharing and comply with data protection laws. These contractual mechanisms are context-dependent and require trusted environments between research and health care institutions. Although federated learning models can help alleviate these risks as only aggregate-level data are shared across institutions, there are still orthogonal risks to privacy from indirect reidentification of patients from partial results . Further"} {"text": "Approximately 400 million people throughout the world suffer from a rare disease. Although advances in whole exome and whole genome sequencing have greatly facilitated rare disease diagnosis, overall diagnostic rates remain below 50%. Furthermore, in cases where accurate diagnosis is achieved the process requires an average of 4.8\u00a0years. Reducing the time required for disease diagnosis is among the most critical needs of patients impacted by a rare disease. In this perspective we describe current challenges associated with rare disease diagnosis and discuss several cutting-edge functional genomic screening technologies that have the potential to rapidly accelerate the process of distinguishing pathogenic variants that lead to disease. Approximately 400 million individuals worldwide are directly affected by a rare disease and whole genome sequencing (WGS) in a clinical setting. While the application of these technologies has greatly facilitated the identification of disease-associated genetic variants, the rate of diagnosis for rare disease remains below 50% over the past several years now provide scalable mechanisms to assign functional properties to large catalogs of variants. These approaches can be used to rapidly distinguish clinically detected variants with an increased likelihood of pathogenicity and facilitate the prioritization of variants that warrant in-depth evaluation.One common experimental approach used to explore the functional consequences of a genetic variant has been the use of plasmid-based reporter assays. These assays can be engineered to harbor specific variant sequences within exons, introns, or even noncoding regulatory regions of a transgenic reporter gene. Individual reporter constructs can be introduced into cultured cells and transgene expression and/or function can be evaluated using relevant methods. In recent years several plasmid-based reporter approaches have been adapted to multiplexed formats that permit the characterization of thousands of genetic variants simultaneously using high-throughput sequencing-based readouts. These massively parallel genomic assays have been utilized to profile published catalogs of disease-associated genetic variants and distinguish variants with functional implications . Distinguishing the functional consequences of these variants may require assays that are capable of profiling cellular phenotypes. Advances in genome editing technology, specifically CRISPR/Cas9, have dramatically improved the ability to engineer cellular models with specific genetic alterations , inhibition (CRISPRi), or activation (CRISPRa) of protein-coding genes or the repression/activation of targeted genomic regions (CRISPRi/CRISPRa). Consequently, these screens do not perfectly model the impact of clinically detected variants. As CRISPR-based screening methods continue to advance it may become possible to functionally screen large numbers of specific variants through pooled format adaptations of precision editing technologies (Shen et al. The ability to rapidly assign experimentally determined functional properties to clinically detected genetic variants will have profound impacts on rare disease diagnosis. In addition to existing resources, clinical geneticists will have access to empirical data that will facilitate more informed decisions related to variant pathogenicity. This information will reduce the time required to analyze individual patient genomes, increase patient throughput, and ultimately translate to improved rates of diagnosis. Moreover, the barriers to generating this data are minimal as many high-throughput functional assays do not require modifications to existing laboratory infrastructure nor do they require patient specimens.The experimental strategies we discuss here are intended to complement, not replace, current standard practices in variant interpretation. Moreover, the functional assays we have described are mainly suited for Mendelian diseases. Experienced clinical geneticists will always be needed to critique experimental results and to investigate diseases with more complex genetic contributions. Rare disease diagnosis will remain a constant challenge, but bridging the gap between clinical and functional genomics could provide an accelerated path to diagnosis for many rare disease patients that are still searching for answers."} {"text": "There is limited literature on formal caregivers\u2019 communication with persons living with dementia (PLWD) in home settings. Most research comes from studies of long-term care home settings or informal home care contexts. Yet, there are expected needs and rising demands for formal caregiver support within home care. The aim of this study was to understand better the lived experiences of personal support workers (PSWs) regarding their communication with PLWD in home settings. A hermeneutic phenomenological approach guided this research. Semi-structured interviews were conducted with 15 PSW participants. Three major themes were identified through thematic analysis: (1) challenged by dementia-related impairments; (2) valuing communication in care; and (3) home is a personal space. PSWs experienced difficulties in their communication with PLWD despite recognizing the importance of communication in providing optimal home care. This suggests that while PSWs possess good intentions, they do not possess the skills necessary to ensure effective interactions. Dementia-specific education and training are recommended to improve PSWs\u2019 communication skills and to enhance quality of care. Findings highlight further the uniqueness of the personal home space itself on PSWs experiences with communication. Aspects of the home care environment can enable, but also complicate, successful communication between PSWs and PLWD. Consequently, findings also have implications for family members of PLWD and home care employers regarding optimizing practice and improving care."} {"text": "This review enhances the existing literature on relationships between problematic smartphone use (PSU), psychopathology, addictive personality, and online social engagement as regards young adults, giving attention to predictive determinants of addictive behavior in smartphone usage. My article cumulates previous research findings on the psychology of addictive smartphone behavior in terms of problematic use, social anxiety, and depressive stress by focusing on the relationship among mobile social media usage, smartphone addiction risk, mental health issues, and individual well-being. The inspected collected findings prove that depression and social anxiety constitute risk determinants for greater PSU and that particular categories of smartphone applications are positively related to well-being. State anxiety and motivations represent significant predictors of PSU. High PSU affects participation in social engagement. As limitations in the current review, my results point towards relevant avenues of research on social consequences of teenagers\u2019 smartphone problematic use. Future directions should clarify whether compulsive smartphone use adversely affects both mental and physical health in the long run. PSU hasPSU shapes subjective and psychological well-being, and may configure associated anxiety and depression psychopathology. Mental health and somatic symptoms are adversely impacted by PSU leading to impaired socio-emotional functioning and possibly causing psychological distress.Users\u2019 psychological features may not clarify every characteristic of PSU. High PSU affects participation in social engagement. Users\u2019 absence of social networks may hinder agreeable social communications and emotParental neglect is considerably related to teenagers\u2019 smartphone addiction. In the link between parental neglect and PSU, the former is not relevantly connected with the relational instability with peers, negatively shaping PSU. The relational instability with teachers has a fragmentary mediation impact between parental neglect and PSU . ParentsParenting style and attachment may mediate young adults\u2019 smartphone use, improving interpersonal adaptation and self-control, while articulating family well-being. Young adults\u2019 addictive personality may be shaped by parental mediation practices and self-regulation.Significant research has considered lately the psychology of addictive smartphone behavior in terms of problematic use, social anxiety, and depressive stress. My article extends previous work by focusing on the relationship among mobile social media usage, smartphone addiction risk, mental health issues, and individual well-being. Progressively relevant degrees of smartphone ownership and utilization give rise to the implicit risk for addictive behaviors and adverse health results, shaping subjective and psychological well-being. The conclusions drawn\u00a0from the above analyses are that depression and anxiety symptoms are associated with PSU severity, generating, among others, emotion dysregulation, psychological distress, poor sleep\u00a0quality,\u00a0and diminished academic performance. Personality traits, social-emotional distress, and duration of daily smartphone use constitute antecedents of PSU, impacting subjective and psychological well-being. As limitations in the current review, my results point towards relevant avenues of research on social\u00a0consequences of young adults\u2019 smartphone addiction. Future directions should clarify whether compulsive smartphone use adversely affects both mental and physical health in the long run.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation. Recent pathological studies reported some of the COVID-19 patients with lung fibrotic lung features. Clinically, the main consequence of SARS-CoV-2 infection is cytokine storm, however previous studies indicate that anti inflammation therapy have no effects on pulmonary fibrosis, thus other mechanisms need to be provided to address this issue. Early micro injuries to alveoli increase local vascular permeability which provokes edema accompanied by inflammatory cytokines which prompt cytoskeletal remodeling and alter cellular mechanical forces. If these mild injuries could not be repaired properly, then fibroblasts will be activated and subsequent excessive deposition of extracellular matrix will result in a mechanical stretched niche. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize and the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.Pulmonary fibrosis (PF), which constitutes a broad range of heterogeneous end stage interstitial lung diseases, is characterized by excessive deposition of extracellular matrix and destruction of the pulmonary parenchyma about 50\u201370\u00a0m2 Weibel , 20-time2 Weibel . In the 2 Weibel .Mechanical sensing and regulating of endothelial cells are involved in the process of lung disease (Fang et al. Taken together the mechanical stress exposed to the endothelial cells is translated to different signals for the initiation and progression of lung fibrosis.2+ to interact with specific intracellular target proteins (Donato et al. 2+ influx can be induced by mechanical stretch in human lung fibroblasts (Murata et al. 2+ mediated S1006A stimulation. Taken together, these data indicate that mechanical stress promotes fibrosis by both stimulating the proliferation and migration of fibroblasts.The migratory and proliferative fibroblasts organizing in distinct clusters is called fibroblastic foci and this depicts the typical phenotype of lung fibrosis featured by accumulation of exaggerated amounts of ECM that forms a stiff milieu where fiMacrophages are involved in the cross-talk between innate and adaptive immunity (Epelman et al. Mast cells, originate from CD34-expressing haematopoietic stem cells in the bone marrow, are best known for their roles in allergic and acute inflammatory diseases (Wernersson and Pejler \u2212/\u2212 AECIIs cannot regenerate new alveoli which resulted in sustained elevated mechanical tension that subsequently activates a TGF-\u03b2 signaling loop in stem-like AECIIs and promote fibrosis (Wu Histologically, PF develops from microscopic fibrotic areas at the very peripheral regions of lung and slowly progress inward (Plantier et al. rosis Wu . Clinicarosis Wu . The lunrosis Wu . This coAccumulating evidence suggests abnormal metabolism in PF (Rowan et al. 6A modifications of pri-miRNA-126 was involved in the process of pulmonary fibrosis (Han The term \u201cepigenetics\u201d describes heritable changes in a cellular phenotype without alterations in the DNA sequence (Berger et al. osis Han . What\u2019s osis Han which maosis Han . Indeed,osis Han . Thus, uIn this review, we highlight the importance of rigid fibrotic niche in orchestrating the mechanical response of alveolar cells in exacerbating lung fibrosis Fig.\u00a0. The alvFurthermore, mechanical stress exerts a more comprehensive impact via metabolic and epigenetic regulation, which should be a promising filed for treating PF since rapid advances have been made in developing drugs to adjust metabolic status and target the epigenetic landscape. Therefore, translating these mechanism insights into clinical utilization may enable novel approaches for alleviating lung fibrosis."} {"text": "Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways, but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, up-regulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents over-proliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target."} {"text": "Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are responsible for the majority of nosocomial infections . Another study achieved successful phytomedited synthesis of green TiO2NPs that proved to be effective for treating biofilm-based bacterial and fungal infections .Seven original research articles spanning diverse disciplines describe the development of NATs for clinically-relevant MDR pathogens. One study describes the one-pot synthesis of Ag-ZnO nanoparticles at low temperatures and demonstrated remarkable antimicrobial activity of these nanoparticles against methicillin-resistant Enterobacterales (CPE). The authors showed how antimicrobial combinations synergized against most CPE expressing resistance genes. These antimicrobial combinations may facilitate the successful treatment of patients infected with CPE . Another original research article identified two potent combinations of antibiotics for clinical MRSA infection, both in vitro and in vivo . A separate study found that the compound 2,4-Di-Tert-Butylphenol isolated from an endophytic fungus substantially reduced the secretion of virulence factors and biofilm and its associated factors controlled by quorum sensing in a dose-dependent manner in Pseudomonas aeruginosa .Another research article assessed the therapeutic efficacy of antimicrobial combinations on carbapenemase-producing Streptococcus pneumoniae infections . New putative antimicrobial candidates were reported by Okella et al. They designed an antimicrobial peptide and performed target identification based on a putative antimicrobial peptide motif derived from fish. From all the peptide motifs generated in this work, the authors identified Pleurocidin (secreted by flatfish) as having strong antimicrobial potential.Furthermore, a study tested the anti-virulence activity of potential uridine diphosphate glucose pyrophosphorylase (UDPG:PP) inhibitors and showed that these inhibitors are a potential drug candidates against Le\u00f3n-Buitimea et al.). Another review explored the possibility of designing antimicrobial nanoparticle-based devices to exploit the potential of antimicrobial nanoparticles to combat MDR pathogens . Finally, a third review describes the mechanisms associated with drug resistance in pyogenic streptococci and discusses the advantages and limitations of innovative therapeutic strategies such as bacteriocins, bacteriophage, phage lysins, and metal nanoparticles .Three review articles included in this special issue address the use of NATs to face MDR bacteria. A mini-review discusses combination treatments as a pathway to develop antimicrobial therapeutics with broad-spectrum antibacterial action, bactericidal instead of bacteriostatic activity, and better efficacy against MDR bacteria (In summary, this group of articles contributes to the search for new therapeutic strategies to combat antibacterial resistance. MDR and XDR infections are growing in incidence; the main challenges facing society are now to design, develop, and evaluate new therapeutic strategies that can spearhead the development of alternative therapies against clinically-relevant MDR pathogens.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Extracellular vesicles (EVs) are lipid bilayer-enclosed microparticles that have prominent roles in the intercellular crosstalk. EVs are secreted after fusion of endosomes with the plasma membrane (exosomes) or shed from the plasma membrane (microvesicles). These microparticles modulate bone marrow microenvironment and alter differentiation and expansion of normal hematopoietic cells. EVs originated from mesenchymal stromal cells have been shown to enhance expansion of myeloid-biased hematopoietic progenitor cells. In addition, megakaryocytic microparticles stimulate differentiation of hematopoietic stem and progenitor cells into mature megakaryocytes. The ability of EVs in induction of maturation and expansion of certain hematopoietic cells has implications in transfusion medicine and in targeted therapeutic modalities. Important prerequisites for these interventions are identification the specific targets of EVs, transferred biomolecules and molecular mechanisms underlying the fate decision in the target cells. EVs are also involved in the pathogenesis and progression of hematological malignancies including acute leukemia and multiples myeloma. In the current review, we provide a summary of studies which evaluated the significance of EVs in normal hematopoiesis and hematological malignancies. Extracellular vesicle, Hematopoiesis, Hematological malignancy Microvesicles (MV) and exosomes include two important kinds of EVs . While M2Normal hematopoiesis is influenced by biomolecules that exist in EVs. For instance, EVs originated from mesenchymal stromal cells have been shown to enhance expansion of myeloid-biased hematopoietic progenitor cells. This speculation is based on an experiment in murine stromal cells where EVs derived from these cells stimulated loss of quiescence in hematopoietic stem and progenitor cells (HSPCs) and enhanced expansion of myeloid progenitors. Such effects were exerted through the MyD88 adapter protein. Notably, inhibition of TLR4 could suppress this process to some extent. Canonical NF-\u03baB pathway and subsequent induction of Hif-1\u03b1 and CCL2 were also involved in this process . Megakar3EVs also mediate different roles in hematological malignancies.3.1Both primary acute myelocytic leukemia (AML) and AML cell lines have been shown to produce exosomes that are transferred to bystander cells. These EVs contain numerous coding and noncoding RNAs which are involved in the pathobiology of AML. EVs entrance into bone marrow stromal cells results in the modulation of their potential in growth factors production. The signals transmitted by these EVs change the proliferative, angiogenic, and migratory features of cocultured stromal and hematopoietic progenitor cells . EVs als3.2Exosomes originated from patients with chronic myelogenous leukemia (CML) patients are enriched in amphiregulin (AREG), therefor inducing EGFR signaling in stromal cells. Activation of this signaling pathway leads to over-expression of SNAIL, MMP9 and IL-8. Prior exposure of stromal cells with CML cells exosomes has enhanced expression of annexin A2 which increases the adhesion of leukemic cells to the stromal monolayer, facilitating the growth and invasion of leukemic cells . CML-der3.3Microvesicles released from MSCs from patients with myelodysplastic syndrome (MDS) have been shown to alter CD34 + cells characteristics .Multiple myeloma (MM) MSCs have also been shown to produce EVs that are conveyed to MM cells, thus changing tumor growth. Exosomal levels of miRNA such as miR-15a were different between MM and normal MSCs. Besides, EVs originated from MM bone marrow MSCs had greater amounts of oncogenes, cytokines, and adhesion molecules. While these EVs enhanced MM tumor growth, normal bone marrow MSC-derived EVs suppressed the growth of MM cells . MM pati4The presence of EVs in the body fluids including saliva, urine, peripheral blood and other body fluids indicates the potential of these vesicles in diagnostic and prognostic procedures . Notably5EVs have been shown to mediate critical functions during normal hematopoiesis and in the course of initiation and progression of hematological malignancies. The cell-cell communication mediated by EVs has important effects in bone marrow milieu and regulation of innate immune responses . The abiFinally, EVs which are released into bone marrow microenvironment might affect response of malignant cells to therapeutic modalities including tyrosine kinase inhibitors. Therefore, EVs components not only predict patients' outcome and their response to therapy, but also they represent potential manipulable resources for conferring drug resistance. Alteration in exosomal level of certain proteins might also reveal responses to chemotherapy. Moreover, the exosomal content may reflect the existence of residual disease in patients thought to be in complete remission . MalignaTaken together, EVs contain several protein and RNA molecules that could alter lineage differentiation, expansion and function of bone marrow cells in both physiological and pathologic conditions. The ability of these microparticles in specific targeting of the recipient cells potentiates them as vehicles for combating drug resistance in hematological malignancies. Moreover, malignant cells-derived EVs are potential diagnostic and prognostic markers in this kind of malignancy.All authors listed have significantly contributed to the development and the writing of this article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data will be made available on request.The authors declare no conflict of interest.No additional information is available for this paper."} {"text": "A 48-year-old-female presented to the emergency department with dislodgement of her percutaneous endoscopic gastrostomy (PEG) tube, necessitating bedside replacement. Replacement was done without difficulty and gastrografin radiography was obtained to confirm positioning. Radiography revealed contrast filling the colon at the splenic flexure and proximal descending colon suggestive of colocutaneous fistula formation.The patient required hospitalization with surgical consultation, initiation of parenteral nutrition, and conservative management of the fistula with surgical replacement of the PEG tube. Although rare, it is paramount for the emergency physician to be aware of this complication when undertaking bedside replacement of PEG tubes. A 48-year-old female with past medical history of failure to thrive requiring percutaneous endoscopic gastrostomy (PEG) tube placement presented to the emergency department (ED) with PEG tube dislodgement. Her PEG tube was initially placed in 2009, with surgical replacements in 2012 and 2018. Examination revealed a soft, nontender, non-distended abdomen with an open gastrostomy tract. ED course included placement of a new gastrostomy tube into the existing tract and confirmatory gastrografin radiography .The confirmatory radiography revealed contrast filling the colon at the splenic flexure and proximal descending colon suggestive of colocutaneous fistula formation, without peritoneal extravasation. This required hospitalization with surgical consultation for removal of the misplaced PEG tube, initiation of parenteral nutrition, intravenous antibiotics, and surgical reinsertion of the PEG tube after conservative management of the colocutaneous fistula. Colocutaneous fistulas are a rare complication of PEG tube insertion with incidence rates of 0.5\u20133%.CPC-EM CapsuleWhat do we already know about this clinical entity?Colocutaneous fistulas are a rare complication of percutaneous endoscopic gastrostomy (PEG) tube insertion mediated by PEG tube penetration of interposed colon between the stomach and abdominal wall.What is the major impact of the image(s)?Contrast filling the splenic flexure and proximal descending colon suggests colocutaneous fistula formation, requiring prompt recognition and surgical consultation.How might this improve emergency medicine practice?Emergency physicians change a large number of PEG tubes; therefore, recognition and awareness of this rare complication is important to clinical practice."} {"text": "Racial and ethnic disparities in age-related cognitive function and dementia risk in the US are well recognized. However, the psychosocial drivers of these disparities and underlying mechanisms are less well studied. This symposium will highlight novel research regarding our current understanding of racial/ethnic differences in brain and cognitive aging and the underlying mechanisms of the disparities. Frist, two papers will describe results regarding racial/ethnic differences in cognitive function and brain aging markers. Few studies have assessed racial/ethnic differences in cognitive function across age groups. Indira Turney will utilize data from a multigenerational study to explore how age impacts racial/ethnic differences in cognitive function. Underlying brain mechanisms of racial/ethnic differences in cognitive outcomes are also not well defined. Sara Godina will present a systematic review of racial/ethnic differences in structural markers of brain aging and neuropathology. Second, three papers will explore how various risk factors may explain the racial/ethnic disparities in cognitive outcomes. Melissa Lamar will demonstrate the differential associations of various blood pressure indicators with cognitive change among black older adults. B. Gwen Windham will present data from two studies that illustrate differential effects of common risk factors by race and region, highlighting inherent difficulties in race-place disparity research. Finally, Laura Zahodne will present results on how psychosocial factors, beyond socioeconomic status, contribute to racial/ethnic disparities in cognitive function. Jen Manly will lead a discussion on the implications of these results for the future of dementia prevention efforts for an increasingly diverse older US population."} {"text": "Using two studies, we examined the late life prevalence and health consequences of discrete positive emotions posited to motivate rest and recovery or pursuit of novelty and stimulation (excitement). Study 1 assessed the salience of these discrete emotions in older adults relative to younger adults over a one-week period. Multilevel models showed that older (vs. younger) adults reported higher calmness and lower excitement. Study 2 examined the longitudinal health consequences of calmness and excitement in old age , as moderated by perceived control. Multilevel growth models showed that calmness, but not excitement, buffered against 10-year declines in psychological well-being and physical health for older adults with low perceived control. Results suggest that positive emotions with disparate motivational functions become more or less (excitement) salient and have diverging implications for health in old age."} {"text": "Indices quantifying allostatic load (AL) and biological aging (BA) have received widespread use in epidemiological and health science literature. However, little attention has been paid to the conceptual and quantitative overlap between these indicators. By reviewing literature utilizing measures of AL and BA, we highlight differences with respect to biological markers employed and approach toward scale construction. Further, we outline opportunities where AL indices might be improved by adopting analytical features of BA measures. We demonstrate the utility of this approach using data from The MIDUS National Survey, constructing three indices of allostatic load: one standard approach modeled after Gruenewald et al, 2012, and two alternative formulations informed by BA procedures. The performance of AL indices are juxtaposed against two commonly employed indices of biological aging: Klemera-Doubal Method Biological Age and Homeostatic Dysregulation. All measures were significantly associated with chronological age. Alternative AL formulations were more strongly associated with biological aging measures than with the standard approach. MIDUS participants with increased allostatic load and older biological ages performed worse on tests of physical, cognitive, perceptual, and subjective functioning. Further, MIDUS participants with history of childhood-trauma and mental-health problems were measured as having increased AL and BA. Alternative AL formulations tended to have effect-sizes equivalent to or larger than those observed for BA measures. In conclusion, indices of allostatic load and biological age approximate similar processes when constructed with comparable biomarkers and rigor, in line with their conceptual overlap as proxies of cumulative wear and tear."} {"text": "Background: Hypoglossal nerve stimulators (HNS) are an increasingly popular form of upper airway stimulation for obstructive sleep apnea (OSA) in adults who are unable to tolerate positive pressure treatment. However, HNS use is currently limited in the pediatric population. Case presentation: We present a case series detailing the anesthetic management of three pediatric trisomy 21 patients receiving HNS for refractory obstructive sleep apnea. The patients tolerated the procedure well and experienced no complications. The average obstructive apnea\u2013hypopnea index (AHI) change was 87.4% with the HNS. Conclusions: Proper anxiolysis, safe and controlled induction, multimodal analgesia, and minimization of post-operative respiratory compromise are all necessary to ensure anesthetic and surgical success. After a tailored anesthetic regimen, proper device placement and close follow-up, our patients had a marked improvement in obstructive symptoms. Patients with trisomy 21 are predisposed to an increased risk of obstructive sleep apnea (OSA) at baseline with as many as 70% meeting criteria ,4. PersiThe HNS is one of several implantable devices that aims to improve upper airway obstruction . The proA previous case series of twenty pediatric trisomy 21 syndrome patients receiving HNS has been published examining post-operative efficacy and safety . HoweverWe present the anesthetic management of the first three patients receiving an HNS at our institution. This manuscript adheres to the applicable EQUATOR guideline. Three patients, two female and one male, underwent hypoglossal nerve stimulator placement from 2017\u20132019 at Egleston Children\u2019s Hospital of Children\u2019s Healthcare of Atlanta as part of trial NCT02344108, \u201cA Pilot Study to Evaluate the HNS in Adolescents with Down Syndrome and OSA.\u201d Currently, HNS use in pediatric populations is still investigational under the Federal Drug Administration. All legal guardians for the subjects gave their informed consent for inclusion prior to participation in this case series.Baseline demographic characteristics are presented in All patients were diagnosed with severe refractory OSA despite previous surgery and non-invasive positive pressure ventilation (NIPPV). The previous surgeries included tonsillectomy and adenoidectomy (two patients) as well as lingual tonsillectomy with turbinate reduction and adenoidectomy (one patient). Despite surgical intervention, all patients then required NIPPV therapies including continuous positive airway pressure (CPAP) in two patients and bi-level positive airway pressure (BiPAP) in one patient. All patients failed NIPPV due to poor compliance, primarily caused by inability to tolerate the CPAP or BiPAP device. Each patient underwent a drug induced sleep endoscopy prior to HNS to characterize their residual OSA. Two patients received premedication with oral midazolam for pre-operative anxiety See . One patThe average case length was 244 min (range 227\u2013260 min). Intra-operative courses were overall uneventful. Glycopyrrolate was used for secretions in two patients. One patient received bolus doses of 0.32 mcg/kg epinephrine and 0.08 mg/kg ephedrine for transient bradycardia. Multimodal analgesia was used in all patients and all All patients were extubated \u201cdeep\u201d during stage 3 of anesthesia, transferred to the post-anesthesia care unit (PACU), and placed on blow-by oxygen supplementation. One patient required post-operative oral airway placement, and one patient was placed on his home NIPPV. One patient required post-operative fentanyl and dexmedetomidine for residual pain in PACU. There was no reported post-operative nausea or vomiting. All patients were transferred to the floor for post-operative observation. No anesthetic complications were noted on follow-up. There were no reported complications to the Federal Drug Administration as no serious adverse events occurred at our institution. On follow-up PSG, all patients had notable improvement see . The aveThis case series specifically addresses the anesthetic management of HNS implants in pediatric trisomy 21 patients with refractory OSA. The patients tolerated the procedure well despite their pre-existing conditions, refractory OSA, and relatively prolonged case time. The unique nature of anesthetic management for HNS placement is in the balance between addressing the high-risk patient and operative factors with minimizing respiratory depression and adequately controlling pain. While the majority of our recommendations follow known anesthesia tenants for the care of trisomy 21 patients with OSA, we feel like our recommendations vary in three major ways: the use of premedication, inhalational induction, and deep extubation.Providing appropriate anxiolysis for parental separation in this patient population is essential. To balance preexisting OSA with the need for preoperative anxiolysis, we found judicious midazolam premedication beneficial in certain patients. Parental presence inductions or other sedative premedications are reasonable alternatives. However, caution should be exercised when administering any sedative medication to this patient population due to theoretical concern of airway obstruction. When sedative premedication is used, either continuous pulse oximetry or direct observation by the anesthesia team is recommended. Inhalational inductions are common in pediatric anesthesia in the United States and are to be used with caution in patients with a high risk of airway obstruction. Airway obstruction during stage 2 of an inhalational induction can limit oxygenation and ventilation, especially in a patient with known OSA. However, patients with trisomy 21 may benefit from an inhalational induction as it avoids awake intravenous line placement, anxiety, and fear of medical procedures. Our patient population had minimal obstruction with inhalational induction despite their refractory OSA. We believe that a smooth and controlled inhalational induction is a safe alternative in these patients. Certain equipment should be immediately available including nasopharyngeal and oropharyngeal devices, CPAP capabilities, intubating materials, and intramuscular doses of emergency medications including paralytic.The intra-operative components attempt to mitigate patient and surgical factors to optimize postoperative patient comfort and safety. We found that the use of primarily short-acting opioids such as fentanyl, multimodal pain control with dexmedetomidine and ketorolac, as well as local anesthetic injected by the surgeon at an insertion site provide satisfactory pain control while avoiding respiratory depression. Other key factors we have recognized include utilizing short-acting inhaled anesthetics such as sevoflurane to ensure timely emergence after deep extubation. We believe that low-dose dexamethasone can decrease the risk of postoperative tongue edema while also synergistically working with ondansetron to prevent post-operative nausea and vomiting, which has the potential to result in subsequent lead dislodgement . Other specific anesthetic considerations include placement of monitors and lines opposite of the operative side to avoid complications with use and secure endotracheal tube taping as the bed is turned 180 degrees. Neuromuscular blocking agents are avoided and bite block placed due to intra-operative nerve monitoring. Eye lubrication and careful pressure point padding is required given the case length. Given that sensing lead placement may be complicated by violation of the pleural space, nitrous oxide should be avoided once induction is complete.Despite the risk of postoperative airway obstruction, operative factors make extubation under a deep plane of anesthesia preferable. The coughing and bucking associated with awake extubation has the potential to cause significant impairment such as a post-operative airway hematoma or HNS lead dislodgement. While no surgical complications occurred in our group, a previous case series on HNS cite a surgical complication risk up to 10% [None of the patients experienced anesthetic complications despite their refractory OSA. There were no airway difficulties or significant post-operative respiratory depression that was not able to be managed with supplementary oxygen or home NIPPV. One patient experienced transient bradycardia without hypotension that was not associated with inhalational induction. While bradycardia is common in trisomy 21 patients during inhalational induction, this bradycardia was not thought to be related due its timing in the maintenance phase of anesthesia . The occPatient selection is an important consideration for success of this procedure. Appropriate patients should have high functional capacity with responsible and involved caretakers. As the device requires on/off capabilities, patients should be monitored during use of the device. Close follow-up immediately after implantation can identify early problems and maximize successful use. Our patients had excellent response to the HNS placement with an improvement in the obstructive AHI, meeting or exceeding previously reported percentages ,13.Pediatric trisomy 21 patients with refractory sleep apnea who present for HNS are a growing population ,13. Prop"} {"text": "Probabilistic Programming offers a concise way to represent stochastic models and perform automated statistical inference. However, many real-world models have discrete or hybrid discrete-continuous distributions, for which existing tools may suffer non-trivial limitations. Inference and parameter estimation can be exceedingly slow for these models because many inference algorithms compute results faster (or exclusively) when the distributions being inferred are continuous. To address this discrepancy, this paper presents Leios. Leios is the first approach for systematically approximating arbitrary probabilistic programs that have discrete, or hybrid discrete-continuous random variables. The approximate programs have all their variables fully continualized. We show that once we have the fully continuous approximate program, we can perform inference and parameter estimation faster by exploiting the existing support that many languages offer for continuous distributions. Furthermore, we show that the estimates obtained when performing inference and parameter estimation on the continuous approximation are still comparably close to both the true parameter values and the estimates obtained when performing inference on the original model."} {"text": "Orofacial pain comprises multiple pain conditions that affect oral, head, face, and neck area. Such pain can be divided into different types based on its origin, including neuropathic, musculoskeletal, neurovascular, psychogenic, and idiopathic pain. Patients with orofacial pain often show sex differences with high prevalence in women. However, mechanisms underlying orofacial pain conditions and their sexual dimorphism remain elusive. With obvious differences in anatomical structures, gonadal hormones, and immune responses between males and females, it is proposed that these factors contribute to sexual dimorphism in orofacial pain. In the Special Research Topic entitled \u201cMechanisms of Orofacial Pain and Sex Differences,\u201d we collected six relevant articles. These studies provide new insights into understanding orofacial pain and may aid target identification for future development of sex-specific therapies for orofacial pain.Bereiter et al.) investigated the effects of ovarian hormones progesterone and allopregnanolone on estrogen-exacerbated nociception in TMJ inflammation model. Using a complete Freund's adjuvant-induced TMJ inflammation model, they observed that ovariectomized female rats show reduced nociceptive behavior in the TMJ inflammation model and daily administration with estradiol benzoate causes recurrence of the nociception in the TMJ, which is rapidly attenuated by the treatment with progesterone or allopregnanolone. This study suggests that supplying progesterone or its metabolite allopregnanolone when gonadal hormone levels get lower may be an effective approach to treating estrogen-evoked inflammatory TMJ pain. It has been demonstrated that estrogen plays a critical role in the pathogenesis of TMD pain. Besides ovarian sources, estrogen can also be synthesized in brain neurons. Interestingly, acute stimulation of nociceptors in the TMJ enhances estradiol secretion in the trigeminal subnucleus caudalis in a sex-dependent manner . In a varicella zoster virus infection-induced postherpetic trigeminal neuropathic pain model, aromatase-derived estradiol attenuates such orofacial nociception by interacting with estrogen receptors to increase \u03b3-aminobutyric acid-mediated neuronal inhibition in the thalamus . In addition, pituitary hormones can regulate nociceptive transmission in different orofacial pain conditions and may contribute to sex-dependent mechanisms of orofacial pain by intermodulation with gonadal hormones .Temporomandibular disorders (TMDs) are associated with chronic orofacial pain, which includes myofascial and/or Temporomandibular Joint (TMJ) pain. Women report TMD pain around three times more than men. Previous studies have demonstrated sex differences and sex hormonal effects in peripheral and central mechanisms of orofacial pain .In a masseter muscle tendon ligation-induced myogenic orofacial pain model, it has been reported . In an immune-competent oral cancer mouse model, neutrophil-mediated endogenous analgesia occurs only in male mice , suggesting that this immune cell-mediated endogenous analgesia for treating oral cancer pain is sex-specific.Additionally, in an oral cancer patient cohort, sex differences in prevalence and severity of oral cancer pain have been identified (In conclusion, giving that there are sex differences in the underlying mechanisms of orofacial pain, we need to consider outcome measurements for each sex in future animal studies and clinical investigations of such pain conditions. Further understanding of sexual dimorphism in orofacial pain will help us develop sex-selective pain therapies and improve pain management for patients with chronic orofacial pain.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Previous research has shown that despite experiencing more negative life events, older adults maintain relatively high levels of well-being compared to their younger counterparts. This effect appears to be at least partially mediated by trait mindfulness in older adults . The current study expanded into an investigation as to how trait mindfulness might intervene on the relationship between age and other well-being indicators: anxiety and depressive symptomology. Participants included 30 older adults (aged 60-83) and 41 young adults (aged 18-35). Trait mindfulness was examined using the Mindful Attention Awareness Scale (MAAS), while depressive symptoms and trait anxiety were measured using the Center for Epidemiological Studies Depression Scale (CES-D) and the State-Trait Anxiety Inventory (STAI), respectively. Two separate mediated multiple regression models were conducted using Hayes\u2019 PROCESS Macro in SPSS. Trait mindfulness exhibited a significant indirect effect on the relationship between age and depressive symptoms , which was also seen for the relationship between age and trait anxiety . Older age predicted higher trait mindfulness, which in turn predicted diminished self-reported anxiety and depressive symptomology. Controlling for mindfulness in these models reduced the direct effect of age on depression and anxiety to non-significance. These findings imply that the relationship between age and trait mindfulness can be extended to alternative markers of well-being."} {"text": "Social ecological models of health identify intrapersonal, interpersonal, institutional, community, and policy-level contexts as social factors influencing individual and population health outcomes. However how institutions such as Area Agencies on Aging (AAA) shape rural older adults\u2019 social networks and influence health is little explored. This research examines institutional influences of social networks for rural older adults, particularly the social connections resulting from their AAA services and programs. AAAs are local social service organizations that coordinate home- and community-based supports. Our 2020 case study of a rural AAA in upstate New York involved in-depth semi-structured interviews with AAA staff, volunteers and participants included key themes related to older adults\u2019 social networks, social wellbeing, and physical and mental health. Our findings have both theoretical implications for rural community social structure as experienced by older adults, and practical implications to build AAA\u2019s capacity to address social isolation for rural older adults. Part of a symposium sponsored by the Rural Aging Interest Group."} {"text": "Because prescribing practices in long-term care settings may reflect regional influences, we examined how potentially inappropriate antipsychotic and antianxiety medication prescribing in assisted living (AL) compared to prescribing in nursing homes (NHs) based on their proximity, using generalized linear models adjusting for facility characteristics and state fixed effects. Data were derived from a seven state sample of AL communities and data for the same seven states drawn from publicly available data reported on the Nursing Home Compare website. In adjusted analyses, AL rates of antipsychotic use were not associated with the rates in the nearest or farthest NHs. However, AL communities that were affiliated with a NH had lower rates of potentially inappropriate antipsychotic use . In a separate model, antianxiety medication prescribing rates in AL were significantly associated with neighboring NHs\u2019 rates of prescribing . Findings suggest efforts to change prescribing in NHs may influence prescribing in AL."} {"text": "The COVID-19 pandemic and the subsequent lockdown brought about an exogenous and unparalleled stock market crash. The crisis thus provides a unique opportunity to test theories of environmental and social (ES) policies. This paper shows that stocks with higher ES ratings have significantly higher returns, lower return volatility, and higher operating profit margins during the first quarter of 2020. ES firms with higher advertising expenditures experience higher stock returns, and stocks held by more ES-oriented investors experience less return volatility during the crash. This paper highlights the importance of customer and investor loyalty to the resiliency of ES stocks."} {"text": "Exposure to maltreatment during childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) is associated with telomere length (TL) in adult females. We further tested the hypothesis of intergenerational transmission of trauma by measuring TL in both CSA-exposed and non-exposed mothers and their children. TL was measured in a subset of participants and their children from a prospective-longitudinal cohort study of sexually abused females and a demographically matched comparison group. Linear regression models were used to test for associations between CSA-exposure and age-adjusted TL in females . Multilevel linear models were used to test the intergenerational effect of maternal-CSA exposure on age-adjusted TL in their children (N=124 children mean age 10.5 years across 61 mothers). CSA-exposure was not associated with TL in females. Replicating previous work in this area, maternal TL and sex were significant predictors of child TL in all models tested. Longer maternal TL predicted longer TL in children, and female children had longer TL than male children. Maternal-CSA exposure did not predict TL in children. This finding is in line with some previous results on CSA and TL measured in adulthood. Previous significant results associating child maltreatment with shorter TL in adulthood may be capturing a population of individuals exposed to either multiple types of maltreatment or maltreatment in childhood with concurrent TL measurements."} {"text": "Measles is a highly contagious respiratory disease; both locally acquired and travel-associated cases continue to occur across the United States after the exposure (The patient recovered and was discharged home from the hospital on April 27. None of his contacts developed measles, and no additional cases were identified through heightened surveillance, which included monitoring ED syndromic surveillance data in ESSENCE-FLThe Advisory Committee on Immunization Practices recommends that adults without documentation of measles immunity who are traveling internationally receive 2 documented doses of measles, mumps, and rubella virus vaccine ("} {"text": "Protamine sulfate is a common reversal agent of systemic heparinization used during procedures. While the exact epidemiology of adverse events is unknown, prior allergic response to protamine-containing compounds or concomitant use of neutral protamine Hagedorn (NPH) insulin is associated with an increased risk of tachyarrhythmias and bradyarrhythmias. We present a case of a 68-year-old woman with no prior history of protamine sulfate intolerance that suffered bradycardic arrest following protamine infusion.Healthcare providers should recognize the potential for life-threatening tachyarrhythmias and bradyarrhythmias following protamine reversal, especially in diabetic patients at risk for autonomic dysfunction; medication and allergy review are encouraged prior to heparin reversal, especially in diabetic patients. Protamine sulfate is a cationic polypeptide that binds to negatively charged unfractionated heparin and can be used to decrease the risk of bleeding during procedures in patients with systemic heparinization . Though A 68-year-old female with a past medical history of hypertension, peripheral artery disease, and type 2 diabetes complicated by peripheral neuropathy underwent a peripheral angiographic intervention on an occluded left femoral arterial stent, after which she received 20 mg of protamine. During the postoperative period, she experienced bradycardia and hypotension progressing to cardiac arrest. Cardiac monitoring at the time indicated no ventricular arrhythmias. Advanced cardiac life support (ACLS) was initiated and the patient received three rounds of epinephrine prior to transport to the emergency department (ED).In the ED, initial evaluation demonstrated agonal cardiac activity on cardiac ultrasound. The patient received three more rounds of epinephrine, two amps of bicarbonate, and one gram of calcium chloride. The initial cardiac monitoring demonstrated pulseless electrical activity, which progressed to ventricular fibrillation. Defibrillation was performed, resulting in the return of spontaneous circulation (ROSC).The patient was admitted to the medical intensive care unit. She was determined to be neurologically intact and targeted temperature management was not initiated. Medical history was notable for insulin NPH use. She had no prior allergic reaction to NPH, exposure to protamine sulfate, or history of food allergies.Labs showed a rise and fall in troponin I with a peak value of 6.21 mcg/L (reference range \u22640.030 mcg/L). Initial electrocardiogram (ECG) after ROSC showed diffuse ST depression suggestive of subendocardial ischemia and potential medication reactions. Healthcare providers should recognize the potential for bradyarrhythmias and tachyarrhythmias before protamine administration, particularly in diabetic patients."} {"text": "Coronary involvement is rare but can be critical in patients with aortitis. Although cardiac ischemia can be resolved by coronary artery bypass grafting (CABG), patients complicated with cardiac ischemia, calcified aorta, and valve insufficiency pose difficult problems for surgeons.A 71-year-old woman was referred to our institution because of unstable angina. She had been previously diagnosed with aortitis and left subclavian artery occlusion. Contrast-enhanced computed tomography revealed severe left coronary main trunk stenosis, right coronary artery occlusion, and porcelain aorta. Ultrasonic echocardiogram showed severe aortic regurgitation. We performed emergent coronary artery bypass grafting, aortic valve replacement and ascending aorta replacement under hypothermic circulatory arrest.The technique of circumferential calcified intimal removal and reinforcement with felt strips was effective for secure anastomosis. Unilateral cerebral perfusion from the right subclavian artery enabled good visualization and sufficient time to perform distal anastomosis. Coronary involvement is rarebit can be critical in patients with aortitis. Although cardiac ischemia can be resolved by coronary artery bypass grafting (CABG), patients complicated with cardiac ischemia, calcified aorta, and valve insufficiency pose difficult problems for surgeons. We present a 71-year-old woman with left main coronary trunk stenosis, occluded right coronary artery, left subclavian artery occlusion, severe aortic valve regurgitation and porcelain aorta with aortitis.A 71-year-old woman was transferred to our institution because of unstable angina. She had been previously diagnosed with aortitis and left subclavian artery (LSCA) occlusion. Her past medical history included hypertension and dyslipidemia. Twelve-lead electrocardiogram showed marked ST-segment depression in the precordial and inferior leads. Contrast-enhanced cardiac computed tomography (CT) revealed severe left coronary main trunk (LMT) stenosis, which had not been detected 9\u2009months previously, right coronary artery (RCA) occlusion which had occurred previously Fig.\u00a0. These fAdditional file 1.Takayasu\u2019s arteritis (TA) is a chronic, granulomatous vasculitis that causes stenosis, occlusion and ectasia of the aorta and its branches. Although coronary involvement is rare, it can be critical. Coronary ostial stenosis (COS) with normal distal part of the artery is a specific feature of TA.In our case, the patient had not been in the active phase of TA for years. LMT stenosis progressively worsened over 9\u2009months. It is not clear whether LMT stenosis in our patient was associated with TA, because stenosis occurred in the distal part of LMT, and not at the coronary ostium. In view of her diagnosis of dyslipidemia, this might have caused LMT stenosis over a short time period.We had to perform emergent CABG because jeopardized left main coronary artery supplying the chronically occluded RCA caused global ischemia of the entire heart. Although percutaneous coronary intervention (PCI) for LMT stenosis can relieve ischemia quickly, it can be more dangerous compared with CABG because the RCA is already occluded and receives blood supply from the left coronary artery. Furthermore, PCI is not able to solve AR. Although the internal thoracic artery (ITA) is commonly used for CABG, it might not be adequate in patients with Takayasu\u2019s arteritis because stenosis often occurs in the subclavian artery. However, the ITAs have been used in young patients in whom the subclavian arteries did not have stenosis , 2. AlthAnother issue is calcified aorta, which is always a concern when surgeons try to clamp it. Transcatheter aortic valve insertion (TAVI)\u2009+\u2009off-pump CABG is the procedure of choice for patients with aortic valve stenosis, porcelain aorta and coronary ostial stenosis . HoweverAnother issue is how to acquire good visualization of the proximal arch during hypothermic circulatory arrest. The proximal aortic arch was severely calcified, and its diameter was normal. Usual elasticity of the aorta was lost. It seemed difficult to obtain good visualization and enough time to apply the abovementioned technique using usual antegrade selective cerebral perfusion (ASCP) in which three perfusion cannulas are inserted into the innominate artery, left common carotid artery and LSCA, respectively. We considered that three cannulas in the calcified proximal aortic arch with normal size would prevent us from performing any maneuvers. Although controversy exists whether UCP can provide sufficient blood supply to both the left and right hemispheres compared to usual ASCP, we believe it is acceptable in emergent surgery . In factAlthough the patient did not have active phase TA, LMT stenosis progressively worsened over a short period. The technique of circumferential calcified intimal removal and reinforcement with felt strips was effective for secure anastomosis and avoiding bleeding from the suture holes in the porcelain aorta. UCP from the RAXA provided good visualization and sufficient time to perform distal anastomosis."} {"text": "Nearly 48 million individuals worldwide have a neurocognitive disorder with projections estimating that as many as 75 million may be afflicted by 2050.Although approximations vary, a substantial portion of those affected live in the community alone, accounting for up to one-third of cases. The true proportion of persons with neurocognitive disorders living alone in the community may be underestimated as dementias are often underdiagnosed and underreported. As the baby boom generation ages and trends towards nuclear families, geographic dispersion of families, and fewer children continue, the number of live-alone persons with neurocognitive impairment is anticipated to rise; creating increased potential for difficult, ambiguous circumstances involving the rights and needs of this population. Despite these trends, available information about this population remains limited. This symposium represents papers from social gerontology, bioethics, and policy; offering unique, but complimentary perspectives on live-alone persons with neurocognitive impairment. The four papers explore 1) how non-traditional & absent support networks impact one\u2019s ability to live alone with dementia [NIA funded], 2) social isolation and vulnerabilities of living alone with dementia [NIA-funded], 3) how bioethics can inform gerontological dementia research [NIA bioethics supplement], and 4) exploration of how law enforcement and adult protective services policies influence the precarity of living alone with dementia. Together, these papers illuminate the importance of actively including live-alone persons with dementia into research and assessing this overlooked vulnerable population from multiple research perspectives ."} {"text": "A substantial number of studies have documented paradoxical findings when examining race differences in later life psychological well-being. Despite experiencing significant structural disadvantages, Black older adults have been found to report significantly higher overall life satisfaction and lower depressive symptoms than White adults. This study relies on double consciousness framework which allows us to understand why satisfaction with material conditions among Black older adults could differ from their evaluation of overall well-being . Based on a survey of successful aging (n=409 aged 60 years or older) conducted by the Elderly Care Research Center (ECRC) in Cleveland, Ohio, we examined race differences in coping resources, and their role in shaping overall life satisfaction, domain-specific life satisfaction, and depressive symptoms. Findings show that Blacks on average have a higher likelihood of experiencing recent negative life events than their White counterparts. Despite adverse life circumstances, Blacks older adults expressed significantly higher overall life satisfaction than Whites. They, however, reported significantly lower domain-specific life satisfaction than their White counterparts. The differences in depressive symptoms between Black and White older adults was not statistically significant. The race differences in overall life satisfaction was explained by religiosity, religious coping, and social support. Education, income, and adverse life events were found to contribute to such differences in domain-specific life satisfaction. Our findings underscore the need to consider the unique role of racialized life course circumstances and coping resources in shaping disparities in later life psychological well-being."} {"text": "Older adults make up the majority of the U.S. patient population and age differences in information avoidance have potential implications for their ability to participate in informed medical decision making. Meta-analytic evidence suggests that older adults seek less information before making a decision than younger adults do . However, age differences in explicit information avoidance have yet to be quantified. We hypothesized that older adults would avoid decision-relevant information more strongly than younger adults do. We also examined the self-reported reasons for information avoidance and hypothesized that older adults would express more concern about unwanted information influencing their affect and decision preferences , both of which are known predictors of information avoidance . To test these assumptions, we conducted a pre-registered online study involving three different health-related decision scenarios. For each scenario, an adult lifespan sample chose to either receive or avoid information. Responses were highly correlated across scenarios and results were pooled into a single avoidance measure. Analyses indicated that concerns about consequences for decision preferences positively predicted decision avoidance (p<.001), whereas concerns about consequences for affect did not (p=.079). Contrary to predictions, older age was not significantly associated with information avoidance (p=.827). Further, self-reported concerns about the influence of unwanted information on affect and decision preferences were negatively associated with age (ps<.001). This suggests that interventions to foster pre-decisional information seeking should be tailored to the target age group."} {"text": "The recent opioid crisis is one of the rising challenges in the history of modern health care. New and effective treatment modalities with less adverse effects to alleviate and manage this modern epidemic are critically needed. The FDA has recently approved two non-invasive electrical nerve stimulators for the adjunct treatment of symptoms of acute opioid withdrawal. These devices, placed behind the ear, stimulate certain cranial nerves with auricular projections. This neural stimulation reportedly generates a prompt effect in terms of alleviation of withdrawal symptoms resulting from acute discontinuation of opioid use. Current experimental evidence indicates that this type of non-invasive neural stimulation has excellent potential to supplement medication assisted treatment in opioid detoxification with lower side effects and increased adherence to treatment. Here, we review current findings supporting the use of non-invasive neural stimulation in detoxification from opioid use. We briefly outline the neurophysiology underlying this approach of auricular electrical neural stimulation and its role in enhancing medication assisted treatment in treating symptoms of opioid withdrawal. Considering the growing deleterious impact of addictive disorders on our society, further studies on this emerging treatment modality are warranted. Approximately 36 million people are affected with opioid use disorder globally , the distress in the first few days after abrupt discontinuation can be rather severe. Without adequate treatment, many patients are unable to complete opioid discontinuation . This stimulation provides relief from symptoms associated with opioid withdrawal, including cravings, anxiety, agitation and depression. The device can be worn up to 5\u00a0days at a time, and company officials report that symptoms have eased within an hour of wearing the device.Relatively recently, in June 2018, an additional auricular stimulation device, the \u201cDrug Relief\u201d aural neurostimulator mobile health device, developed by DyAnsys, also received FDA 510(k) premarket approval for patients dealing with opioid addictions (Fig.\u00a0Pain and emotional disturbances are common symptoms during opioid withdrawal. Of note, auricular neural stimulation had been used for chronic pain management with success in various health settings (e.g., reviewed in (Chen et al. Experimental evidence indicates that non-invasive device-generated auricular neural stimulation of certain cranial nerves, primarily vagus nerve, provides an innovative approach to alleviate opioid withdrawal symptoms. This approach may specifically help expedite the recovery phase during acute detoxification from opioids. This can ultimately reduce the need of supportive medications and can facilitate smooth transition from detoxification to commencing medication-assisted treatment in opioid dependent patients. This treatment modality has so far been associated with only minor local side effects at the device placement site. While this non-invasive modality appears to be an exciting new opportunity in alleviating the current opioid epidemic, more studies are clearly needed to further validate the potential of this intervention and support its use with the hope of helping our patients and their families."} {"text": "Portal vein thrombosis (PVT) poses a unique challenge in liver transplant. The management of PVT differs according to the extent of thrombosis. Anastomosis of a donor portal vein to a varix is a viable option when an adequate size varix is identified on preoperative imaging or intraoperatively. Here, we describe our experience in two liver transplant cases with cavernous transformation of the portal vein where the donor portal vein was anastomosed to a varix using a donor iliac vein interposition graft. In 1985, Shaw and colleagues described successful liver transplantation in seven patients with severely reduced or absent portal flow, and since that time, portal vein thrombosis (PVT) has no longer been considered an absolute contraindication to liver transplantation . As fibrOur first patient was a 58-year-old male with primary biliary cirrhosis and nonalcoholic steatohepatitis. Portal flow was not visualized on preoperative Doppler ultrasound. Contrast enhanced CT demonstrated complete PVT with cavernous transformation and clotOur second case was a 61-year-old male with cryptogenic cirrhosis and hepatocellular carcinoma. Preoperative imaging revealed cavernous transformation with numerous portal venous collaterals most prominent in the paraesophageal and periIntraoperative portal vein thrombovenectomySMV jump graftingEstablishing renal-portal inflow from left renal vein and donor ileac vein conduitVarix-to-portal anastomoses with or without conduitPortacaval transpositionPortal vein thrombosis can range from mild partial nonocclusive thrombus to complete occlusion with cavernous transformation, and varied surgical techniques are required to handle each scenario . QualityIn all cases, we consider left renal vein ligation or ligation of other collateral vessels to enhance portal inflow. Preoperative IR-guided portal vein recanalization has been described , as has Physiologic portal inflow is associated with better 1-, 5-, and 10-year outcomes than any alternative described , and theIn summary, successful surgical management of PVT requires preoperative imaging, thoughtful planning, surgical creativity, and adherence to a practice-based algorithm for establishing portal inflow."} {"text": "Providing interprofessional geriatric care via telehealth is a unique clinical skillset that differs from providing face-to-face care. The lack of clear guidance on telehealth best practices for providing care to older adults and their care partners has created a systems-based practice educational gap. For several years, GRECC Connect has provided interprofessional telehealth visits to older adults, frequently training interprofessional learners in the process. Using our interprofessional telehealth expertise, the GRECC Connect Education Workgroup created telehealth competencies for the delivery of care to older adults and care partners for interprofessional learners. Competencies incorporate key telehealth, interprofessional and geriatric domains, and were informed by diverse stakeholders within the Veterans Health Administration. During this symposium, comments will be solicited from attendees. Once finalized, these competencies will drive the development of robust curricula and evaluation measures aimed at training the next generation of interprofessional providers to expertly care for older adults via telehealth."} {"text": "Changing age demographics are reshaping societies and challenging institutions of higher education to consider how they can respond to aging populations through new approaches to teaching, research, and community engagement. As well, institutions are facing a range of challenges as they look to respond to the contemporary needs of traditional-aged students. The pioneering Age-Friendly University (AFU) initiative, endorsed by GSA\u2019s Academy for Gerontology in Higher Education (AGHE), offers a framework within which institutions can begin to address these issues through more age-friendly programs, practices, and partnerships. This symposium will feature AFU advocates discussing innovate ways in which older adults can serve as teaching allies and support the educational mission of higher education. Farah (Lasell University) will discuss how older adults can engage in diverse teaching and learning activities with examples as crime scenario developers in a forensics class, conversation partners in an international oral communication class, and professional interviewers in an internship skills class. Kaye (University of Maine) will discuss how older adults can serve as citizen scientists performing critical functions in participatory research and in community-based test-beds and co-design laboratories. Ermer (Montclair State University) will discuss how older adults can engage students in discourse as guest speakers and panel participants in classes across the curriculum. Manoogian (Western Oregon University) will describe the innovative ways that older adult students (for credit or audit) mentor and engage younger student peers in course activities as well as increase their own understanding of the aging process."} {"text": "Liquid biopsy has emerged in the last ten years as an appealing noninvasive strategy to support early cancer diagnosis and follow-up interventions. However, conventional liquid biopsy strategies involving specified biomarkers have encountered unexpected inconsistencies stemming from the use of different analytical methodologies. Recent reports have repeatedly demonstrated that integrated detection of multiple liquid biopsy biomarkers can significantly improve diagnostic performance by eliminating the influence of intratumoral heterogeneity. Herein, we review the progress in the field of liquid biopsy and propose a novel integrated liquid biopsy framework consisting of three categories: elementary, intermediate, and advanced integration. We also summarize the merits of the integration strategy and propose a roadmap toward refining cancer diagnosis, metastasis surveillance, and prognostication. Bodily fluids, such as blood, urine, cerebrospinal fluid, and saliva, contain numerous biomarkers corresponding to patient-specific pathological information. From the perspective of biodetection, any biomarkers that are highly associated with tumor growth and metastasis, including circulating proteins (CPs), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), extracellular vesicles (EVs), circulating tumor cells (CTCs), and tumor-educated blood platelets (TEPs), can be indicators of carcinomas. Liquid biopsy has been recognized as one of the most promising strategies for conquering cancers owing to its unparalleled advantages over classical solid biopsy in improving patient compliance, partially due to its noninvasive sample collection and reduced potential for surgical complications e.g., protein-protein, RNA-RNA or DNA-DNA combinations e.g., protein-DNA combinations This review will intensively discuss the hurdles facing liquid biopsy prior to its clinical application and propose potential solutions. Here, we propose a novel analytical framework, termed \u201cintegrated liquid biopsy\u201d, that could be a useful toolkit bridging conventional liquid biopsy and clinical requirements. \u201cIntegrated liquid biopsy\u201d is defined as integrating multiple liquid biopsy biomarkers or detection methods for improved analytical sensitivity and specificity to refine cancer management. Since a single biomarker is inefficient in accurately identifying most cancers, integrated liquid biopsy using multiple markers might be a promising method to facilitate early detection and treatment of cancer. According to the complexity of the combined data types, we categorize integrated liquid biopsy into the following three groups: 1) Elementary integration refers to the combination of biomarkers or methods of the same type,e.g., CA19-9, CEA, AFP, and prostate-specific antigen (PSA)) achieved prevalence due to its convenience and low cost + exosomes containing diverse RNA and proteins may distinguish healthy subjects from patients with pancreatic cancer Liquid biopsies have been regarded as robust tools for routinely screening and identifying tumors before symptoms appear. Historically, the detection of a single CP mutations and CA19-9 provided an improved sensitivity of 64%, compared to 30% for KRAS alone Regarding intermediate integration, CP-ctDNA integration is particularly attractive because ctDNA indicates specific genetic alterations and because the relatively high concentrations of CPs compensate for the drawback of low ctDNA abundance. Joshua et al. reported that the conjunction of Despite the popularity of liquid biopsy in a clinical setting, the conventional detection of a single biomarker has encountered numerous obstacles in assessing samples with tissue or organ heterogeneity. These reported discrepancies among different detection approaches primarily originate from the small amounts and easy degradability of these biomarkers, features that severely compromise their value in indicating abnormal clonal cell proliferation. The latest studies have revealed that a CP-ctDNA integration strategy significantly improves the sensitivity of earlier cancer detection without substantially decreasing specificity. Additionally, integrated assays of CPs and genetic alterations further localize the original organs of these cancers, which could greatly benefit further therapy. Meanwhile, the CP-ctDNA integration concept could be expanded to other liquid biomarkers, such as metabolites, mRNA transcripts, miRNAs, methylated DNA sequences, or markers in EVs to increase the efficiency of early cancer detection.N-ras and phosphatidylinositol 3-kinase mutations in ctDNA can predict drug resistance against monoclonal antibodies targeting EGFR, potential negative errors have been observed due to biological heterogeneity Surviving cancer cells tend to develop drug resistance due to mutation and evolutionary selection when different therapeutic means are employed on heterogenic tissues Figure 33. TherEGFR mutation detection in plasma, and significant improvement was observed in NSCLC patients without distant metastasis EGFR T790M detection, overcoming the limitation of low T790M abundance in the blood (58% sensitivity and 80% specificity using an FDA-approved cobas\u00ae test) Integrated liquid biopsy might be an effective means of eliminating such discrepancies and probing unknown mutations. RNA-seq is a typical form of detection included in elementary integration, and a recent ctDNA profiling method known as cancer personal profiling by deep sequencing (CAPP-seq) found a high frequency of inter- and intrapatient heterogeneity in resistance mechanisms after initial EGFR tyrosine kinase inhibitor therapy Dozens of studies employing integrated liquid biopsy have demonstrated its effectiveness in improving the sensitivity of cancer diagnosis, suggesting that this strategy is ideal for cancer management. Therefore, it is highly desirable to elucidate the biological origins and mutual interactions of different biomarkers in anticipation of clinical applications.CPs are secreted from diverse human cells, including immune cells and tumor-associated cells, and were the first such biomarkers to be exploited and commercialized. The demonstrated high specificity of CPs in reflecting tumor-associated characteristics makes them attractive for cancer surveillance. In contrast to CPs, ctDNA fragments are principally released from apoptotic or necrotic cells. Given the short circulating time of ctDNA (ranging from 16 min to 2.5 h), the dynamic and continuous monitoring of ctDNA fragments plays a paramount role in cancer prediction in vitro, it is necessary to use an indirect strategy involving an enrichment step prior to detection e EVs, comprising exosomes, microvesicles, and apoptotic bodies, are free-floating bodies enwrapped by lipid rafts and contain tumor-specific signatures of nucleic acids and proteins. Briefly, exosomes emerge by budding in multivesicular bodies and are released into the plasma by fusion of multivesicular bodies with the cell membrane, whereas microvesicles and apoptotic bodies are leaked from dying cells due to external stimulation. Notably, selective accumulation of certain functional mRNA, microRNA, and protein species in microvesicles can occur. In contrast to normal cell sprouting, CTCs are spontaneously released from primary tumors to the peripheral blood circulation, constituting seeds for subsequent metastases in distant organs epithelial cell adhesion molecule (EpCAM), human EGFR2, PSA and oncolytic viruses In vivo CTC enrichment using either an inserted metal wire or magnetic separation in vitro integration of biomimicry and nanotechnology have remarkably improved capture efficiency Integrating methods with distinctive principles to strengthen integrated liquid biopsy is likely the most reliable strategy for ideal cancer management. The quantification and characterization of CTCs/EVs represent major technological challenges in liquid biopsy due to the extremely low concentrations of these targets. All the methods developed to quantify CTCs and EVs in the peripheral blood could be categorized as biological or physical. Biological methods are typically based on antigen-antibody or ligand binding; these methods are involved in typical tests for + CTCs, which reduces cell adhesion and promotes polarization and metastasis. Meanwhile, platelets immediately adhere and mechanically protect CTCs from anoikis or destruction by forming a cell fibrin-platelet aggregate surrounding CTCs Tumorigenesis, metastasis and tumor evolution are the typical forms of cancer development, and the above-noted biomarkers can reflect the accumulation of either genetic mutations or epigenetic modifications Figure . During in vitroin silico target prediction.In summary, any detection approach based on a single biomarker reflects limited information that may result in misleading predictions regarding tumor progression. Thus, integrating multiple biomarker approaches provides comprehensive information that may compensate for the drawbacks of single biomarkers in facilitating early cancer detection and intervention Table . MeanwhiKRAS mutant cells effectively drive cancer progression after the suppression of the MEK1 mutant population by panitumumab and trametinib Early and accurate cancer diagnosis is the key to reducing the economic burden of cancer. Classical tissue biopsy has arguably presented a heavy burden according to US Medicare analysis: as of 2017, the average cost of a solid biopsy for lung cancer is $8,869, and the total cost per patient will reach $37,745 for the 20% of needle biopsies that lead to follow-up complications. Compared with single liquid biopsy alone, integrated liquid biopsy provides improved cost-effectiveness in the following ways. First, integrated liquid biopsy is less expensive per marker than its counterpart. For instance, the current cost for single ctDNA mutant detection with digital PCR is approximately $300, while the cost for elementarily integrated detection of all ctDNA mutants with DNA sequencing is < $1,000 with Illumina Several fundamental questions need to be answered prior to effective integration under physiological and pathophysiological conditions: What is the relationship between the degree of ctDNA variations and the RNA/protein abundance of hundreds of functionally coherent gene sets? What are the differences between primary circulating biomarkers such as ctRNA or CP and secondary biomarkers such as RNA/protein analysis from EVs or CTCs? Will different cancer stages and mesenchymal-to-epithelial transition (MET)) or tumor cell status (primary or circulating) significantly affect the spatial and temporal distributions of ctDNA or exoRNA? Understanding the gene regulatory networks of biomarker integration will lead to significant insights and has tremendous implications for cancer intervention and management. Therefore, for integration detection, the core purpose is to reflect the real developmental stage and increase therapy efficiency for cancer.How can users predict and confront the inconsistent results stemming from different biomarkers or detection methods in integrated detection? Considering the complexity of tumorigenesis, any single-marker-based diagnosis will have a risk of error, integrated detection may naturally increase the possibility of exposing these errors by presenting contradictory results, by which the error can be significantly reduced in further diagnosis.What types of integration could be optimal? Both elementary integration and intermediate integration can provide characteristic molecular profiles of cancers in the spatial scale. Advanced integration might provide integrated information in a higher dimension by combining these comprehensive evidences, including medical imaging, tissue diagnosis, and molecular profiling, to map the characteristics of a cancer in detail based on the complementarity of these results.How can we establish a risk prediction model using the acquired integrated data from a time series? Integration in the temporal domain will help us characterize the law of cancer progress or metastases. Therefore, combining the dynamic changes in various biomarkers with previous medical records would facilitate the prognosis analysis of cancers. It is highly plausible that this type of dynamic method focusing on the whole process, including patient diagnosis and treatment, will become the mainstream of prognostic analysis in the near future.KRAS mutation rate reached 94% in a pancreatic intraepithelial neoplasm population The feasibility of integrated liquid biopsy is largely guaranteed by the quality control and standardization of each detection method. In particular, the standardization of annotations resulting from liquid biopsy is challenging due to varied cohort compositions and diverse environmental factors when analyzing the same biomarker. For instance, noticeable discordance exists among different populations: the Integrated liquid biopsy produces data that are substantially more complicated than data from any single biomarker, requiring a canonical big data processing methodology. Deep learning has recently been introduced to assist with diagnostic and therapeutic decision making by reading patients' medical images Liquid biopsy has demonstrated unparalleled advantages over conventional tissue biopsy and medical images in terms of earlier cancer detection and better surveillance of cancer metastasis and prognosis. Different from conventional imaging approaches, which mainly reveal changes in tumor size, profiling the dynamic distribution of various tumor-associated molecular biomarkers may provide continuous genetic mutation information, which will reflect different cancer stages and provide improved guidance for clinical therapy. Furthermore, the rational integration of liquid biopsy, solid biopsy, and medical imaging would prevent discordance or disagreements caused by tumor heterogeneity or individualized analytical methodologies. This advantage would facilitate cancer prevention and early intervention.Integrated liquid biopsy covers both the integration of different detection methods and the combination of multiple biomarkers, including proteomics, genomic sequencing, and DNA methylation profiling, that could reveal mechanistic differences in the development of different cancers. During carcinogenesis, integrated biomarkers could provide an earlier diagnosis than any single biomarker alone. Furthermore, ctDNA could identify the position of the tumor by detecting DNA methylation in an accurate and noninvasive manner Socioeconomic factors should also be considered in the clinical implementation of the integrated liquid biopsy strategy. In the early stage, additional blood tests for enriching the database will carry relatively high costs. However, with the gradual growth of the database, we will benefit from the mathematical model as it provides increasingly accurate and specific guidance on cancer management."} {"text": "Globally, conservation efforts have moved millions of people out of protected areas since the 1970s, yet quantitative studies on post-resettlement well-being remain a challenge due to poor documentation. Since 2008, the Indian forest department records demographic and financial details at the household level under standardized guidelines for resettlement. Here, we examine the food security of approximately 600 households\u2019 post-resettlement from Kanha National Park (KNP) in central India between 2009 and 2014. We compare food security of resettled households with host community households with a total of 3519 household surveys, conducted over three seasons within one year. We measure food security using food consumption scores (FCSs), coping strategies index (CSI) and household hunger scale (HHS). Food insecurity is widespread in the landscape, with over 80% of households reporting poor or borderline FCSs year-round. Additionally, we recorded food insecurity increases in monsoon for all households regardless of resettlement status. Results indicate that resettled households are comparable to their host community neighbors in FCS and all households use mild coping strategies to combat food insecurity. While widespread, food insecurity in the KNP landscape is not acute with very few (<10) reports of severe hunger (as measured by the HHS). Almost all foods are market bought (>90%) and sometimes supplemented by gathering locally prevalent greens or from kitchen gardens (forest dependency for food was negligible). Accruing assets and diversifying incomes from non-labor avenues would alleviate food insecurity for all households. The patterns of market dependence and food security associated with diversified stable incomes around protected areas is in contrast with many studies but is likely to occur in similar human-dominated landscapes. Conservation-related resettlements trace back to the establishment of Yellowstone National Park in 1872 and spread rapidly with fortress management policies to conserve endangered species habitats. Globally recognized areas of high biodiversity are inhabited by more than a billion people and populations in these regions continue to grow at a rapid pace \u20135. In InUnderstanding the impacts of conservation-related resettlement on people requires meaningful measures of human well-being. Income based metrics of well-being are unidimensional and do not reflect livelihoods reliant on goods with little economic value (for example\u2013wild foods or self-provisioning via non-economic landscape resources) , 25. MorIn India, the current resettlement policy is explicit in its goal to resettle people to expand and maintain critical tiger habitats within 50 protected areas (Tiger Reserves) with detailed resettlement records and standardized compensations . ResettlWe explore food security at resettled households compared to their neighbors at their new settlement locations across the Kanha National Park landscape to answer the following questions:Are resettled households moving into remote areas compared to all existing villages in the study site, specifically with respect to\u2013road access, food markets and forest availability?Do resettled households have comparable Food Consumption Scores (FCSs) and Coping Strategy Index (CSI) measurements to their host community neighbors? , leopard (Panthera pardus), wild dog , sambar (Cervus unicolor), chital (Cervus axis), barasingha (Cervus duvaucelii) and gaur (Bos gaurus) . We. We51]. The FCS and CSI are weighted scores based on the food groups consumed and coping behaviors exhibited in the last seven days in the surveyed household respectively , 57. We We used propensity scoring and visual inspection (of the overlap between resettled households and host community households) for all measured variables to test balance in our study sample, especially to ensure that our sampled host community households provided a comparable baseline for surveyed resettled households . AdditioIn the KNP landscape, households buy foods from weekly markets and therefore restock each week for fresh vegetables, meats and staples. For availability of market items and their prices, we visually compared market checklists as most markets in the landscape have the same produce with similar prices . We alsoWe used Euclidean nearest neighbor distances to find distances between household locations and nearest road, border of protected area (KNP core), market and built up area. We used existing GIS layers of roads, protected area borders, built up area and our GPS locations of markets , 59. We tehsil\u2014for all households) and origin village (only when modelling food access in resettled households) (http://www.r-project.org) and QGIS 2.10.0- Pisa . Data is available at (https://bit.ly/2GvxGid).To understand patterns and associations in our household level data we used cluster analyses (ClustVis PCA\u2013see ), randomseholds) . We stanResettled households have predominantly moved into existing villages in similar proportions to host community human densities across the KNP landscape . HoweverHouseholds in the KNP landscape typically access the bulk of their foods (>90%) from weekly markets at their village or a neighboring village See . Thus, rtehsil during summer, resettled households had higher mean FCSs compared to host community households . However, across all surveyed households with acceptable FCSs, vegetables were not consumed every day and meats very occasionally.Resettled households reported similar Food Consumption Scores when compared to their host community neighbors across all three survey seasons . The yeaResettled households had higher CSIs in monsoon across two administrative units (Baihar and Panderia) and higher CSIs than host community households in winter in Baihar and in summer in Panderia . MoreoveWhile resettled households consume food groups in similar frequencies to host community households, we find that approximately 80% of all households have inadequate levels of food consumption (borderline or poor) . ResettlAll households predominantly access food through market purchases (>90%) supplemented by self-provisioning year round . Only a Our results of modelling livelihood characteristics associated with resettled and host community households highlight that increasing asset index values were positively associated with FCSs year-round . PredomiApart from the above livelihood associations with FCSs, resettled households supplement market bought foods with self-provisioned foods while host community households engage in winter cropping to attain similar FCSs . Owning Our study contributes to the growing quantitative assessment of resettlement on human well-being measurements, tying together conservation and social goals , 65, 66.Our study finds widespread food insecurity for all households. However, the current state of food insecurity around KNP is not acute with very few reports of hunger and coping strategies associated with higher food access. Food insecurity is largely due to the economic inability to access high nutrient food groups (tehsil (administrative block) there were seasonally changing differences in resettled and host community household FCSs and CSIs but these require further study to understand the underlying mechanisms while host community households predominantly rely on winter cropping to end up with similar FCSs . Our resThese differences aside, both resettled and host community households with increasing assets and diversified incomes showed positive associations with FCSs. Households with incomes from poultry and agriculture had comparable positive associations with FCSs as salaried jobs. We suggest that gains from poultry farming might be an avenue for on-the-ground interventions that aid alleviation of poverty as well as food insecurity , 73. We The key objective of our study was to assess post-resettlement food security of resettled compared to their host community households at the new settlement location in the KNP landscape. Our findings suggest that the current resettlement does not constrain resettled households and that they are comparable to host community households in terms of livelihood opportunities, physical food availability and food access. Approximately 20% of our surveyed households are within the KNP buffer. Households within the administrative buffer of KNP are more similar to households outside the KNP than those previously living within the KNP core in terms of economic activities, access to the road network in the KNP landscape and commercial livelihoods . The multiuse buffer around KNP is predominantly agricultural land with more than 260 existing villages. Resettled households join existing villages outside of KNP and comprise a minor proportion of the total village population .To increase overall wealth, an obvious but difficult application of our results would be to generate more opportunities for salaried jobs and make agricultural practices more profitable. Such an obvious result seems a moot point to discuss but we do so to ensure our results are not seen as a contrast of two separate livelihoods\u2013resettled households with forest livelihoods separated from rural host community households with more wealth driven livelihoods. Our results confirm that the reality is one where rural livelihoods predominantly feature wealth accruement and market bought foods regardless of being resettled and host community households . Our stuOwning more cattle suggests that households have means to increase assets which are in turn associated with higher FCSs. Cattle are culturally important, most often as work animals and easily traded assets in times of distress. Cattle for dairy incomes are rare in the KNP landscape. Incomes from cattle might be occasional or low (dairy farming practices). Similar findings about the complicated relationship between livelihoods and cattle owning have been found in Ghana . We alsoFood security for resettled households, and their host community neighbors, in the Kanha National Park landscape will be best achieved by integrating the poorer households into the economy with more opportunities, such as steady jobs and poultry farming, for higher incomes and seasonal stability. Managers for resettlement and rural development around KNP, and in other human-dominated conservation landscapes, might consider the importance of training for employment with steady incomes in future interventions. At the national policy level, the NTCA can use the methods from our study to explore links between livelihoods and social goals in resettlement from tiger reserves across India that vary ecologically, geographically and culturally. While this study concluded that steady incomes are highly relevant for food security in the KNP landscape, other landscapes around tiger reserves might indicate the need for access to forests or efforts to improve food availability.Our study focuses on a short time-frame after resettlement to look at immediate impacts on food security as a metric of human well-being. Longer studies or studies after a decade of resettlement might provide further insight into how compensations under the current guidelines allow resettled households to integrate into their new locations. Furthermore, studies that include metrics of well-being that are difficult to quantify are important to understand social impacts on people living around protected areas , 65. StuWe conclude that there is low level of food insecurity in the KNP landscape that is largely driven by low and unstable household incomes. Resettled households are comparable to their host community neighbors in food availability . We also found that resettled households are comparable to their host community neighbors in food security (FCSs and CSIs) and that households with higher food security had more assets as well as more income sources. Resettled households have more seasonal income sources and supplement foods locally (kitchen gardens) while their more established host community neighbors rely on winter cropping incomes to attain similar food security. Our results suggest that increased opportunities for diversifying non-labor incomes could be effective to alleviate food insecurity for both resettled and host community households in the KNP landscape. This result reinforces multiple studies that highlight livelihood diversification as a means for alleviating household food insecurity , 66. OurS1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.S4 File(PDF)Click here for additional data file.S5 File(PDF)Click here for additional data file.S6 File(PDF)Click here for additional data file.S7 File(PDF)Click here for additional data file.S8 File(PDF)Click here for additional data file.S9 File(PDF)Click here for additional data file.S10 File(PDF)Click here for additional data file."} {"text": "Older adults with subjective memory complaints (SMCs) are at increased risk for episodic memory decline. Episodic memory decline is an important predictor of objective memory impairment (one of the earliest symptoms of Alzheimer\u2019s disease) and an often-suggested criterion of successful memory aging. Therefore, it is important to explore the determinant factors that influence episodic memory in older adults with SMCs. Roy adaptation model and preliminary evidence suggest that older adults with SMCs undergo a coping and adaptation process, a process influenced by many health-related risks and protective factors. This study aimed to explore the relationship between coping capacity and episodic memory, and the mediating role of healthy lifestyle between coping capacity and episodic memory in a sample of 309 community-dwelling older adults with SMCs. Results from the structural equation modeling showed that coping capacity directly affects episodic memory , and there is a partial mediating effect (60.5%) of healthy lifestyle among this sample of older adults with SMCs. This study demonstrates that coping capacity and adaptation positively correlate with episodic memory in older adults with SMCs, and that these correlations are mediated by healthy lifestyle. The results suggest that older adults with poor coping capacity should be assessed and monitored regularly, and clear lifestyle-related interventions initiated by healthcare providers that promote healthy lifestyles may effectively improve coping capacity and episodic memory in this population group. Note: First author: Feilong Wang, Co-first author: Shijie li, Corresponding author: Yanni Yang"} {"text": "This study investigated the association between childhood socioeconomic status (cSES) risk of cognitive impairment but not dementia (CIND), cognitive impairment (dementia or CIND), and dementia and whether adult personality mediated this association. A sample of 10,289 participants (aged 50 and older) from the Health and Retirement Study (HRS) were followed across 2-year periods between 2006 - 2018. Estimates of mediation effects in Cox Proportional Hazards regressions were conducted using Mplus software to approximate the total effects of cSES on the cognitive outcomes and the natural indirect effects and natural direct effects derived when personality causally mediated this outcome. cSES was associated with increased risk of all three cognitive outcomes. Conscientiousness partially mediated the relationship between cSES and dementia, CIND, and cognitive impairment risk while neuroticism partially mediated dementia and impairment, but not CIND. Personality improved the overall model fit between cSES and both CIND and impairment, and conscientiousness was specifically associated with significantly lowered cognitive impairment risk over time. Conscientiousness and neuroticism substantially mediated the relationship between cSES and risk of impairment in old age. This research adds to lifespan models and suggests that distinct personality traits attenuate early childhood factors that contribute to lifespan development and cognitive aging. Conscientiousness in particular may act as a protective buffer mediating risk factors associated with cognitive impairment in old age."} {"text": "Cereals and legumes play a major role in the production systems and diets of farmers in the semi-arid eastern region of Kenya. Efficient postharvest management can tremendously contribute to food security in these regions. A study was carried out in three counties in eastern Kenya to assess pre and postharvest management practices among farmers. Data was collected using semi-structured questionnaires designed and administered using Kobo Toolbox via android tablets. Results showed that farmers cultivated three main crops: maize (98%), beans 66%), and pigeon peas (28%). The most saved seed crops were beans (80%) and pigeon peas (50%). Majority of the farmers (80%) experienced pre-drying losses due to insects (48%), rodents (40%) and birds (39%). Farmers stored grain for consumption (80%) and for sale (19%). About 48% of farmers stored the grain for more than 9 months. Challenges during grain storage were insects (57%) and rodents (43%). Primary methods of grain preservation included hermetic methods (61%) followed by insecticides (33%). While progress is being made in addressing storage challenges, there still a need to continue building awareness about improved storage technologies and find solutions for pest infestations in the field and drying after harvest. Cereals and legumes are the most important food staples in Sub-Saharan Africa , beans (Phaseolus vulgaris L.), green grams (Vigna radiata L.), pigeon peas (Cajanus cajan L.), millets (Pennisetum spps), sorghum (Sorghum bicolor L.), cowpea (Vigna uncguiculata L.) and dolichos lablab (Lablab purpureus L.) to ensure self-sufficiency in the face of climate change in the Eastern region of Kenya . The surWe purposively selected 50 villages in the three counties . The number of villages per country was determined based on cereal and legume production. We targeted to interview 13 farmers randomly selected in each village. We were able to survey a total of 613 farmers . The selected farmers were interviewed using a semi-structured questionnaire with open and close-ended questions. Questions included qualitative and quantitative data focused on the socio-economic characteristics of the respondents; major cereal and legume crops produced, the quantity produced; seed sources and storage, grain drying before and after harvest, storage practices; farmers\u2019 knowledge of the causes of postharvest losses and loss prevention measures. The questionnaire was uploaded to Kobo Toolbox, deployed and administered via handheld devices (android tablets). Five enumerators collected data and received consent from individual farmers before each interview. Data collected were coded and analyzed using the SPSS 24.0 (IBM Corp., About half of the farmers were an aging demographic, above 50 years. Older farmers are usually viewed least productive because most field work require physical effort. In addition, this may be a hindrance to adoption of new technologies which has a negative impact on food security. This is a universal trend caused by youth migration to urban centers among other factors. Policy-makers need to develop programs that incentivize the youth to be involved in agriculture. The average household size was five members which is similar to the Kenyan national average of between 4.9 to 5.7 people Munene, . Bigger The three major crops grown across the three counties were maize, beans and pigeon pea. Most farmers grew at least two major crops including a cereal and a legume. This agrees with the report that farmers in semi-arid areas of eastern Kenya grow two major and one minor grain crops (Wambugu & Muthamia, There was little variation in postharvest practices among the three study sites. Ideally, rainfall in these regions is bimodal with the long rains occurring from March to May and short rains from October to December. However, all these counties have been experiencing an overall decrease in precipitation and increase in temperatures, with negative impact on crop yields (Ojwang\u2019 et al., Farmers had a good understanding of storage and its implications for food security. Studies have shown the importance of storage in enhancing food security in semi-arid areas (Nduku et al., The major challenges during storage were insects and rodents. Farmers reported using new storage technologies and insecticides to deal with these pest challenges. Farmers have relied on pesticides for grain preservation, but they have been shifting towards hermetic storage in recent years. Concerns with pesticides stem from food poisoning due to overuse and misuse of insecticides as well as their ineffectiveness linked to insect resistance (Nicolopoulou-Stamati et al., Overall, farmers have a greater understanding of postharvest practices in the three counties in Eastern Kenya. Maize and common beans are the most important crops grown by farmers in these areas. Postharvest challenges linked to drying and storage such as aflatoxins and insects are serious challenges. Farmers are increasingly accessing new technologies and solutions to deal with these issues. Maize being such a staple crop grown by all farmers, there is a need to improve and promote pre-harvest and postharvest management practices to increase the use of new technologies such as improved seed, dryers, and hermetic storages devices."} {"text": "Durable left ventricular assist device therapy has improved survival in patients with advanced heart failure refractory to conventional medical therapy, although the readmission rates due to device-related comorbidities remain high. Left ventricular assist devices are designed to support a failing left ventricle through relief of congestion and improvement of cardiac output. However, many patients still have abnormal hemodynamics even though they may appear to be clinically stable. Furthermore, such abnormal hemodynamics are associated with an increased risk of future adverse events including recurrent heart failure, gastrointestinal bleeding, stroke, and pump thrombosis. Correction of residual hemodynamic derangements post-implantation may be a target in improving longitudinal clinical outcomes during left ventricular assist device support. Automatic and timely device speed adjustments considering a patients\u2019 hemodynamic status are potential improvements in forthcoming devices. Despite considerable improvement in available heart failure-specific medical therapies including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aldosterone antagonists, angiotensin receptor-neprilysin inhibitors, and arginine vasopressin type II receptor antagonists, morbidity and mortality in patients with advanced heart failure remain exceedingly high .In addition to mechanical circulatory support technologies including the intra-aortic balloon pump, extra-corporeal membrane oxygenation, and percutaneous axial-flow left ventricular assist device (LVAD), cardiac replacement therapy (heart transplantation and durable LVAD) remains the gold-standard therapy for those with refractory stage D heart failure . Given tLVAD therapy improves survival in patients with advanced heart failure compared to medical therapies alone ,5; howevLVADs correct hemodynamic derangements by mechanically unloading the failing left ventricle that decreases intra-cardiac pressure and subsequently increasing systemic circulation that increases total cardiac output. However, one report showed that many LVAD patients have abnormal hemodynamics despite appearing clinically stable in the ambulatory setting . FurtherDurable LVAD technology is improving, from para-corporeal models to the implantable and smaller iterations, including both pulsatile and continuous-flow types. Notably, the dominant types in the current era are implantable continuous-flow devices 12]. Th. Th12]. 2. Notably, we can measure directly or calculate various other hemodynamic parameters using right heart catheterization, as discussed later.Nevertheless, our group recently found that many LVAD patients had abnormal hemodynamics despite showing no apparent clinical symptomology . Here, wParticularly, many LVAD patients seem to have inappropriately elevated central venous pressure indicative of sub-clinical right heart failure ,14. LVADFor several reasons, we believe that invasive right heart catheterization should be routinely performed following LVAD implantation . First, Our team recently demonstrated that the presence of abnormal hemodynamics post-LVAD implantation, even without heart failure symptoms, was associated with future instances of clinical volume overload and heart failure recurrence . As one Optimal device positioning also affects the device\u2019s ability to effectively unload the left ventricle, with malposition of the inflow cannula associated with an increased risk of future heart failure exacerbations . LateralBleeding, particularly gastrointestinal bleeding, is among the most common comorbidities during LVAD support with an estimated incidence of 25% . Some gaThe mechanism of gastrointestinal bleeding is multifactorial . In addiThe most apparent risk factor for LVAD-associated stroke is uncontrolled systemic blood pressure . This rePump thrombosis is one of the major causes of device malfunction that requires device exchange . AbnormaSeveral unique hemodynamic patterns vary by disease state including right heart failure, pulmonary hypertension, and aortic insufficiency.We should state at first that there is no comprehensive and consistently agreed-upon definition of right heart failure . Right hAs mentioned above, right heart failure remains a highly morbid complication of contemporary LVAD therapy. Despite the pump\u2019s purpose to restore systemic perfusion in the failing heart by unloading the left ventricle, adverse right ventricular remodeling resulting from longstanding left ventricular failure is common and challenging to correct by durable mechanical circulatory support alone. Following LVAD implantation, right ventricular preload dramatically increases due to improved systemic circulation. The right ventricle, however, is often unprepared for this drastic increase in flow due to maladaptive structural changes from the afterload of a chronically failing left heart. As a result, right heart failure can become apparent both early and in later periods following LVAD implantation. Furthermore, a decrease in the size of the left ventricle due to mechanical unloading also facilitates a geometrical unbalance between the left and the right ventricle, resulting in further impairment of normal right ventricular contractile mechanics .Elevated central venous pressures in the setting of normal pulmonary capillary wedge pressure are one of the hallmarks of right heart failure and tend to be difficult to correct alone through mechanical unloading . Right hInvasive right heart catheterization provides the clinician valuable information regarding right ventricular performance. Pulmonary artery pulsatility index, which is calculated as a pulse pressure of the pulmonary artery divided by the central venous pressure, is a recently proposed index of right ventricular function , with a Many patients with advanced heart failure have secondary pulmonary (combined pre and post-capillary) hypertension due to chronically elevated left-sided filling pressures . HoweverAortic insufficiency is a unique and progressive comorbidity during long-term LVAD support. Continuous left ventricular unloading leads to aortic valve closure and pressure increases in the aortic root via the outflow graft. This can lead to valvular degeneration, and subsequent continuous and eccentric valvular regurgitation . Aortic The severity of aortic insufficiency is assessed usually using conventional color Doppler echocardiography for visual estimation. Accurate quantification is challenging given non-physiologic continuous and eccentric regurgitant flow. Our group recently proposed several methods to more accurately quantify the severity of aortic insufficiency .First, we can estimate the degree of aortic insufficiency using a device flow monitor, which is equipped in the HeartWare LVAD . This stSecond, we can quantify the severity of aortic insufficiency using Doppler echocardiography obtained at outflow graft 53]. Th. Th53]. As discussed above, abnormal hemodynamics are associated with various adverse clinical outcomes during LVAD support. Furthermore, there are several hemodynamically unique comorbidities during LVAD support which have unique and specific management strategies.2. We simultaneously perform echocardiography to assess for aortic valve opening, to understand the interventricular septum position, and to determine the presence of mitral valve regurgitation at each speed interval . It. It61]. The CardioMEMS device might have the potential to be utilized in LVAD patients to monitor and adjust device parameters in response to hemodynamic status . This isReDS is another promising tool to noninvasively estimate intra-thoracic fluid levels , which mThe HeartWare LVAD provides an estimated instantaneous flow waveform that shows insights into patients and device properties. For example, low pulsatility and low mean flow indicate hypovolemia, whereas low pulsatility and high mean flow let us detect suspected device thrombosis. High pulsatility and low mean flow might indicate continuous suction, whereas high pulsatility and high mean flow indicate volume overload. LVAD flow is determined by the pressure difference between the aorta and left ventricle at a fixed device speed. When aortic pressure is assumed to be constant at the diastole phase, LVAD flow is dependent on left ventricular pressure. When left ventricular pressure increases, LVAD flow often increases. Given this mechanism, pulmonary capillary wedge pressure can be estimated by the slope of LVAD flow at the end-diastolic phase 66]. We. We66]. Future advances in durable mechanical support may include a smart pump concept, which can automatically adjust device speed by continuously monitoring hemodynamic data points. For example, a novel smart pump might automatically measure the HeartWare LVAD flow slope and adjust its rotational speed considering estimated intra-cardiac pressure . If the Despite durable LVAD support, many patients can have abnormal hemodynamics due to a variety of clinical conditions even when clinically stable. LVAD therapy has improved survival in patients with advanced heart failure, though considerable limitations remain including unacceptably high readmission rates due to these various comorbidities, including volume overload and hemocompatibility-related adverse events. Assessment and optimization of hemodynamics might be one of the modifiable targets which could reduce the burden of these common post-implant complications. Interventions to optimize the hemodynamic status by adjustments of device speed and medications might improve clinical outcomes, though further large-scale prospective randomized control trials are needed to study these interventions. In the interim, noninvasive methods that estimate hemodynamics, including CardioMEMS, ReDS, and HartWare LVAD waveform analyses, may prove to be useful in more precisely guiding daily LVAD management."} {"text": "Previous cross-sectional research suggests that age-related decreases in Rapid-Eye Movement (REM) sleep may contribute to poorer cognitive functioning (CF); however, few studies have examined the relationship at the intraindividual level by measuring habitual sleep over multiple days. Applying a 14-day daily diary design, the current study examines the dynamic relationship between REM sleep and CF in 69 healthy older adults . A Fitbit device provided actigraphy indices of REM sleep , while CF was measured four times daily on a smartphone via ambulatory cognitive tests that captured processing speed and working memory. This research addressed the following questions: At the within-person level, are fluctuations in quantity of REM sleep associated with fluctuations in next day cognitive measures across days? Do individuals who spend more time in REM sleep on average, perform better on cognitive tests than adults who spend less time in REM sleep? A series of multilevel models were fit to examine the extent to which each index of sleep accounted for daily fluctuations in performance on next day cognitive tests. Results indicated that during nights when individuals had more REM sleep minutes than was typical, they performed better on the working memory task the next morning . These results highlight the impact of REM sleep on CF, and further research may allow for targeted interventions for earlier treatment of sleep-related cognitive impairment."} {"text": "The house acts as both an environment of care and a vehicle to financially potentiate long-term community-based support. While housing can empower a diverse set of options for a person-centered aging process, inadequate housing can also impede healthy aging in the community. This symposium teases out the nodes where housing acts to benefit or limit safe community-based aging. The first paper in this symposium, Homeownership Among Older Adults, describes typologies of older adult homeownership and sensitively highlights trends, disparities and important considerations of homeownership in later life. The next two papers take these older adults and explores situations where their housing acts as an asset or as a burden. Identifying Cost Burdened Older Adults acknowledges that housing cost burdens look different for older adults than younger cohorts. A more precise definition of older adult housing cost burden is proposed to help researchers and policymakers better synthesize the complex relationships between older adult housing and their long-term care decisions. The Long-Term Care Financing Challenge then explores the role of home equity in expanding the community-based long-term care choice set for older adults. This paper demonstrates benefits in home equity and suggests policy implications moving forward. Finally, Cardiometabolic Risk Among Older Renters and Homeowners disentangles the relationship between housing and health by demonstrating health disparities that are associated with housing tenure, conditions and affordability. Taken together, this symposium explores the complex and multidirectional relationships between housing, long-term care and older adult health."} {"text": "Loneliness is a distressing yet adaptive emotional experience that alerts us to socially re-engage. However, loneliness can also lead to social withdrawal and isolation. To reconcile the seemingly contradictory consequences of loneliness, we unpack the timing of the underlying processes by distinguishing between the roles of state loneliness and trait loneliness in predicting social re-engagement. Using ten days of electronic daily assessments from 95 older adults , initial findings indicate that trait loneliness moderates time-varying associations between state loneliness and prosocial behavior: On days of elevated state loneliness, older adults low in trait loneliness report increases in prosocial behavior, whereas older adults high in trait loneliness show decreases in prosocial behavior. Findings suggest that transient loneliness may motivate older adults to actively re-engage with others; chronic loneliness may undermine such adaptive responses."} {"text": "Emerging data from epidemiological studies have confirmed elevated prevalence rates for mental health conditions among the lesbian, gay, bisexual and transgender (LGBT) populations. An estimated 2.8% of Asian Americans identify as LGBT and 26% of Asian LGBT are 40 years or older. This study analyzed the California Health Interview Survey to examine differences in psychological distress between LGBT and non-LGBT older Asian Americans, and further evaluated the role of discrimination in medical care and intimate violence on psychological distress. Regression results showed older LGBT Asians had a higher psychological distress score compared to non-LGBT Asians. After adjusting for discrimination or violence, this association no longer existed. Experiencing discrimination in medical care and intimate violence were associated with higher levels of psychological stress. This study increases our knowledge of mental health among older Asian LGBT, enhancing our ability to design culturally-targeted and trauma-informed psychosocial interventions to improve outcomes in this population."} {"text": "Existing evidence suggests that individuals\u2019 subjective experience of cognitive decline may be a risk state for dementia. However, whether self-awareness of positive changes confer cognitive protection is unknown. We examined the extent to which awareness of positive (AARC gains) and negative (AARC losses) age-related changes explains variability in objective cognitive performance in a sample of 6,231 UK residents without cognitive impairment. We tested a structural equation model with AARC gains and losses as predictors of cognitive performance and depressive symptoms as a mediator of the association of AARC losses with cognitive performance. The model fit the data well. The correlation between AARC gains and losses was negligible, yet higher levels of both AARC gains and losses predicted poorer cognitive scores. Hence, higher AARC gains did not confer cognitive protection. This unexpected pattern of results underscores the complexity of mapping individuals\u2019 awareness onto objective outcomes."} {"text": "Cancer cells directly control nutrient uptake and utilization in a different manner from that of normal cells. These metabolic changes drive growth, proliferation of cancer cells as well as their ability to develop resistance to traditional therapies. We review published studies with pre-clinical models, showing the essential roles of lipid metabolism in anticancer drug resistance. We also discuss how changes in cellular lipid metabolism contribute to the acquisition of drug resistance and the new therapeutic opportunities to target lipid metabolism for treating drug resistant cancers.Metabolic reprogramming is crucial to respond to cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown to modulate cancer cells\u2019 sensitivity to chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance to anticancer agents. In this review, we highlight changes in lipid metabolism associated with therapy resistance, their significance and how dysregulated lipid metabolism could be exploited to overcome anticancer drug resistance. Many oncogenic mutations resulting in the aberrant activation of several signaling pathways can reprogram cancer cell metabolism to such an extent that metabolic reprogramming is considered one of the major hallmarks of cancer . Cancer i) overproduction of neutral lipids such as triacylglycerols stored in LD that accumulate in cancer to provide a reserve of energy; (ii) production of phospholipids is used to build cancer cell membranes to satisfy the increased demand for cancer proliferation. Moreover, phospholipids also act as lipid messengers and intracellular signaling molecules in cancer . Among r review . Particur review ,17. Humar review . Orlistar review . Besidesr review . Many enr review .Secondly, apart from lipogenesis, it was observed that FAs, either from extracellular sources or mobilized from internal lipid stores, can be oxidized in cancer cell mitochondria B. Under Furthermore, lipolysis and lipogenesis may coexist in cancer cells . Lipid mEmerging evidence also suggest that dysregulated lipid metabolism could play a role in resistance to anticancer drugs. Furthermore, the dependence of cancer cells on aberrant lipid metabolism could point to lipid metabolism being a potential source of new attractive targets to eradicate cancer cells. This review highlights the role and mechanisms of lipid metabolism reprogramming induced by anticancer drugs during the development of chemoresistance in cancer cells. In addition, we discuss the potential of reversing chemoresistance via lipid metabolism regulation.It is now well-established that lipid metabolism changes are associated with resistance to conventional chemotherapies and targeted therapies in several cancers. Lipid metabolic reprogramming of resistant cancer cells includes both changes in de novo lipogenic synthesis and/or lipolytic pathway. With some exceptions , cancer Secondly, changes in the lipid metabolism of resistant cells vary depending on the environment and cellular context. Thus, radiation resistance was associated with a significant increase in CPT1A-dependent lipolysis in nasopharyngeal carcinoma whereas radiation resistance was linked to de novo lipogenesis in head and neck squamous carcinoma ,51. MechOverall, these data indicate that changes in lipid metabolism of resistant cells are treatment specific but also environmental and cellular context-dependent resulting in a high heterogeneity of lipid metabolisms.Of note, it is interesting to stress out that lipid metabolism changes, de novo lipogenesis or lipolysis, can be unveiled upon anticancer drug exposure. Comparison of paired NSCLC tumor tissues from patients before and after Gefitinib treatment revealed a significant increase in lipid droplet content and in SCD1 expression . Upon 5-Firstly, several studies suggested that aberrant lipid metabolism could be seen as metabolic shift allowing cancer cells to adapt to treatment-induced cellular stress. Almost all anticancer drugs including conventional chemotherapies and targeted therapies induce cancer cell stress that can ultimately lead to cell death. It was reported that several cellular stressors like lack of nutrients, high levels of reactive oxygen species (ROS) promote de novo lipogenesis . Thus, lSecondly, apart from an adaptive process, cancer cell exposure to anticancer drugs can result in an enrichment of a pre-existing cellular subpopulation characterized by aberrant lipid metabolism. According to this hypothesis, lipid metabolism is a metabolic state allowing a sub-population of cancer cells to escape the effects of anticancer drugs when other cancer cells die. This subpopulation could be represented by cancer stem cells (CSCs), a highly resistant subset of cancer cells. Indeed, it is well established that even if a successful cancer therapy abolishes the bulk of tumor cells, CSCs can survive to standard cancer treatments and are at the core of clinical relapse . InteresIn many preclinical models, lipid metabolism inhibition can reverse the resistance of cancer cells to cancer drugs suggesting that lipid metabolism may play a role in drug resistance. The question is how can lipid metabolic reprogramming contribute to anticancer drug resistance?The oxidative stress induced by anticancer drugs result in peroxidation of lipid membranes, oxidative modifications of proteins and DNA. Doxorubicin, which possesses an anthracycline skeleton, generates ROS leading to DNA damage followed by anticancer activity. Likewise, vinca alkaloids increase intracellular ROS production by depleting the intracellular GSH causing DNA damages. Changes in lipid metabolism elicit a cytoprotective response to oxidative stress in several different ways: (i) lipid droplets decrease ROS toxicity thereby increasing cancer cell survival ProductiLipid droplet accumulation was evidenced to support colorectal cancer resistance to 5-fluorouracil (5-Fu) and oxaliplatin by inhibiting ER stress . Indeed,Overexpression of FAS, the key enzyme of de novo lipogenesis pathway, triggers cancer resistance to genotoxic drugs by increasing DNA repair . MechaniTargeted therapies such as MAPK inhibitors inhibit glucose uptake and antiglycolytic effects triggering energy stress conditions contributing to the promotion of cancer cell death (see above). Acetyl-CoA derived from fatty acid oxidation can fuel the mitochondrial TCA cycle to reduce energetic stress. This metabolic shift towards FAO, is often orchestrated by the AMP-dependent protein kinase (AMPK). Activation of AMPK in response to low energy levels boosts energy production through a mitochondrial FAO increase and therLipid metabolism can also interfere with the process of apoptotic cell death induced by anticancer drugs through two distinct mechanisms: (i) LDs were shown to remove apoptosis-related proteins, such as BCl-2 family members, from mitochondria by direct contact between outer mitochondrial membrane and lipid droplet surface . This pr+ CSC content in the MCF7 breast cancer cell line [A large body of evidence indicates that human cancers emerge from CSCs, which are intrinsically resistant to many anticancer treatments including conventional chemotherapies, targeted drugs and radiation. CSCs are also the main source of cancer relapse. Interestingly, lipid metabolic reprogramming contributes to CSCs expansion and survival therefore enhancing the occurrence of chemoresistance . Severalell line . Activatell line converseell line . HMG-CoAell line ,94,95,96ell line . Similarell line .Overall, these observations identify the rewiring of lipid metabolism as a novel and important mechanism of adaptive resistance to anticancer drugs.As detailed above, recent studies have shown that cancer cells develop changes in lipid metabolism, which is different from that of non-proliferative differentiated cells. These observations open up new avenues for the exploitation of lipid metabolism as a source of new therapeutic targets. Natural and synthetic agents that affect lipid metabolism in cancer is a rapidly growing field that was recently reviewed elsewhere . The focNumerous pharmacological inhibitors have been developed for almost all enzymes of lipid metabolism and some compounds are used in clinical trials in association with conventional therapies . CombinaBesides, due to the role of lipid metabolism in the acquisition of treatment resistance, targeting lipid metabolism could be used to re-sensitize cancer cells to standard treatments. FAS inhibitors have shown in-vivo and in-vitro anticancer effects and are also responsible for re-sensitization of cancer cells to conventional therapy ,106,107.One major interest in lipid targeting for cancer treatment is the possibility of using existing clinically-approved drugs originally developed for other lipid-related diseases. This drug repositioning in oncology has the main advantage of improving safety and reducing costs. Besides the anti-obesity drug, orlistat (see above), statins represent a classic example of drug repositioning in oncology. Statins are currently the most efficient drugs to reduce circulating cholesterol, with few side effects including muscle pain and occasionally liver inflammation, and thereby are used in preventing the development of cardiovascular diseases . MoleculBased on preclinical data presented above, combination therapy consisting of standard anticancer therapies and lipid metabolism inhibitors would be effective for treating resistant cancers.Lipid metabolism plays a central role in cancer resistance, not only via an increased availability of lipids conferred by adipocyte environment but also through profound changes in cancer cell lipid metabolism. It is particularly interesting to note that CSCs, cells that are known to be at the center of resistance mechanisms and relapse, have an increased dependence on lipid metabolism. This could offer a very large number of potential targets, as reported in this review. Changes in the lipid metabolism of cancer cells has been overlooked since conventional 2D cell culture is unable to recapitulate the tumor environment. Moreover, conventional culture medium does not recapitulate normal fatty acid environment as reported by Else . Optimiz"} {"text": "Teaching point: Hoarseness is a common condition that can be the initial symptom of cardiovascular disorder. A 76-year-old women who quitted smoking ten years earlier presented with recent-onset hoarseness of the voice. She had history of pulmonary commissurotomy. Fiberoptic laryngoscopy revealed paramedian left vocal cord paralysis. Chest computed tomography showed hiatus hernia and left pulmonary artery aneurysm (largest diameter 66 mm) Figures and 2 wiThe recurrent laryngeal nerves originate from the vagus nerves at different levels. The right recurrent laryngeal nerve exits anterior to the right subclavian artery and runs underneath and behind it. On the left side, the recurrent laryngeal nerve leaves the vagus nerve on the anterior surface of the aortic arch, running inferiorly around it through the aortopulmonary window posterior to the ligamentum arteriosum. Then they both rise up between the trachea and esophagus to reach larynx and innervate the intrinsic laryngeal muscles, except the cricothyroid muscle. Because of its longer course in mediastinum, the left recurrent laryngeal nerve is more vulnerable . This neThere are various mediastinal causes for vocal cord paralysis including surgical or iatrogenic injuries, traumatic lesions, inflammatory or infectious diseases, amyloidosis, tumours, and cardiovascular diseases. Ortner syndrome refers to hoarseness resulting from left recurrent laryngeal nerve paralysis caused by cardiovascular disease . It was Pulmonary artery aneurysms are rare, predominantly involving main pulmonary arteries, and may be idiopathic or result from congenital or acquired causes. It has been reported that early pulmonary valve commissurotomy may induce pulmonary artery aneurysm development due to eccentric right ventricular outflow jet.This case emphasizes the need to investigate neck and chest when looking for a causative lesion to hoarseness."} {"text": "Anabaena sp. ATCC 33047 is a marine, heterocyst forming, nitrogen fixing cyanobacteria with a very short doubling time of 3.8 h. We developed a comprehensive genome-scale metabolic (GSM) model, iAnC892, for this organism using annotations and content obtained from multiple databases. iAnC892 describes both the vegetative and heterocyst cell types found in the filaments of Anabaena sp. ATCC 33047. iAnC892 includes 953 unique reactions and accounts for the annotation of 892 genes. Comparison of iAnC892 reaction content with the GSM of Anabaena sp. PCC 7120 revealed that there are 109 reactions including uptake hydrogenase, pyruvate decarboxylase, and pyruvate-formate lyase unique to iAnC892. iAnC892 enabled the analysis of energy production pathways in the heterocyst by allowing the cell specific deactivation of light dependent electron transport chain and glucose-6-phosphate metabolizing pathways. The analysis revealed the importance of light dependent electron transport in generating ATP and NADPH at the required ratio for optimal N2 fixation. When used alongside the strain design algorithm, OptForce, iAnC892 recapitulated several of the experimentally successful genetic intervention strategies that over produced valerolactam and caprolactam precursors.Nitrogen fixing-cyanobacteria can significantly improve the economic feasibility of cyanobacterial production processes by eliminating the requirement for reduced nitrogen. As production hosts, cyanobacteria have several advantages over eukaryotic plants and algae, including faster growth and higher photosynthetic efficiency 68]. The ming FVA . Unfortubacteria . Among tna 33047 was usedg strain . The fluiAnC892, for the fast-growing, N2-fixing cyanobacteria, Anabaena 33047 by pooling together annotation information from diverse databases. Because Anabaena 33047 forms heterocysts under diazotrophic conditions, the iAnC892 model featured two super-compartments: vegetative cell and heterocyst. iAnC892 was able to accurately capture several aspects of the diazotrophic metabolism of heterocyst forming cyanobacteria. Reaction content comparison with Anabaena 7120 and Anabaena 29413 indicated that iAnC892 is different from these models in terms of its reaction content. Cell specific shutdown of heterocyst-LETC revealed its importance in generating ATP and NADPH at ratios optimal for N2 fixation. Similar analysis of heterocyst central carbon metabolism revealed the existence of alternative routes other than PPP that can supply reducing equivalents for N2 fixation. The usefulness of iAnC892 was further tested by using it alongside OptForce to predict genetic interventions for overproduction of valerolactam and caprolactam. The study recapitulated several of the experimentally successful strategies. Further improvement in predictions can be achieved by using flux distributions specifically generated for Anabaena 33047. Availability of species-specific flux distribution would also help pin down exchanges between vegetative cell and heterocysts which would provide a clearer picture of the energy production pathways active in the heterocyst.In this study we constructed a comprehensive GSM model,"} {"text": "Assessment of metabolic cost as a metric for human performance has expanded across various fields within the scientific, clinical, and engineering communities. As an alternative to measuring metabolic cost experimentally, musculoskeletal models incorporating metabolic cost models have been developed. However, to utilize these models for practical applications, the accuracy of their metabolic cost predictions requires improvement. Previous studies have reported the benefits of using personalized musculoskeletal models for various applications, yet no study has evaluated how model personalization affects metabolic cost estimation. This study investigated the effect of musculoskeletal model personalization on estimates of metabolic cost of transport (CoT) during post-stroke walking using three commonly used metabolic cost models. We analyzed walking data previously collected from two male stroke survivors with right-sided hemiparesis. The three metabolic cost models were implemented within three musculoskeletal modeling approaches involving different levels of personalization. The first approach used a scaled generic OpenSim model and found muscle activations via static optimization (SOGen). The second approach used a personalized electromyographic (EMG)-driven musculoskeletal model with personalized functional axes but found muscle activations via static optimization . The third approach used the same personalized EMG-driven model but calculated muscle activations directly from EMG data . For each approach, the muscle activation estimates were used to calculate each subject\u2019s CoT at different gait speeds using three metabolic cost models . The cal Metabolic cost has been used to evaluate human performance during daily activities such as walking and athlin silico. Specifically, within the field of exoskeleton design, musculoskeletal models can eliminate the time and expense of iteratively designing and building physical prototypes. With advances in computational biomechanics, musculoskeletal models incorporating metabolic cost models have emerged as tools to estimate metabolic cost. These tools have been used to predict human movement and response to mechanical interventions . AlthougPrevious studies that estimated metabolic cost during walking have focused on using scaled generic musculoskeletal models. However, several studies have reported that personalization of anatomical and physiological characteristics of a musculoskeletal model can influence prediction of muscle forces, joint moments, and novel movements, factors that also play a role in metabolic cost calculations. This study evaluated the influence of musculoskeletal model personalization on metabolic cost estimates of walking post-stroke. To evaluate the physical realism of different metabolic cost modeling methods, we compared metabolic cost estimates to trends reported in the literature for individuals post-stroke. Experimental walking data collected from two male stroke survivors\u2013one high functioning and one low functioning\u2013were used as inputs to the metabolic cost analyses see , 2008.tf Hz (tf is the period of the gait cycle being processed (tf Hz) using a fourth-order zero-phase lag Butterworth filter. EMG amplitudes for each muscle were normalized to the maximum value over all trials and resampled to 101 time points per gait cycle, as described in The experimental data were processed using standard methods. The ground reaction and marker motion data were low-pass filtered using a fourth-order zero-phase lag Butterworth filter with a cut-off frequency of 7/tf Hz , where trocessed . On averA generic full-body OpenSim musculoskeletal model served alsqnonlin algorithm, which iteratively ran OpenSim Inverse Kinematics analyses to calculate marker location errors.Personalization of the joint functional axes for the hip, knee, and ankle of each leg was performed by following a two-step process. First, the geometry of the generic OpenSim model was scaled to match the dimensions of each subject using the OpenSim Scale Model tool and the static standing trial data. Second, marker positions and functional axes of the model\u2019s lower body joints were personalized as described in Experimental data from ten gait trials collected at each available walking speed were used to calibrate an EMG-driven model of both legs for each subject. Before performing EMG-driven model calibration, we analyzed marker data from each gait trial using the OpenSim Inverse Kinematics tool to generate joint angle trajectories. The OpenSim Inverse Dynamics tool was then used to calculate the joint moments produced by muscle forces. Next, a surrogate model of each subject\u2019s musculoskeletal geometry was generated to allow the EMG-driven model to modify musculoskeletal geometry , 2017. Tfmincon algorithm with sequential quadratic programming, we adjusted the model parameter values to best match calculated experimental inverse dynamic joint moments and published passive joint moments , Hill-type muscle-tendon model parameters , and surrogate musculoskeletal geometry parameters. Using Matlab\u2019s moments . In addi moments , S2. A dTo evaluate the extent to which model personalization affects estimated metabolic cost, we developed three musculoskeletal models for each subject with varying levels of personalization. The least personalized model was a scaled generic OpenSim model where muscle activations were calculated via static optimization using quadratic programming (SOGen) . The intTo evaluate the physical realism of each musculoskeletal model/metabolic cost model combination, we identified five experimental trends in the literature for how CoT varies as a function of other clinically relevant quantities for individuals post-stroke. The first three quantities were step length asymmetry, stance time asymmetry, and double-support time asymmetry, all of which have been reported to increase as the CoT increases . The twoWe performed statistical analyses to evaluate whether trends in CoT as a function of the five quantities described above were different between each musculoskeletal model/metabolic cost model combination and the experimental data published in p-values tended to increase as the level of musculoskeletal model personalization increased, with the EMGCal musculoskeletal model generally exhibiting the largest p-values and thus the greatest statistical similarity to experimental measurements. In contrast, the p-values tended to be comparable across the three levels of musculoskeletal model personalization.The ability to predict CoT trends consistent with experimental measurements varied across the nine modeling combinations \u20135. Overap-values < 0.05). However, when absolute values of y-intercept differences were calculated , and the subject provided written informed consent prior to participation.CP and BF performed the experiments. MA performed all model personalization tasks, prepared the figures, and drafted the manuscript. MA and MS analyzed the data. MA, MS, and BF interpreted the results of analyses. All authors revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Aging is a major risk factor for chronic diseases and is directly linked to increasing mortality and healthcare costs worldwide. A key contributing factor to the aging process is a loss of stem/progenitor cell function which leads to a dysregulated tissue microenvironment and reduced repair/regeneration . Over thThe bone marrow is an important reservoir of stem/progenitor cells which cross-talk with peripheral organs to help maintain tissue function. Hematopoietic stem/progenitor cells (HSCs) are responsible for producing blood cells throughout life and these downstream cells play an active role in maintaining tissue homeostasis. With aging reduced function of bone marrow cells correlates with dysfunction of peripheral organs. For example, the decline in immune function with age, referred to as immuno-senescence, contributes to the accumulation of senescent cells, persistent low grade inflammation, and reduced responses to injury . The bon+ bone marrow stem cells and examined 4 months later to allow cross talk between the bone marrow and heart. Young bone marrow reconstitution rejuvenated cardiac endothelial cells which contributed to improved repair and better outcome following myocardial infarction. Mechanistically, young cells which migrated to the heart expressed more Cxcl12 and Vegf, key cytokines involved in angiogenic responses. This correlated with greater expression of CXCR4 and phospho-AKT in resident cardiac endothelial cells isolated from mice receiving young vs. old bone marrow. In addition to improved angiogenesis, our lab has shown that rejuvenation using reconstitution of young cells improves multiple repair processes. Young bone marrow cell transplantation increases the proliferation of resident cardiac cells [We recently utilized this bone marrow rejuvenation approach to study the effect aging has on the repair processes initiated post-myocardial infarction . Aged miac cells , increasac cells , and enhac cells . TogetheBeyond cardiac repair, we have shown that bone marrow cells interact with other tissues and that bone marrow rejuvenation can benefit multiple organ systems. Reconstituting aged mice with young cells leads to the repopulation of the retina with young bone marrow derived microglia . Within Together our studies as well as studies by others demonstrate that introducing young bone marrow into aged mice is an effective rejuvenation strategy with systemic benefits . Bone ma"} {"text": "The journal retracts the article, Dinitrosopiperazine-Mediated Phosphorylated-Proteins Are Involved in Nasopharyngeal Carcinoma Metastasis cited abFollowing publication, concerns were brought to the attention of the publisher regarding the figures. Some stained tissue pictures in Figure 6 are duplWe apologize to our readership that this went undetected until now."} {"text": "Bipolar disorder (BD) is a complex and serious psychiatric disorder characterized by mood dysregulation difficulties (American Psychiatric Association Emotion-related urgency (hereto referred as ERU) is defined as a tendency to act rashly in the context of extreme emotions, including trouble inhibiting impulses and risk-taking behaviors (e.g., Cyders and Smith negative urgency (defined as the tendency to behave rashly during extreme negative emotions; e.g., Whiteside and Lynam positive urgency (defined as the tendency to behave rashly during extreme positive emotions; Cyders This brief letter suggests the importance of considering impulsivity during mixed states. Both negative and positive ERU have been implicated in BD (Giovanelli et al. We suggest increased investigation into transdiagnostic presentations and clinical implications of ERU. Indeed, recent recognition of mixed features also occurring in the context of major depressive disorders underscores the important transdiagnostic utility of ERU across mood disorders. We suggest three key areas for future research. First, it will be important to develop well-validated assessment tools to measure mixed-mood ERU across self-report and clinician-rated instrument domains. Second, it will be important to carefully assess the maladaptive behaviors that may predict, and result from, ERU during mixed states and differentiate those from more general risk-taking behavior. Third, future research should carefully consider lifespan approaches that consider ERU in the context of BD onset, risk and recurrence at critical developmental junctures. We believe the time is ripe to call greater attention to examining risky and potentially fatal consequences of impulsivity during strong and co-occurring negative and positive emotion states."} {"text": "Sepsis survivorship is associated with cognitive decline and complex post-acute care needs. Family caregivers may be unprepared to manage these needs, resulting in decline or no improvement in patient outcomes. Using a national dataset of Medicare beneficiaries who were discharged from the hospital for sepsis and received post-acute HHC between 2013 and 2014 , we examined the relationship between unmet caregiving needs and improvement or decline in cognitive functioning. Multivariate logistic regression was used to determine associations between unmet caregiving needs at the start of HHC and changes in cognitive functioning. Unmet caregiving needs included seven items from the start of care Outcome and Assessment Information Set (OASIS). Changes in cognitive functioning were measured using the start of care and discharge OASIS assessments. Twenty-four percent of patients either declined or did not improve in cognitive functioning from HHC admission to discharge, with variation seen by unmet need type. Sepsis survivors with unmet caregiving needs for activities of daily living assistance , medication assistance , and supervision and safety assistance were more likely to decline or not improve in cognitive functioning, even after accounting for clinical and demographic characteristics. Older sepsis survivors with both cognitive impairment and unmet caregiving needs in the post-acute HHC setting are at high-risk for worsening cognition. Alerting the care team of cognitively impaired sepsis survivors with unmet caregiving needs may trigger evidence-based strategies to enhance caregiver training and reduce unmet caregiving needs."} {"text": "Prior studies suggesting associations between cortical brain areas and gait speed has been largely cross-sectional and limited to one modality neuroimaging. Using machine learning from 506 cognitively normal BLSA participants aged 55+ who had repeated measures of brain volumes, diffusion tensor imaging (DTI), and gait speed, we examined multimodal neuroimaging predictors of gait decline, accounting for demographics, body composition, and grip strength. Significant predictors of gait decline included changes in volumes and DTI measures of gray matter in selected frontal, parietal, temporal, and subcortical areas, as well as white matter changes in both fractional anisotropy and diffusivity of tracts connecting frontal areas to subcortical motor areas. This predictive model highlights the importance of atrophy and microstructural deterioration in selected frontal and subcortical motor areas in predicting gait speed decline."} {"text": "C. elegans. As shown in et al. 1986). Serotonin and Gao signaling, which regulate egg laying behavior, can also signal to inhibit defecation . Because evidence shows that both the egg-laying active state and the defecation motor program (DMP) are both linked to changes in forward and reverse locomotion , we reasoned there may be a similar relationship between expulsive behaviors that drive either egg laying or defecation. Our experiments document an association between HSN Ca2+ activity and a reduced frequency of defecation (Ravi and Collins 2019) [See accompanying microPub Ravi and Collins (I) 2019]. Animals lacking HSNs have a reduced defecation frequency (Garcia and Collins 2019) [See accompanying microPub Garcia and Collins (II) 2019]. We hypothesize that egg-laying and defecation behaviors are coordinated because they use the same internal hydrostatic pressure to drive expulsion of uterine or intestinal contents, respectively.We have identified a relationship between egg-laying and defecation behaviors in et al. 2002; Gilpin et al. 2015; Fechner et al. 2018), releasing waste about once per minute and ~3-5 fertilized eggs (~20 pL each) about every 20 minutes . During defecation, sequential activity of the anterior and posterior body wall muscles contracts the animal, increasing internal pressure that drives expulsion of liquid waste through the anus . Mutations that eliminate the defecation motor program still expel gut contents at much reduced frequency. This is thought to be caused by a gradual accumulation of internal pressure by ongoing pharyngeal pumping of food that eventually ejects waste through the anus independent of circuit activity or muscle contractility (Avery and Thomas 1997).Worms continuously internalize bacterial food via pumping of a muscular pharynx . Animals lacking HSNs still enter active states with strong vulval muscle contractions driving release of embryos which additionally supports this model . Electrical silencing of the postsynaptic muscles renders animals egg-laying defective with embryos often hatching inside the mother . Unlike gut contents which are more fluid, fertilized embryos are more mechanically rigid, requiring full opening of the vulva for efficient release . We propose that changes in the internal hydrostatic pressure that accompany food consumption and embryo production activate mechanoreceptors that facilitate the onset of defecation and egg-laying behaviors. As animals age, they continue to eat and grow larger, but their defecation frequency decreases . Egg laying frequency also increases with age for as long as animals have sufficient sperm for oocyte fertilization . This increase in egg laying in older adults reflects both an increase in the number of eggs expelled with each vulval opening and longer active behavior states. We propose that the timing of expulsive behaviors including defecation and egg laying is regulated by sensory mechanisms that detect changes in internal pressure and/or stretch to maintain homeostasis. Feedback of successful egg laying might also signal to the germ line to ensure the continued production of oocytes for fertilization.Our recent data suggest egg-laying behavior is regulated by a stretch-dependent homeostat. Feedback from embryo accumulation in the uterus activates the postsynaptic muscles which drives burst-firing in the presynaptic HSNs as visualized by Ca"} {"text": "Stroke is a devastating condition characterized by widespread cell death after disruption of blood flow to the brain. The poor regenerative capacity of neural cells limits substantial recovery and prolongs disruptive sequelae. Current therapeutic options are limited and do not adequately address the underlying mitochondrial dysfunction caused by the stroke. These same mitochondrial impairments that result from acute cerebral ischemia are also present in retinal ischemia. In both cases, sufficient mitochondrial activity is necessary for cell survival, and while astrocytes are able to transfer mitochondria to damaged tissues to rescue them, they do not have the capacity to completely repair damaged tissues. Therefore, it is essential to investigate this mitochondrial transfer pathway as a target of future therapeutic strategies. In this review, we examine the current literature pertinent to mitochondrial repair in stroke, with an emphasis on stem cells as a source of healthy mitochondria. Stem cells are a compelling cell type to study in this context, as their ability to mitigate stroke-induced damage through non-mitochondrial mechanisms is well established. Thus, we will focus on the latest preclinical research relevant to mitochondria-based mechanisms in the treatment of cerebral and retinal ischemia and consider which stem cells are ideally suited for this purpose. Stroke is currently the fifth leading cause of death in the United States and can cause disabling neurological deficits including cognitive impairment, hemiparesis, sensory disturbance, and aphasia . StudiesThe ischemic cascade triggereMitochondrial dysfunction plays a key role in the pathological progression of ischemic stroke . MitochoThe body has multiple mechanisms to combat oxidative stress and clear damaged mitochondria. Cells can sequester functional mitochondria while degrading dysfunctional mitochondria via mitophagy ,16. In aThe discovery that stem cells can replace dysfunctional mitochondria in damaged cells has primed the field of stroke therapy for critical improvements in treatment outcomes . In the The ideal cell source to leverage the therapeutic benefits of mitochondrial transfer is bone marrow-derived mesenchymal stem cells (BM-MSCs). This cell type gives rise to endothelial progenitor cells (EPCs), which produce nearly all of the endothelial cells in the body . In the An in vitro stroke model proved that EPCs could successfully discharge their mitochondria . ProteinThe next step in confirming a mechanism of EPC-mediated mitochondria transfer is to assess whether endothelial cells take up these extracellular mitochondria and whether this would aid the recipient cell. In that same study, confocal microscopy demonstrated evidence of mitochondria-containing, EPC-derived extracellular vesicles within endothelial cells in the cerebral vasculature . TherefoAlthough at this point there is considerable evidence for the role of EPCs in restoring mitochondrial function via a transfer mechanism, there was still much uncertainty surrounding the benefits of stem cell mitochondrial therapy. Additional studies on EPC-derived mitochondria addressed these concerns. FACS-assisted proteome analysis of OGD-exposed brain endothelial cells reveals that uptake of EPC-derived mitochondria enhances the production of angiogenic and BBB proteins, including Serpin E1, plasminogen, FGF-4, and bFGF . These fThe ischemic conditions brought about by stroke damage endothelial cells and predispose them towards undergoing intrinsic pathway apoptosis, which is mediated by mitochondrial dysfunction . IntegraImportantly, astrocytes can also transfer their mitochondria to damaged neurons but do so in a transient fashion. Thus, they do not produce the same neuroprotective effects that occur via stem cell transplantation and cannot prevent secondary cell death . Given tExamination of the electron transport chain (ETC), specifically complexes I\u2013IV, can be performed using ETC complex inhibitors to study each portion of the chain in isolation. Mouse models with mutated mitochondria are instrumental in this investigation in order to definitively determine whether it is the mitochondria themselves that confer the neuroprotection or whether a different characteristic of the stem cell is responsible . When diThe safety of BM-MSCs compared to other sources of stem cells is relatively well established . NeverthUp to this point, we concentrated on literature that characterizes the transfer of mitochondria from stem cells to endothelial cells and neurons in the context of the ischemic brain. However, stroke patients often suffer maladies that extend beyond the brain, and complete functional improvement must address these aspects of recovery as well. A prime example of this is that ischemic stroke may cause damage to the eye, leading to visual impairment and a significant delay in recovery ,37. ImpoIt is valuable to understand the role of mitochondrial dysfunction in cerebral and ocular disease post-stroke due to the markedly similar pathology and treatment options between these two conditions . In addiThere are considerable benefits to using MSC therapy to treat ischemia-induced eye damage, such as enhanced preservation of retinal ganglion cells. The decreased cell death is likely due to improved mitochondrial function, which may be due to MSC-derived mitochondrial transfer to the retinal ganglion cells . MSC traThe interaction of creatine and phosphocreatine conversion prevents lapses in cellular energy supplies under healthy conditions. However, it is still possible for the energy supply to be damaged under ischemic conditions, worsening mitochondrial dysfunction. Creatine supplementation possesses therapeutic characteristics in various neurodegenerative disorders that may address the lack of energy supply and the normal function of the mitochondria . TherefoBased on previously mentioned studies, transferring healthy mitochondria by exogenous MSCs can potentially restore respiratory functions in ischemic retinal cells, reducing cell loss. Future studies should investigate how MSCs successfully transfer healthy mitochondria to retinal ganglion cells. Studies should also observe and describe the metabolic and proteomic properties of MSC-derived mitochondria post-transplantation into ischemic retinal cells. EPCs\u2019 affinity for BBB repair makes them a favorable MSC subtype. EPCs are known for being safe and effective to use in stem cell therapy. Additionally, their ability to donate healthy mitochondria justifies the need to further investigate its effects on retinal ischemia. However, the study presents a significant limitation. Specifically, no known study provides a detailed report regarding the physical characteristics of MSC that are involved in the mitochondrial transfer in retinal ischemia . The funStroke-induced ischemia results in insufficient oxygen delivery to cells and prevents mitochondria from performing cellular respiration. The ensuing loss of ATP is not compatible with cellular viability and ultimately precipitates mitochondrial dysfunction and cell death. In response to stroke and stroke-like lesions, cells upregulate mitochondrial synthesis to compensate for damaged mitochondria . A varieDespite the innovations in stroke therapy over the past decade, novel methods of research continue to elucidate fundamental information on the mechanistic role of mitochondria in stroke and enable the development of powerful new therapeutic strategies. A novel technology, Seahorse XFe24, measures mitochondrial respiration and allows investigators to directly detect changes in cellular energetics, rather than relying on cellular signaling . This teSeveral pharmaceutical agents, such as the dopamine D2 receptor antagonist pramipexole (PPX), facilitate neuroprotection through the action of mitochondria. Administration of PPX to transient MCAO model rats after an ischemic stroke reduces infarct volume, neurological deficit severity, mitochondrial ROS formation, mitochondrial calcium concentration, and swelling of the mitochondrial membrane, while simultaneously increasing oxygen consumption and the respiratory control ratio . TherefoThe pharmacological administration of tetrahydrocurcumin (THC) also alleviates mitochondrial dysfunction and improves functional capacity and motor coordination. THC epigenetically reduces plasma and tissue homocysteine (Hcy) levels and Hcy-induced mitochondrial oxidative stress . THC treAnother drug-based approach to mitochondrial dysfunction is the use of nicotinamide mononucleotide (NMN) to increase NAD+ levels. NMN extends the lifespan of mice with the mitochondrial disease Leigh Syndrome by normalizing NAD+ redox imbalance and lowering H1F1a accumulation in skeletal muscle . FurtherCationic arginine-rich peptides (CARPs) are another candidate pharmacological therapeutic that specifically enhance mitochondria-mediated neuroprotection in stroke. CARPs are small peptides, composed of up to 30 amino acids, that cross the BBB and localize to mitochondria in neurons. This property alone highlights their value as a pharmacologic treatment for stroke, as many other promising drugs do not effectively cross the BBB, making their administration difficult or ineffective. Once in the mitochondria, CARPs efficiently eliminate ROS that accumulate during ischemia and restore proper function of the mitochondria, rescuing the cell from free radical damage and reestablishing cellular viability .Although restoring the respiratory functions of mitochondria improves stroke outcomes, this is not the only strategy for recovery. Autophagy, the process of degrading and recycling damaged or unnecessary cellular components, can also mitigate mitochondrial dysfunction. A high salt diet is particularly dangerous because it increases the risk of hypertension-related stroke occurrence, reduces the efficiency of autophagy, and downregulates the production of the electron transport chain enzyme NDUFC2 . HoweverThe proteins ULK1, NDP52, and TANK-Binding Kinase 1 (TBK1) are also meaningful targets for stroke therapies through targeting autophagy. TANK1 recruits the ULK1 complex to the NDP52 receptor to initiate autophagy under conditions of starvation . TherefoAnother potential target of autophagy-based treatments involves the small molecule Compound R6 and its regulation of mitochondria-mediated apoptosis. The release of cytochrome c from damaged mitochondria activates the intrinsic apoptotic caspase-9/3 cascade and results in cell death . CompounAlong with autophagy, manipulating the discrete molecular mechanisms of mitochondria to enhance mitophagy is another approach to ameliorate stroke-induced mitochondrial dysfunction. Cell cycle progression in the presence of impaired mitochondria generates damaged daughter cells, further exacerbating tissue injury and delaying recovery. However, the serine/threonine kinase PINK1 and the E3 ubiquitin ligase Parkin mediate the elimination of these impaired mitochondria through induction of TBK1 to upregulate mitophagy, the targeted recycling of mitochondria. By directing TBK1 to the mitochondrial membrane, away from its role at the centromere during mitosis, PINK1 and Parkin halt the cell cycle at the G2/M phase . TherefoIn addition to enhancing TBK1-mediated mitophagy, PINK1 upregulates the Parkin-induced mitophagy pathway in the presence of damaged mitochondria. During an ischemic injury, the depleted mitochondrial membrane potential inhibits PINK1 importation to the inner mitochondrial membrane (IMM). Instead, PINK1 binds to Tom 7, accumulates on the outer mitochondrial membrane (OMM), then activates Parkin-induced mitophagy. However, the IMM-resident protease OMA1 cleaves PINK1 in the absence of Tom 7, abolishing mitophagy . Hence, While the PINK1/Parkin pathway is valuable to preserve non-neuronal cells, Parkin-induced mitophagy is not as effective in neurons as only a small fraction of mitochondria in axons undergo mitophagy . HoweverMultiple cellular pathways spur mitochondrial deterioration in ischemic stroke. Apoptosis in mitochondria is upregulated during ischemic stroke and is associated with continuous mitochondrial permeability transition pore (MPTP) opening in the inner and outer mitochondrial membranes . ROS proMitochondrial transporters are also important in preventing atherosclerosis, the accumulation of fatty plaques on the inner wall of arteries, which is a significant risk factor for stroke. Poor metabolism or excess intake of lipids intensifies atherosclerotic plaque buildup and heightens the chance of stroke and ischemic brain injury. The mitochondrial calcium uniporter (MCU) prevents lipid accumulation and maintains appropriate bioenergetics by facilitating oxidative phosphorylation in the mitochondria . HoweverAnother source of mitochondrial dysfunction that may exacerbate stroke pathology is the mitochondrial ADP/ATP carrier. Mitochondrial ADP/ATP carriers are located in the impermeable mitochondrial membrane and transport ADP into the mitochondrial matrix and ATP out for use as energy . InapproAstrocytes transfer their healthy mitochondria to neurons in the peri-infarct area post-stroke, and this endogenous neuroprotective mechanism is a candidate for stroke-therapy. In particular, the nuclear and desmosome-associated protein Pinin (Pnn) upregulates anti-apoptotic Bcl-2 expression, promotes ERK signaling, reduces pro-apoptotic cleaved caspase-3 production, and enhances astrocyte survival. Therefore, therapeutically augmenting Pnn expression may improve the endogenous capacity of astrocytes to protect neurons and repair ischemic tissue in the brain .Hyperbaric oxygen therapy (HBOT), which delivers pure oxygen to patients in special high-pressure rooms, modulates inflammation in traumatic brain injury (TBI) when given after the onset of tissue damage. However, pretreatment with HBOT also reduces cell death and improves post-stroke outcomes by inducing endogenous astrocyte-based mitochondrial transfer to neuronal cells. The prophylactic use of HBOT to enhance neuroprotection circumvents the need for invasive surgical treatment and potentially toxic drug-based approaches . AdditioMitochondrial repair for stroke highlights the integral role of mitochondrial function on cell survival and neurological improvement. Mitochondrial dysfunction closely accompanies post-stroke secondary cell death. The hypoxic environment reduces energy production, further exacerbating stroke symptoms. Identifying a reliable method of mitochondrial transfer represents the first step towards developing an effective stroke treatment and is crucial to restoring cell function . To thisWhile the benefits of stem cell therapy are clear, the mechanism is not. Determining the precise location of transfer between the donor and recipient cells will provide crucial insights into the mechanism and therapeutic actions of mitochondria. Such knowledge will guide efforts to optimize transfer conditions and maximize the beneficial effects of stem cells . To thisAlthough mitochondrial transfer is theoretically bidirectional, molecular signals released by damaged cells preferentially direct the movement of mitochondria and mtDNA from MSCs to damaged neurons . One sucDeleting mitochondria from stem cells abolishes the regenerative benefits they confer to damaged endothelial cells, supporting the hypothesis that these organelles are responsible for repair. Furthermore, transferring mitochondria directly into ischemic brain tissue restores cellular energetics, facilitates homeostasis of the central nervous system (CNS), and resolves the inflammation that causes secondary cell death . Stem ceMSCs are the most common stem cell source for mitochondrial transfer and provide a protective mechanism to save damaged cells from mitochondrial dysfunction in response to stress. The transfer of MSC-derived mitochondria to endothelial cells can repress apoptosis after an IR injury by restoring aerobic respiration. The results of studies investigating this transfer are encouraging, paving the way for stem cell transplantation therapy for ischemic stroke . An in vMSCs achieved efficacy of mitochondrial transplantation via intravenous transplantation into a middle cerebral artery occlusion (MCAO) mouse model. Here, retinal ischemia caused ganglion cells to deteriorate, impairing mitochondrial activity. These findings suggest that MSCs ameliorate mitochondrial dysfunction and ganglion cell death, as was observed 14 days after the stroke . In vitrThe effect of OGD on MSCs derived from the perivascular region, cord lining, and Wharton\u2019s jelly of the human umbilical cord also implicated a key role of mitochondria in these specific MSC tissue sources. The mitochondria in the perivascular region MSCs showed the greatest activity while the MSCs from the cord lining demonstrated the highest survival rate. These findings suggest that hUC-MSCs may be a good source for mitochondrial transplantation for ischemic stroke treatment . AdditioHuman induced pluripotent stem cells (iPSCs) are also the subject of recent studies of mitochondrial transfer. PD model astrocytes derived from human iPSCs spontaneously release healthy mitochondria in damaged neuron cultures. This iPSC-induced mitochondrial transfer significantly ameliorates dopaminergic neuron damage and imparts neuroprotective effects . iPSC\u2019s Spinal cord injury (SCI) models of mitochondrial transfer via bone marrow mesenchymal stem cells (BMSC) show promising results as well. Symptoms of both diseases are very similar: hypoxia, mitochondrial degeneration, oxidative stress, vascular injury, and axonal degeneration . HealthyThe omnipresent phenomenon of mitochondrial transfer allows for many applications in combination with stem cells. Contemporary literature details the efficacy of mitochondrial transfer in improving stroke, cardiovascular injury, spinal cord injury, and Parkinson\u2019s disease outcomes. The regenerative capacity demonstrated in a variety of tissues warrants its consideration as a primary therapeutic option. In particular, the physiological and pathological improvements seen in treating ischemic stroke illustrate the capability of mitochondrial transfer therapy. However, before moving into clinical trials, the optimal stem cell type must be identified to maximize the efficacy and potency of treatment. Further investigation is needed to discover the true potential of stem cell-based mitochondrial transfer therapy and improve long-term stroke outcomes."} {"text": "Research has shown the amount of effort we expend towards our goals depends on a sense of self-efficacy, perception of task difficulty, and likelihood of achieving our goal. All of these processes are susceptible to the influence of affect. For example, negative moods may impede goal achievement by increasing perceptions of difficulty . Negative experiences (such as past failures) can encourage these negative moods and subsequently impact self-efficacy . Findings from self-efficacy research suggest that older adults may be particularly susceptible to the impacts of negative affect on effort mobilization, especially when tasks already seem challenging, with little chance of success. Perception of task difficulty, then, impacts the amount of effort exerted in completing the task. The present study sought to examine the factors that impact perceptions of difficulty and subsequent effort expenditure, represented by systolic blood pressure responsivity (SBP-R). Younger (N = 41) and Older (N = 163) adults completed a difficult cognitive task as part of a larger, longitudinal study, as well as measures of trait affect before study sessions. Our findings indicate younger adults exert less effort overall than older adults; however, when negative trait affect is considered, we find that higher levels of negative affect in older adults reduced task engagement. These results provide support for an effect of negative affect on task appraisals and posited age-related differences in effort mobilization."} {"text": "Brain pathologies are increasingly understood to confer mobility risk, but the malleability of functional brain networks may be a mechanism for mobility reserve. In particular, white matter hyperintensities (WMH) are strongly associated with mobility and alter functional network connectivity. To assess the potential role of brain networks as a mechanism of mobility reserve, 116 participants with MRI from the Brain Networks and Mobility Function (B-NET) were categorized into 4 groups based on median splits of SPPB scores and WMH burden: Expected Healthy , Expected Impaired , Unexpected Impaired and Unexpected Unhealthy . Functional brain networks were calculated using graph theory methods and white matter hyperintensities were quantified with the Lesion Segmentation Toolbox (LST) in SPM12. Somatomotor cortex community structure (SMC-CS) was similar between UH and EH with both having higher consistency than EI and UI. However, UH displayed a unique increase in second-order connections between the motor cortex and the anterior cingulate. It is possible that this increase in connections is a signal of higher reserve or resilience in UH participants and may indicate a mechanism of compensation in regards to mobility function and advanced WMH burden. These data suggest functional brain networks may be a mechanism for mobility resilience in older adults at mobility risk due to WMH burden."} {"text": "The recurrence of symptoms present before cholecystectomy may be caused by a cystic duct remnant. The resolution of cystic duct remnant syndrome may require surgical resection, but identification of the duct remnant during laparoscopic surgery may be difficult because of adhesions following the previous procedure. Open surgery, which is more invasive than laparoscopic surgery, is frequently chosen to avoid bile duct injury.The patient was a 24-year-old woman with previous laparoscopic cholecystectomy for chronic cholecystitis and repeated attacks of biliary colic. The postoperative course was uneventful, but computed tomography revealed a remnant cystic duct calculus. Ten months after surgery, the patient returned to our department for right hypochondriac pain. Laparoscopic remnant cystic duct resection was performed with intraoperative near-infrared (NIR) fluorescence cholangiography to visualize the common bile duct and remnant cystic duct. The postoperative course was uneventful and the patient was discharged on day 3 after surgery. At the 6-month follow-up, she had no recurrence of pain.Laparoscopic surgery with NIR cholangiography is a safe and effective alternative for the removal of a cystic duct remnant calculus after cholecystectomy. Post-cholecystectomy syndrome (PCS) is a recurrence of upper abdominal and right hypochondriac pain, jaundice, dyspepsia, gastrointestinal disorders, and vomiting experienced before cholecystectomy . PCS mayA 24-year-old woman with chronic cholecystitis and episodes of biliary colic underwent laparoscopic cholecystectomy at our hospital. Although preoperative computed tomography (CT) revealed a cystic duct calculus, the complete removal of the calculus could not be confirmed considering bile duct injury because there were moderate chronic inflammations around the cystic duct. The postoperative course was uneventful and without pain. Ten months later, the patient visited the outpatient clinic because of hypochondriac pain. Laboratory results showed normal liver function, and inflammation and jaundice were absent. CT revealed a cystic duct remnant calculus at the same site as before Fig. . MagnetiPCS is characterized by the recurrence of symptoms experienced before cholecystectomy . In CDRSPrevious systematic reviews have described the potential advantages of fluorescence cholangiography over conventional cholangiography during laparoscopic cholecystectomy . In addiThis patient was safely and successfully treated for a cystic duct remnant calculus by relatively noninvasive laparoscopic surgery in combination with NIR fluorescence cholangiography and ICG."} {"text": "Viruses on \u201cPlant Virus Pathogenesis and Disease Control\u201d give new, important information addressing different aspects of this topic.Plant viruses are emerging and re-emerging to cause important diseases in many plants that humans grow for food and/or fiber, and sustainable, effective strategies for controlling many plant virus diseases remain unavailable. However, cutting-edge technological approaches in cell and molecular biology and rapidly accumulating virus sequence datasets are allowing us to gain new insights into mechanisms involved in pathogenesis and how interactions between plants and viruses affect disease development. In some cases, these offer opportunities for novel approaches to target plant viruses and help control the diseases they cause. Seven original articles in this Special Issue of Solanum lycopersicum) in several parts of the world. Klap and colleagues show further complexity associated with TBRFV-induced disease. They show that when TBRFV co-infects plants with the potexvirus, pepino mosaic virus (PepMV), more severe symptoms develop [Tomato brown rugose fruit virus (TBRFV) is a recently described and rapidly spreading tobamovirus affecting tomatoes ( develop . PepMV cGlycine max) are a globally important crop plant and soybean mosaic virus (SMV) occurs wherever soybeans are grown, in part due to its seed transmissibility. Bao and colleagues developed a GFP-recombinant SMV system to assess SMV-soybean interactions [Soybeans technology to assess the role of microRNA nbe-miR1919c-5p in infections of N. benthamiana plants by tobacco curly shoot virus (TbCSV) and its betasatellite (TbCSB) DNA [Three groups addressed the roles of non-coding RNAs in plant virus infections ,6,7. LiuThese papers are representative of the approaches and opportunities that are available now to gain a better fundamental understanding of plant virus-induced pathogenesis. Obtaining a more fundamental understanding of plant-virus interactions is necessary if we are going to develop efficacious, environmentally sound approaches to control plant diseases caused by plant viruses. We now have fantastic new tools including NGS and bioinformatics approaches to look at virus diversity and host responses to virus infection at the transcriptome but also small and large non-coding RNA levels, not only in different plant genotypes but also in different plant tissues. However, the diversity of papers here also shows that we cannot ignore virus-host biology, and we must consider biology to help us accurately interpret and use what we are finding with modern technologies."} {"text": "Although the physical and cognitive benefits of moderate-vigorous intensity physical activity (MVPA) for older adults is well documented, this population often faces age-related functional and physical limitations impeding recommended MVPA participation. Recently, there has been a surge of interest in the independent health benefits of light-intensity physical activity (LPA) and its association with morbidity and mortality risk. LPA is the most common form of activity among older adults and its potential to combat cognitive aging needs to be investigated. The purpose of this scoping review was to catalog existing evidence on the association between device-based or technologically measured LPA and cognition among healthy older adults, identify trends in the literature, and pinpoint future areas of research. Six electronic databases were searched between January and August 2020. Eighteen published studies met the inclusion criteria: one acute exercise study, two randomized control trials (RCTs), twelve cross-sectional studies, and three longitudinal studies. Overall, n=9 studies reported a significant, positive relationship between LPA and one or more cognitive outcomes including memory, attention, executive function and global cognition (MMSE/MOCA). These heterogeneous findings can largely be attributed to the diverse study designs, inconsistent definitions of LPA and numerous assessments used to test the cognitive domains. Collectively, these findings suggest LPA may be a potential lifestyle intervention to improve cognition among healthy older adults. However, the inconsistent approaches used among these studies suggests a more concerted, unified scientific approach and rigorous methodology are needed to further understand the LPA-cognition relationship."} {"text": "Social engagement may confer cognitive benefits in older adulthood, but studies have typically been restricted to largely non-Hispanic White (NHW) samples. Levels of social engagement vary across race such that NHW report larger social networks, more frequent participation in social activities, and greater social support than non-Hispanic Blacks (NHB). Associations between social engagement and cognition may also vary by race, but research is sparse. The current cross-sectional study examined associations between different aspects of social engagement and episodic memory performance, as well as interactions between social engagement and race among NHB and NHW participants in the Michigan Cognitive Aging Project . Social engagement was self-reported. Episodic memory was a z-score composite of immediate, delayed, and recognition trials of a list-learning task. Separate hierarchical linear regression models quantified interactions between race and each of the three social engagement variables on episodic memory, controlling for sociodemographics, depressive symptoms, and health conditions. Results showed a main effect of more frequent social activity on better episodic memory, as well as an interaction between race and social support indicating a significant positive association in NHB but not NHW. These preliminary findings suggest that participating in social activities may be equally beneficial for episodic memory across NHB and NHW older adults and that social support may be particularly beneficial for NHB. Future research is needed to determine the potential applications of these results in reducing cognitive inequalities through the development of culturally-relevant interventions."} {"text": "Choir interventions confer psychological benefits for persons with dementia (PwD) and their caregivers. However, less is known about whether physiological function also exhibits improvements pursuant to such social-cognitive interventions. The present study, based upon a subsample of the Voices in Motion (ViM) project, explored whether participation in an intergenerational choir results in systematic improvements in gait velocity for both informal caregivers and PwD . Longitudinal burst data from the first of three cohorts spanning 4 assessments over 3.5 months was analysed using multilevel modeling. Whereas caregivers exhibited significant improvements (p<.05) in gait velocity, PwD showed no improvement. Ongoing analyses are exploring additional cohorts, and whether improvements in gait dynamically covary with reductions in comorbidities . These results underscore the potential of choir for facilitating both psychosocial and physiological function for caregivers and PwD."} {"text": "An integrated approach for assessing ventricular pump function, diastolic compliance (EDPVR), myocontractility and pulmonary vascular resistance would be of clinical interest. In addition to pump function, MRI guided catheterization was demonstrated to accurately measure myocontractility and vascular resistance. We now extended this method for acquisition of the EDPVR. Subsequently, this approach was applied in patients with Fontan hemodynamic in which abnormalities in pulmonary vascular, myocontractile and diastolic properties are debated.The EDPVR was determined by synchronizing invasive ventricular pressures with cine and real-time MRI derived ventricular volumes and pulmonary/aortic blood flow measurements.In 7 pigs the MRI and conductance-catheter method (gold standard) were compared for measuring the EDPVR at rest and during dobutamine.Parameters of global function, myocontractility (ESPVR), vascular resistance and EDPVR were measured with MRI at rest and under dobutamine in 14 patients with Fontan circulation.Bland-Altman test showed agreement between the conductance-catheter and MRI method. In the pigs, there was in both ventricles during dobutamine a right/bottom shift of the EDPVR, the stiffness co efficient decreased slightly (p < 0.051). In the patients during dobutamine we noted failure to increase stroke volumes despite increased contractility and evidenced diastolic dysfunction. Active relaxation was inconspicuous but the EDPVR shifted towards the left/top, the stiffness constant remained unchanged. Pulmonary resistance decreased slightly (p = 0.058) and thus showed adequate response to augmented cardiac outputs.This novel MRI method provides differential information about diastolic, systolic and vascular function. The method evidenced that in Fontan patients diastolic dysfunction is an important pathophysiologic cause of heart failure."} {"text": "Chronic stress creates vulnerability to adverse mental and physical health outcomes in later life. While claims about the negative effects of stress on health are primarily based on self-report, it is unclear how subjective stress measures (chronic or perceived stress) and other environmental or individual characteristics relate to physiological stress response. This study examines which contextual features contribute to differences in physiological stress reactivity among adults at risk of type II diabetes . Psycho-social stress was induced via Trier Social Stress Test. Using advanced selection methods, we simultaneously explore multiple predictors and illustrate how different sets of risk and protective factors contribute to normal or abnormal stress reactivity profiles. Preliminary results suggest that the top five important predictors are education, contact with friends, perceived stress, ruminative coping, and sedentary behavior. Implications for research and targeted interventions are discussed."} {"text": "Our purpose was to document the swept source optical coherence tomography (SSOCT) findings in a patient with Shaken baby syndrome (SBS).SSOCT was obtained without sedation in a six-month-old girl with bilateral multilayered retinal hemorrhages due to SBS. It documented vitreoretinal interface abnormalities, including internal limiting membrane (ILM) detachment with retinal traction, in association with other specific changes in the inner and outer retinal layers. Six weeks later, retinal hemorrhages had substantially resolved, and there was optic disc pallor. OCT showed ILM reattachment with release of retinal traction and the development of severe diffuse retinal atrophy involving the fovea.SS OCT can provide useful information in SBS, revealing a wide variety of vitreoretinal interface, inner, and outer retinal changes not detected by clinical examination. It also may have a prognostic value over follow-up. Shaken baby syndrome (SBS), also known as abusive head trauma, refers to a constellation of clinical findings including bilateral retinal hemorrhages, subdural hemorrhage, and anoxic encephalopathy . RetinalA previously healthy six-month-old girl was brought to the emergency department for paroxysmal crying with brief episodes of loss of consciousness. On physical examination there was a bulging fontanel with associated weak axial posture. A cerebral computed tomography (CT)-scan demonstrated extensive bilateral subdural hemorrhages. The child was admitted to the Pediatric Intensive Care Unit. Ophthalmological examination revealed a poor pupillary response to bright light in both eyes. There were no external signs related to ocular trauma. Fundus examination by indirect ophthalmoscopy revealed bilateral preretinal and intraretinal hemorrhages involving the posterior pole and midperiphery. There was a bilateral boat-shaped premacular hemorrhage. This hemorrhage was larger and associated with a prominent surrounding ring-shaped white retinal fold in the right eye Fig.\u00a0. A diagnThree days after hospitalization, the patient underwent swept source OCT imaging with the DRI OCT Triton plus . Multiple SS-OCT scans could be obtained without sedation, the infant being held and her eyelids kept open by an assistant. OCT confirmed multilayered retinal hemorrhages in both eyes. It showed a dome-shaped detachment of the internal limiting membrane (ILM) overlying the macular hematoma bilaterally, with associated perifoveal retinal traction corresponding to the retinal fold seen clinically in the right eye Fig. . Other SSequential follow-up examinations showed gradual resolution of the neurological symptoms and improvement of pupillary response to light. Six weeks after initial examination, retinal and preretinal hemorrhages had substantially resolved, and there were bilateral areas of subretinal fibrosis and optic disc pallor, mainly in the right eye Fig.\u00a0.Fig. 2aSS OCT, six weeks after initial presentation, showed complete reattachment of the detached ILM, with release of retinal traction and resolution of other acute findings. There was a bilateral marked diffuse retinal atrophy involving the fovea with associated subretinal hyperreflective lesions corresponding to the areas of subretinal fibrosis seen clinically Fig. .To the best of our knowledge, this report is the first to describe the use of SS OCT in the assessment and monitoring of retinal disease associated with SBS. Thanks to the faster acquisition times of SSOCT technology, OCT scans could be obtained without sedation, although an assistant was required to hold the infant\u2019s head. Until recently, time domain and conventional or hand-held spectral domain (SD)-OCT have been rarely used in very young children with acute SBS \u20135. OCT iAnother dimension of ocular changes in SBS was described in the field of forensic pathology. OCT findings may provide valuable information suggestive of child abuse in the absence of external evidence of trauma .Our study expands the OCT spectrum of SBS to include a wide variety of previously undescribed vitreous and retinal changes, including alterations of the outer retinal layers. On follow-up OCT examination, severe retinal atrophic changes became evident after resolution of hemorrhages and other acute findings. Our data show that macular atrophy may be an important causative mechanism of severe vision loss in children with SBS.In conclusion, thanks to its faster acquisition time and deeper penetration, SSOCT may be useful in the evaluation and monitoring of ocular disease in awake young children with SBS. It can provide useful information, revealing a wide variety of vitreoretinal interface, inner, and outer retinal changes not detected by clinical examination. It also may have a prognostic value over follow-up."} {"text": "The geometric framework for nutrition has largely been applied to macronutrients in experimental settings. Here, we utilize the framework to examine both macro and micronutrient intake patterns in observational human data. We used nutritional intake patterns of 1754 older Quebecers from the NuAge cohort to predict multi-system homeostatic dysregulation scores calculated from 30 biomarkers. Intermediate intake of both macro- and micronutrients was generally associated with lower dysregulation scores . Furthermore, there were often nutrient-nutrient interactions, such that the optimal level of one nutrient depends on the intake level of others. However, higher protein intake was generally associated with better health, and results varied substantially across different dysregulation systems. Accordingly, even though nutrition does have important effects on health trajectories during aging, it will be challenging to arrive at population-level recommendations to fine-tune nutrient intake patterns to optimize health beyond \u201ceverything in moderation.\u201d Part of a symposium sponsored by the Nutrition Interest Group."} {"text": "The current study takes a dyadic perspective to understand how self-perceptions of aging are associated with C-reactive protein, an inflammation marker, among older adult married couples. The potential moderating role of marital support and strain are also examined. Respondents include 668 married couples who participated in the 2014 wave of the Health and Retirement Study. Actor-Partner Interdependence Models were conducted in Mplus. Age, functional limitations, income, and race served as covariates. Husbands\u2019 greater positive perceptions of aging were significantly associated with their own lower levels of inflammation. Husbands\u2019 greater positive perceptions of aging were significantly associated with lower levels of inflammation for women who reported lower levels of marital strain; this was not the case for women who reported higher levels of marital negativity. This study exemplifies how relationship factors are necessary to consider when examining age perceptions and health among marrieds."} {"text": "The knowledge regarding hypothalamic integration of metabolic and endocrine signaling resulting in regulation of food intake is scarce in fish. Available studies pointed to a network in which the activation of the nutrient-sensing systems would result in AMP-activated protein kinase (AMPK) inhibition and activation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). Changes in these signaling pathways would control phosphorylation of transcription factors cAMP response-element binding protein (CREB), forkhead box01 (FoxO1), and brain homeobox transcription factor (BSX) leading to food intake inhibition through changes in the expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opio melanocortin (POMC), and cocaine and amphetamine-related transcript (CART). The present mini-review summarizes information on the topic and identifies gaps for future research. Two neuronal populations in the mammalian hypothalamic arcuate nucleus respond to a rise in the levels of circulating metabolites . They renucleus lateralis tuberis (NLTv), an analog of arcuate nucleus , specific fatty acid receptors (FFAR), fatty acid translocase, and lipoprotein lipase. Evidence is also available in other species like grass carp induced a rise in hypothalamic Bsx mRNA abundance (In fish, evidence regarding BSX role in hypothalamus is limited with a f nucleus as well nucleus in paralbundance .Npy and Agrp leading to a decrease in food intake (Npy and Agrp (cAMP response-element binding protein is another transcription factor hypothesized to be involved in the connection between brain metabolism and neuropeptides expression. Accordingly, in mammals, a decrease in CREB levels induced a decrease in mRNA abundance of d intake . CREB prand Agrp while leand Agrp or food and Agrp .In fish, available information regarding CREB involvement in food intake regulation is restricted to rainbow trout. In this species, CREB phosphorylation status decreased in response to raised levels of oleate , octanoaAgrp mRNA values while those of Pomc decreased, changes favoring a decrease in food intake (Forkhead box01 is likely involved in the relationship between metabolic changes in hypothalamus and the production of neuropeptides . Thus, id intake .Foxo1 to changes in nutrient levels. However, changes observed in fish would be comparable with those observed in mammalian hypothalamus under anorectic conditions like feeding a high-fat diet (In fish, FoxO1 was characterized in brain in rainbow trout and turbfat diet or treatfat diet . Akt actfat diet , which afat diet . In fishfat diet , octanoafat diet , or insufat diet but not fat diet . These rAgRP/NPY and CART/POMC neurons involved in the integration of signals from nutrient sensors also have receptors for hormones like leptin, ghrelin, insulin, CCK, or GLP-1, among others . The binbsx and mtor mRNA abundance as well as in the presence of oleate for Akt phosphorylation status, and foxo1 and creb1 mRNA abundance. No other studies characterized in fish putative interactions in hypothalamus. However, in rainbow trout treatment with different hormones alter nutrient sensing mechanisms in hypothalamus (In fish, only two studies carried out in rainbow trout demonstrated interactive effects in hypothalamus between nutrient-sensing mechanisms and hormones such as ghrelin and insulin. The presence of oleate counteracted ghrelin effects on AMPK . In the thalamus as demonThe knowledge available in fish about hypothalamic integration of information of metabolic and endocrine nature eliciting changes in expression of neuropeptides ultimately regulating food intake is limited . StudiesThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Introduction. We present a case of serpiginous choroidopathy (SC) with novel OCTA and en face OCT reflectance findings which help identify subclinical disease progression. Case Presentation. En face OCT reflectance images demonstrated outer retinal tubules (ORT) at the serpiginous lesion margins of affected and unaffected retina on multimodal imaging. OCTA findings demonstrate variable dropout of choriocapillaris in \u201cnormal\u201d retina beyond lesion borders which was not visible on standard imaging and which demonstrated a clear transition zone beyond the ORT. Discussion. This is the first report of choriocapillaris atrophy identified on OCTA not identified on traditional multimodal imaging in serpiginous choroidopathy. Damage to vasculature only visible with OCTA may help characterize the distribution of inflammation, aiding in monitoring of suppression not illustrated by traditional imaging and which may threaten the central macula. ORT in SC suggest death and reorganization of outer segments from dysfunction of the choriocapillaris and RPE, as well as serve to demarcate the area of chronic or old inflammation, supporting the hypothesis that the choriocapillaris is the primary site of inflammation in SC. Based on these findings, we recommend OCTA on all patients with serpiginous choroidopathy to monitor underlying state of inflammation and help determine immunosuppressive threshold. The pathogenesis of SC is poorly understood, with clinical and histologic studies suggesting autoimmune, infectious, vasculopathic, and retinal degenerative etiologies , 2. ReceA 37-year-old female with no past medical or ocular history presented with 2 weeks of redness, pain, and photophobia of her right eye (OD). She was diagnosed with acute anterior uveitis by an outside provider and started on topical difluprednate four times daily (QID) and cyclopentolate once daily (QD) OD. Upon presentation to our facility, she reported slight improvement in her symptoms 2 weeks into treatment.On initial examination, visual acuity was 20/20 in her right and 20/20 in her left eye (OS) with unremarkable pupillary exam and normal intraocular pressure. Anterior segment examination of the right eye (OD) revealed 2 areas of anterior corneal stromal scarring and 0.5+ anterior chamber cell without flare. One area of anterior stromal scarring and trace cell without flare was seen OS. Fundoscopy revealed 0.5+ vitreous cell without haze in both eyes (OU); healthy appearing optic nerves OU; and extensive, serpentine peripapillary chorioretinal scarring OU with extension into the macula Figures . There wThe patient rapidly improved, and immunomodulatory therapy was initiated with a standard steroid taper. At one-month follow-up, en face OCT reflectance and OCTA imaging were obtained, which demonstrated severe atrophy with outer retinal tubules and patchy dropout of choriocapillaris in areas of otherwise normal-appearing retina, respectively . Over thWe present a case of serpiginous choroidopathy (SC) imaged with OCTA and en face OCT reflectance imaging. Images were obtained and processed based upon previously described methodologies in the literature , 4.OCTA imaging showed dropout of the choriocapillaris at lesion margins and discontinuously in adjacent areas centrally which appeared normal on traditional imaging such as FA . Prior tOCT angiography allows a noninvasive assessment of choroidal and deep vasculature sometimes not evident on fluorescein angiography (FA). Recently, several small case series of OCTA in SC have suggested extensive inflammation in deep retinal vessels, RPE, and choriocapillaris. Desai et al. reported a series of 6 eyes of 3 patients with active and inactive SC. In this series, active patients demonstrated absence of choriocapillaris with thickening of overlying RPE and outer retinal layers on OCTA in areas of atrophic serpiginous lesions . InactivWe analyzed en face OCT reflectance image slabs, as well as cross-sectional OCT images. En face OCT reflectance imaging demonstrated outer retinal tubules at the quiescent serpiginous margins just adjacent to those areas of atrophic choriocapillaris on OCT which were normal-appearing on funduscopy and FA . Cross-sOn SD-OCT imaging, outer retinal tubules appear as circular areas of hyporeflectivity with a ring of hyperreflectivity contained within the outer nuclear layer. Prior investigations of outer retinal tubules have centered around age-related macular degeneration (AMD) and spectral domain OCT (SD-OCT) but never reported in SC. Of the 69 eyes with outer retinal tubules identified in one study, 81% were attributable to AMD , 11. GivSevere choriocapillaris inflammation may be the cause of outer retinal atrophy in serpiginous choroidopathy, with the presence of ORT signifying reorganization of photoreceptors localizing inflammation to this area. Current multimodal imaging without use of OCTA is widely accepted for the diagnosis and monitoring of SC. In this report, we describe a patient with OCTA findings of choriocapillaris atrophy demonstrating subclinical disease beyond serpiginous lesion borders visible on standard imaging. Loss of choriocapillaris integrity in areas outside of the serpiginous borders suggests subclinical activity which, if followed with OCTA, may aid in earlier identification of progression or more targeted timing for tapering of immunomodulatory therapy if stable. This suggests that OCTA may be more sensitive than SD-OCT and FA in identifying activity in SC and should be more widely adopted in the long-term management of these patients."} {"text": "Understanding age-related change in cognition and identification of pathological changes requires sensitive and valid measurement of cognitive performance across time. Technological advances, such as ambulatory assessment of cognition using smartphones, have enabled intensive longitudinal methods where data is collected with many measurements over time. Our research group has developed novel ambulatory assessments that provide reliable, sensitive, and ecologically valid measurement of cognition across multiple timescales; from momentary changes to change across years. This symposium will present a spectrum of approaches to analysis of intensive longitudinal data that can inform models of cognitive aging. All three presentations will draw on data from measurement burst studies that apply our ambulatory cognitive assessment methods in community-based samples . For each measurement burst, participants undergo assessment consisting of brief surveys and cognitive tests via smartphone, up to 7 times per day across 14 days. Oravecz et al. will discuss the application of a Bayesian multilevel implementation of the double exponential model to account for retest effects while quantifying change in peak cognitive performance across time. Kang et al., will demonstrate a growth curve modeling approach for assessing the effects of between-person variables on change in cognition across measurement bursts. Harrington et al., will demonstrate a model-based cluster analysis approach, leveraging ambulatory assessments of subjective and objective cognitive function to unpack latent groups as a function of age and loneliness. Measurement, Statistics, and Research Design Interest Group Sponsored Symposium."} {"text": "Evidence suggests a growing retirement crisis in the United States among older adults placing many of them at risk of falling into poverty. While Social Security provides income assistance to retirees, the average monthly benefit is $1,300. Among older adults nearing or in retirement, the use of public assistance programs is increasing. Using data collected by the Associated Press-NORC Center for Public Affairs Research we examine retirement preparedness, borrowing from retirement plans, and use of social welfare programs. Findings indicate increased borrowing from retirement plans due to debt, significant differences in racial and gender groups accessing and receiving services among those 75 and older. Increasing rates of unpreparedness for retirement exist among older Americans, particularly among adults of color. An increase in the use of safety net services among older adults is occurring concurrently with severe funding reductions in social welfare programming."} {"text": "Migraine is a multifaceted brain disorder where multisensory disturbances are associated with headache. Yet sensory symptoms are conventionally justified by dysfunctions confined to the cerebral cortex, a perspective through the complex interplay of thalamocortical network would provide the entire picture, more pertinent to the central sensory processing. It is important to consider thalamus as a hub that integrates multiple domains via extensive connections among anatomically and functionally separate cortical areas. Accordingly, cortical spreading depression (CSD), implicated in migraine pathophysiology can be seen as a tool to disconnect thalamocortical network by functionally eliminating cerebral cortex. Hence, including thalamic reticular nucleus and higher order thalamic nuclei, which conveys the information transthalamically among visual, somatosensory, language and motor cortical areas, would greatly improve our current understanding of migraine. Migraine is the most prevalent brain disorder under age of 50 all around the globe and the first cause of disability due to severe headache and associated sensory disorders [1]. The characteristic features of pain are one sided, severe, pulsating headache attacks, worsening by daily movements and lasting 4\u201372 h. Accompanying sensorial symptoms suggesting hyperresponsivity in the somatosensory, visual, auditory, and olfactory systems are distinguishing features of migraine attacks and multisensory stimuli may worsen the headache severity [2]. Additionally, prior to the headache phase more pronounced sensorial disruptions can occur in the visual and somatosensory system such as scintillations, scotoma or paresthesia, numbness in the extremities. These slowly propagating sensory deficits are recognized as aura symptoms and implicated by underlying cortical spreading depression (CSD) waves [3]. CSD is a neuronal and glial depolarization wave that slowly propagates within the cerebral cortex, causing transient electrical and functional silence of the involved area. Propagation of massive depolarizations and accompanying electrical DC shift and regional blood flow increase along the cortex, left long-lasting decreased neuronal excitability and reduced regional blood flow behind . The sensory aura symptoms are considered solely due to cerebral cortical dysfunction by CSD. However, this conventional approach disregards several facts that i) propagation of CSD in gyrencephalic brains such as humans, primates and even felines is very restricted [4], ii) cerebral cortex functions in a synchrony with thalamus and brain network systems. In that sense CSD was essentially used to generate functional ablation of cerebral cortex in thalamic studies [4]. Understanding the function of cerebral cortex requires knowledge of complex interaction between the cortex and the thalamus, known as thalamocortical network. The cerebral cortex and the thalamus operate in continuous interaction during the process of any information particularly related to somatosensory, visual and auditory sensory systems, movement, language, cognition and consciousness . The thalamus sends projections to majority of the cerebral cortex, and receives cortical outputs in return. Thalamic nuclei transmitting peripheral sensory inputs to the primary cerebral cortical areas are considered as the first-order relay nuclei such as the ventral posteromedial (VPM) and lateral geniculate nucleus (LGN) that relay cephalic somatosensory inputs and visual stimuli respectively. Likewise, the higher-order thalamic nuclei receive inputs from the deep cerebral cortical layers and relay information from one cortical area to another . By this means, higher-order thalamic nuclei function as hubs that synchronize distant cerebral cortical areas via transthalamic cortico-cortical connections [7]. The deep cortical cells particularly from the 6th layer, also project to inhibitory neurons in the thalamic reticular nucleus (TRN) and modulate the frequency-dependent thalamic function [6\u20138]. The TRN consists of GABAergic inhibitory neurons and surrounds the dorsal thalamus. While the TRN exclusively projects to the thalamus and inhibits thalamic drive to the cortex, its neurons are driven by the first- and higher-order thalamic nuclei as well as the cerebral cortex . TRN involvement during CSD was demonstrated in awake, consciously behaving experimental animals . CSD induced SD waves were recorded in TRN and neuronal activation was demonstrated. It is likely that either SD in the cerebral cortex could provoke SD in TRN or SD waves propagate from cerebral cortex to the TRN, as subcortical structures are more susceptible compared to highly convoluted cerebral cortex in humans [4]. Involvement of the TRN may play a role in reduced sensory discrimination, lateral inhibition and increased response to sensory stimuli in different modalities such as light, sound and touch during migraine attacks. A subset of cortical deep projection neurons was shown to project selectively to higher order thalamic nuclei in mice and recently the higher order thalamic dysfunction was proposed to be involved in the development of migraine symptoms . Instead of attributing sensory dysfunctions merely to the cerebral cortex, alternative view proposes a complex interaction of first- and higher-order thalamocortical areas along with TRN . A minimum critical volume of 1 mm3 rodent cortical brain tissue was estimated to be depolarized to ignite CSD [11]. Even if the propagation of CSD is blocked, such a depolarized cortical focus is sufficient to create a change in ongoing cortico-thalamic drive on thalamic relay nuclei and thalamic reticular nucleus. During CSD, abrupt cessation of cortical neuronal firing, would result in decreased excitatory glutamatergic drive from cortexto the thalamus, leading to a reduced GABAergic output from TRN on to thalamic relay nuclei and increased sensory impulses through thalamic relay to the cortex . That would account for the increased sensory excitation, sensory hyperresponsivity, reduced discrimination and reduced lateral inhibition and bidirectional role of sleep in migraine. Therefore, the processing of somatosensory stimulus and sensory discrimination was investigated in migraine patients [12\u201316]. For that purpose, somatosensory temporal discrimination (STD) test was employed. STD detects the temporal threshold to perceive two consecutive somesthetic stimuli as undoubtedly distinct [12\u201314]. STD was remarkably prolonged during the migraine attack while STD threshold values outside the migraine attacks were comparable to healthy volunteers [12]. STD studies also revealed that such a prolongation was specific to migraine attacks and was not detected during tension type headache, which is another common headache disorder [14]. It is an intriguing finding that discrimination of somatosensory stimuli applied to the hand that is transmitted through a pathway via thalamic ventral posterolateral nucleus (VPL), is disturbed during migraine attacks. Indeed, migraine headache is transmitted through a different pathway via trigeminal nerve to the thalamic ventral posteromedial nucleus (VPM). Hence, it is unlikely that prolonged temporal discrimination of somatosensory stimulus applied to hand is merely mediated as a direct result of trigeminal nerve or thalamic VPM activation. Transient impairment in the ability of discriminating the exact entry of somatosensory stimuli suggested a central processing dysfunction. Further study was conducted by short afferent inhibition (SAI) paradigm using transcranial magnetic stimulation [16]. SAI evaluates integration of somatosensory input through the thalamic relay neurons in the sensorimotor cortex. The SAI results revealed that impaired sensorimotor integrity and reduced cortico-cortical inhibition between somatosensory and motor cortices were associated with migraine attacks [16]. SAI impairment during migraine attacks, indicated a disinhibition in the sensorimotor integration. Remarkably, the facilitation of motor responses to a conditioned sensory stimulus was detected even several hours prior to the onset of migraine headache [16]. Therefore, the possible involvement of higher order centers seems undisputable. In the higher order thalamic nuclei such as pulvinar, that would be manifested by the disrupted visual information processing and may be related to positive visual hallucinations superimposed on to a first-order incoming information, similar to the patients\u2019 visual auras [4]. Also, higher order visual areas and somatosensory areas are associated with medial and anterior part of the pulvinar that is a multimodal sensory integration area [17]. Therefore, loss of any incoming information by CSD from one of the interconnected cortical areas such sensorimotor cortex or visual cortex to the pulvinar would change impulse trafficking and may yield multisensory sensory symptoms synchronously and/or sequentially.Thus, the view of thalamocortical network dysfunction would clarify positive aura symptoms and simultaneous manifestation of different symptoms related to distant cortical areas such as visual, sensorimotor and language cortices interconnected through a thalamic hub. Additionally, sensorial disruptions in more than one domain accompanying migraine headache can be attributed to multisensory integration dysfunction of the higher order thalamocortical network. Involvement of TRN would contribute sensory hypersensitivity in multiple sensory modalities, lateral inhibition and sensory discrimination problems associated with migraine headache. Additionally, activation of trigeminal pain nucleus through central pathways as a result of thalamocortical dysfunction could also contribute to the development of lateralized migraine headache."} {"text": "The proportion of women of reproductive age who are overweight or obese is increasing globally. Gestational obesity is strongly associated in both human studies and animal models with early-onset development of adult-associated metabolic diseases including metabolic syndrome in the exposed offspring. However, animal model studies have suggested that gestational diet in obese pregnancies is an independent but underappreciated mediator of offspring risk for later life metabolic disease, and human diet consumption data have highlighted that many women do not follow nutritional guidelines prior to and during pregnancy. Thus, this review will highlight how maternal diet independent from maternal body composition impacts the risk for later-life metabolic disease in obesity-exposed offspring. A poor maternal diet, in combination with the obese metabolic state, are understood to facilitate pathological in utero programming, specifically through changes in lipid handling processes in the villous trophoblast layer of the placenta that promote an environment associated with the development of metabolic disease in the offspring. This review will additionally highlight how maternal obesity modulates villous trophoblast lipid processing functions including fatty acid transport, esterification and beta-oxidation. Further, this review will discuss how altering maternal gestational diet may ameliorate these functional changes in lipid metabolic processes in the obese placenta. Throughout the gestational period, maternal nutrient handling must adapt to the increasing needs of the growing fetal-placental unit to ensure developmental processes continue in a healthy and physiological manner. For example, maternal insulin sensitivity diminishes, and fasting serum lipid levels rise late in gestation to preserve necessary macronutrients for trans-placental transport into fetal circulation ,2,3. HowFurthermore, alterations in lipid processing functions of the placenta\u2014including fatty acid (FA) transport, lipid esterification and FA beta-oxidation\u2014have been thought to modulate materno-fetal lipid transport and the resulting changes to fetal lipid exposures may underlie metabolic disease programming. This review will additionally highlight how maternal obesity modulates these lipid handling processes in the placenta and discuss how maternal diet may program these placental processes independently from increased maternal adiposity.The study of the impacts of maternal gestational environment on fetal growth and development is encompassed within the field of research known as The Developmental Origins of Health and Disease (DOHaD) ,5. This 2), whereby a BMI > 25 is overweight and a BMI > 30 is obese palmitate oxidation rates in cultured villous trophoblast cells from otherwise healthy obese Ohioan women [Maternal diet has been identified to impact placental lipid oxidative function in some obese women. Specifically, obese Hawaiian women, who consume the Pacific diet, have been found to have similar mRNA expression levels of mitochondrial and peroxisomal beta-oxidation enzymes as lean Hawaiian women Figure . This maan women . While POne potential method to quantify placental beta-oxidative function is to examine the acylcarnitine profiles of maternal blood products. Under normal physiological conditions, complete beta-oxidation occurs whereby all carbon atoms in the FA backbone are converted into acetyl-CoA molecules that are oxidized for ATP production ,96. HoweAcylcarnitine profiles have previously been examined as potential biomarkers for the early detection of other placental diseases such as pre-eclampsia ,111. SpeAccumulation of shortened acylcarnitine species has also previously been linked to an increased expression of pro-inflammatory molecules . For exaOverall, acylcarnitine analysis may represent a relatively unexplored field in placenta physiology. Analysis of differences within these profiles of obese and lean women may allow clinicians to diagnose placental mitochondrial dysfunctions in conjunction with inflammatory responses early during the gestation period. In turn, acylcarnitine biomarkers may allow clinicians to monitor the impact of dietary interventions on placental lipid handling during gestational period and modulate the course of treatment to limit the risks of offspring development of later life disease.A maternal consumption of a diet high in saturated FA species and low in PUFA species during the gestational period may promote adverse placental function that underlies the development of placental and fetal metabolic dysfunction, independent to maternal body composition. Understanding the mechanisms that underlie placental metabolic dysfunctions associated with dietary fat in obese pregnancies and the accompanying offspring metabolic disorders will require a robust understanding of placental lipid transport, esterification and oxidation . A great"} {"text": "Human brain organoids cultured from human pluripotent stem cells provide a promising platform to recapitulate histological features of the human brain and model neural disorders. However, unlike animal models, brain organoids lack a reproducible topographic organization, which limits their application in modeling intricate biology, such as the interaction between different brain regions. To overcome these drawbacks, brain organoids have been pre-patterned into specific brain regions and fused to form an assembloid that represents reproducible models recapitulating more complex biological processes of human brain development and neurological diseases. This approach has been applied to model interneuron migration, neuronal projections, tumor invasion, oligodendrogenesis, forebrain axis establishment, and brain vascularization. In this review article, we will summarize the usage of this technology to understand the fundamental biology underpinning human brain development and disorders. The human central nervous system (CNS) develops from several distinct vesicles into multiple intertwined regions. During this process, a range of migratory streams arise where progenitors generated in one place migrate and integrate into other areas : the medial ganglionic eminence (MGE) and the caudal ganglionic eminence /CGE cells were observed to migrate into dorsal regions. Slice culture of dorso-ventral fusion organoids and time-lapse imaging analysis revealed characteristic interneuron migratory dynamics. Administration of the CXCR4 antagonist AMD3100 onto organoid slice cultures perturbed the migration, supporting a potential application of the fusion platform for drug screening.Bagley et al. also estNKX2-1::GFP reporter human embryonic stem cell (hESC) line. RNA-seq, scRNA-seq, and chromatin accessibility analysis revealed that hMGEOs exhibited a strong correlation with the transcriptional signature of the MGE tissues from of human fetal brain. By fusing human cortical organoids (hCOs) and hMGEOs, they established hMGEOs-hCOs fusion organoids, named hfMCOs. GFP+ but RFP\u2212 interneuron progenitors migrated into the neuronal layer of hCOs. Their migration can be inhibited by the application of blebbistatin, a myosin II inhibitor. Besides, functional synapses in hfMCOs were also observed by calcium imaging analysis.Further, Xiang et al. generateFurthermore, using a dorsoventral organoid fusion model, Yuan et al. showed tLong distance-projections play essential roles in brain functions. According to recent reports, corticothalamic interactions are relevant for sensorimotor interplay, selective attention, and arousal behaviors is the deadliest and most widespread primary brain tumor in adults. Their property to spread through infiltration in the host brain tissue is associated with high resistance and recurrence rate. To understand the mechanism underpinning this invasive phenotype, organoid-GBM fusion models are particularly appropriate. Ogawa et al. fused tuv\u03b25 axis as a potential mechanism for ZIKV tropism. Thus, organoid-GSC fusion models could be used as in vitro platforms to characterize GBM invasiveness and screen for potential therapeutics.Tumor-organoid fusion models have been used for preclinical therapeutic studies. Previously, the Zika virus (ZIKV) has been proven to be a potential oncolytic virus for brain tumor therapy because of its tropism towards tumor cells are the myelinating glial cells of the brain and the last type of neural cells to be generated after neurons and astroglial cells during mammalian brain development spheroids, endothelial cell (iEC) spheroids, and mesenchymal stem cells (MSCs; Song et al., in vivo vascularization during brain development, and significant improvements still need to be done before obtaining functional vascular networks in organoid cultures.During brain development, the vasculature is one of the important niche components for neural stem cells and plays critical roles in neurogenesis (Bjornsson et al., in vitro. The fusion strategy should not be limited to the fusion of brain tissues as it can be applied to assemble brain organoids with other types of organoids to study the interaction between different organs. For instance, hepato-biliary-pancreatic organogenesis has been modeled using a multi-organoid fusion approach (Koike et al., Brain organoid fusion technology allows us to study more complicated biology during human brain development and neural disorders using hESCs or patient-derived iPSCs, including interneuron migration, and neuronal projections. Using the same technique, researchers can also study other pathological processes and potential mechanisms, such as corpus callosum deformity. Assembling multiple different brain regions would be the next step towards a more complete human \u201cmini-brain,\u201d which could then be used to study biological mechanisms requiring the interaction of several brain regions AC, ZG, and LF wrote the manuscript. AC and ZG prepared the figures. SB directed the manuscript preparation and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "We discuss synergies between sequencing and imaging techniques for the discovery and validation of local molecular signaling mechanisms regulating synaptic development, plasticity, and maintenance in circuits.A key challenge in developmental neuroscience is identifying the local regulatory mechanisms that control neurite and synaptic refinement over large brain volumes. Innovative molecular techniques and high-resolution imaging tools are beginning to reshape our view of how local protein translation in subcellular compartments drives axonal, dendritic, and synaptic development and plasticity. Here we review recent progress in three areas of neurite and synaptic study In neuroscience, physical maps of synaptic connections between neurons (\u201cconnectomes\u201d) help to refine hypotheses about neural computation and provide a shared anatomical resource to guide investigations of circuit function and pathologies associated with human brain disease. Physical maps of developing circuits can also help to identify progressive structural changes across stages of neuronal and synaptic maturation. Connectomic maps are produced using volumetric electron microscopy (EM) techniques that provide dense reconstructions of all cellular processes and synaptic connections in brain tissue. Continued progress in automated sample collection, high-throughput imaging, and computational analysis molecular-genetic approaches for quantifying mRNA diversity, abundance, and regulation of the local transcriptome/translatome in targeted subcellular compartments; (2) proteomic techniques for labeling, isolating, and quantifying nascent proteins and protein-protein interaction networks in specific synaptic connections; and (3) super-resolution fluorescence microscopy for multi-scale imaging and quantitative analysis of subsynaptic molecular organization within developing microcircuits. When applied together, advanced techniques in these areas have important synergies that facilitate discovery, validation, and throughput in new experiments designed to study the local molecular regulation of neural circuit development.In this review article, we discuss a bottom-up \u201cdevelopmental molecular connectomics\u201d approach for investigating the regulation of local molecular remodeling during circuit refinement . We highNeural circuit development requires the precise formation and selective plasticity of synaptic connections distributed across each neuron\u2019s polarized geometry (axons/dendrites) at significant distances from the soma. Because each synapse is an intricate molecular machine assembled from thousands of proteins, the development of circuit connections creates a significant metabolic demand for individual neurons and perform RNA sequencing analysis of compartment-specific isolates for comparison . Such exTo address questions about directed trafficking and mRNA enrichment in specific spatiotemporal contexts, an immunopurification approach called Translating Ribosome Affinity Purification (TRAP) was developed for isolating genetically-tagged ribosomes and their associated mRNAs in targeted circuits uses the transgenic expression of synapse-specific fluorescent fusion proteins to purify specific synapse types from total synaptosomal fractions based on fluorescence-activated cell sorting granules over long distances to dendrites and axons to establish local transcriptome pools axons is developmentally-regulated and shifts during different stages of circuit refinement where mRNAs encoding essential respiratory chain complex proteins are locally translated and assembled into mitochondria in response to stimulation . The induction of hippocampal LTP/LTD Direct evidence for local (synaptic) protein production in response to synaptic stimulation comes from glutamate photouncaging experiments which drive spine growth and local protein synthesis in single activated spines to isolate proteins for quantitative analysis , genetically-encoded proximity-labeling tools have been developed to selectively tag and purify interacting protein complexes from synapses Proximity-labeling experiments with APEX2 fused to presynaptic terminal protein alpha-synuclein identified hundreds of interactors including synaptic proteins, vesicle trafficking proteins, RBPs, and translation initiation factors important for local protein synthesis has been mapped both with BioID or inhibitory (gephyrin) scaffolding molecules conjugated to BirA, the promiscuous biotin ligase was used to study the developmental maturation of olfactory projection neurons provides unparalleled image resolution for synapse analysis but is difficult to combine with conventional molecular labeling tools due to challenges imposed by the use of strong chemical fixatives and epoxy resins in the sample preparation. Further development of EM-compatible transgenic labeling tools will be useful for identifying specific molecular targets and cell/synapse types in EM images patterned excitation approaches [e.g., STimulated Emission Depletion (STED) microscopy , a structural protein at the Drosophila neuromuscular junction (NMJ) essential for the developmental positioning of Ca2+ channels and synaptic vesicles to reconstruct the relative spatial positions of pre/postsynaptic proteins in thin cryosections of brain tissue to map synaptic structure with molecular specificity and nanoscale resolution organization and antibody elution on ultrathin sectioned brain material to achieve multiplexed proteomic imaging with improved axial image resolution while further enabling correlative electron microscopy (Micheva and Smith, in situ (Lein et al., in situ RNA sequencing (FISSEQ; Lee et al., in situ hybridization methods such as multiplexed error-robust fluorescence in situ hybridization (MERFISH; Chen K. H. et al., in situ hybridization (seqFISH; Lubeck et al., in situ and has been further used to identify cell populations that are specifically active during social behaviors (Moffitt et al., in situ hybridization has been performed with expansion microscopy (Chen et al., Multi-round labeling has also been used to develop spatial transcriptomic approaches for mapping RNA identity and position in vitro using PAINT (Guo et al., in situ hybridization strategies for spatial transcriptomic imaging (Chen K. H. et al., In a step toward this goal, multiplexed super-resolution synaptic proteome imaging has been achieved using DNA-oligo-linked primary antibodies which are imaged across multiple rounds of hybridization using complementary detection oligos (Wang et al., The developmental connectomics strategy presented here enables new experiments to determine the molecular blueprint for synaptic development and plasticity in neural circuits. The application of complementary techniques in transcriptomics, translatomics, proteomics, and super-resolution structural imaging establishes an integrative framework for investigating mechanistic links between mRNA trafficking, local protein synthesis regulation, and changes in subsynaptic molecular organization underlying circuit development.Molecular sequencing experiments, both at the RNA and protein levels, generate foundational databases identifying regulators of connectome development and plasticity. Also, proteomic (Sharma et al., Several analytical approaches for integrating multiomic data have been applied to better define cell types in the mature and developing brain (Stuart et al., Though deep learning methods have thus far been developed for analyzing cell types and spatial organization, related approaches should facilitate integrative analysis of subcompartment-specific multiomic and super-resolution imaging data to characterize molecular networks driving synaptic/neurite maturation and plasticity (Poulopoulos et al., JM and CS wrote the manuscript and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Continuous, long-term monitoring with remote capabilities using wearable technology is ideal for capturing information about patient/participant symptoms synced to sensor-based information. The Real-time Online Assessment and Mobility Monitor (ROAMM) is a smartwatch framework configured to collect data in free-living settings from both sensor-based (location and movement) and responses to symptom notifications through a visual display. The symposium presents the overall framework and preliminary findings from a demonstration study in older adults with knee osteoarthritis. Karnati will present the general framework of ROAMM explaining the data flow from the smartwatch to end users (clinicians and research). He will highlight components in the design that makes the framework unique and highly flexible to serve different studies with different research questions. Rouzaud evaluated satisfaction, usability and compliance wearing a smartwatch and using the ROAMM app. Participants were compliant to ecological prompts about pain, fatigue and mood three times a day (82.5% compliance rate). Additionally, > 70% reported being satisfied with the function/usability and comfort with using ROAMM and wearing the smartwatch. Mardini examined the temporal relationship between ecological pain and derived life-space mobility features from Global Positioning System coordinates. Results suggested that higher level of knee pain in older adults was associated with lower life-space mobility. Manini examined physician perception towards an electronic health record (EHR) graphical interface of top ranked patient attributes of pain, falls, hydration and mobility patterns. Results indicated a relatively high level of usability of the EHR interface depicting smartwatch data."} {"text": "We propose that trauma history is important context for understanding the adaptive capacity of aging adults to achieve a suitable person-environment fit. We conducted a scoping review using bibliographic databases to identify studies focused on aging in place, vulnerability and traumatic personal experiences, and aging adults\u2019 maladaptive behaviors. Our review showed little research directly exploring the connection between trauma-related needs and aging in place and limited research about the community\u2019s role in supporting those needs. Literature about the impacts of trauma revealed that trauma could stem from adverse childhood experiences and adult adverse experiences . Adults who have experienced trauma may have increased physiological and psychological conditions. Sensory sensitivities in the home environment\u2014including sounds , air quality , and lighting \u2014can substantially decrease quality-of-life. Strong emotional reactions can make interpersonal relationships, such as those with a landlord or neighbors, difficult and increase the likelihood of eviction. Aging adults with trauma histories also experience greater poverty rates, increasing the likelihood of substandard housing . Because the housing environment is a significant aspect of overall well-being, challenges to aging in place for adults with trauma histories warrants further research, as does the role of community supports in mitigating housing-related stressors. Examples may include trauma-informed approaches in universal design, the availability of safe affordable housing, community education, and funding for intermediaries who can support aging adults."} {"text": "Suillus brevipes, a mycorrhizal fungus adapted to coastal and montane habitats in California. In order to assess whether gene copy number variation mirrored population structure and selection in this species, we investigated two previously studied locally adapted populations showing a highly differentiated genomic region encompassing a gene predicted to confer salt tolerance. In addition, we examined whether copy number in the genes related to salt homeostasis was differentiated between the two populations. Although we found many instances of CNV regions across the genomes of S. brevipes individuals, we also found CNVs did not recover population structure and known salt-tolerance-related genes were not under selection across the coastal population. Our results contrast with predictions of CNVs matching single-nucleotide polymorphism divergence and showed CNVs of genes for salt homeostasis are not under selection in S. brevipes.Gene copy number variation across individuals has been shown to track population structure and be a source of adaptive genetic variation with significant fitness impacts. In this study, we report opposite results for both predictions based on the analysis of gene copy number variants (CNVs) of Brachipodium distachyon (Zymoseptoria tritici and Aspergillus fumigatus (Copy-number variants (CNVs) are genes or genomic regions of varying size with different numbers of copies across individuals. Copy-number differences can arise through genomic rearrangements or produce functional divergence across gene copies resulting in differentially adaptive phenotypes . Furthermore, no SNP variation was found in this gene across coastal individuals strongly suggesting a selective sweep for adaptive alleles allowing colonization of saline environments in coastal California. Nha-1 homologs have been reported as important for salt tolerance in other organisms, including increased Nha-1 expression levels in Arabidopsis thaliana allowing survival in high sodium concentrations and montane California populations previously analyzed in Suillus brevipes is a dikaryotic fungus which means two haploid genomes inhabit the same cell, we therefore assumed diploidy of our samples and followed ST following ST formula is available from https://github.com/abazzical/sbrevCNV). Given the reference genome is rather fragmented .We estimated gene copy number variation from the processed Illumina reads of 27 ape package enrichment analysis on the top 1% diverged CNVs between the two Suillus brevipes reference genome , there were no significant differences in CNV number or CNV size between montane and coastal populations (Wilcoxon rank sum test P > 0.05). The vast majority of CNVs were losses across the whole genome , suggesting salt homeostasis genes are not under selection for different copy numbers in the two populations. However, as shown in the heatmap in We found 83 genes involved in salt homeostasis across the Nha-1-like gene; ProteinID 1095265) showed a range of copy numbers across individuals and its annotation incomplete and based on sequence similarity-based gene predictions and there might be adaptive CNVs related to salt tolerance in the remainder of the genome that remained undetected.Both biological and technical factors likely contributed for the absence of concordance between CNVs and SNPs in lifornia , the preS. brevipes (In conclusion, our results complement findings from previous studies on environmental adaptation in the mycorrhizal fungus"} {"text": "Biliary and pancreatic cancers occur silently in the initial stage and become unresectable within a short time. When these diseases become symptomatic, biliary obstruction, either with or without infection, occurs frequently due to the anatomy associated with these cancers. The endoscopic management of these patients has changed, both with time and with improvements in medical devices. In this review, we present updated and integrated concepts for the endoscopic management of malignant biliary stricture. Endoscopic biliary drainage had been indicated in malignant biliary obstruction, but the concept of endoscopic management has changed with time. Although routine endoscopic stenting should not be performed in resectable malignant distal biliary obstruction (MDBO) patients, endoscopic biliary drainage is the treatment of choice for palliation in unresectable MDBO patients. Self-expanding metal stents (SEMS) have better stent patency and lower costs compared with plastic stents (PS). For malignant hilum obstruction, PS and uncovered SEMS yield similar short-term outcomes, while a covered stent is not usually used due to a potential unintentional obstruction of contralateral ducts. Percutaneous transhepatic biliary drainage was introduced ~40 years ago for the Differences in the level of obstruction of the biliary system allow for a further division of these kinds of problems into resectable or unresectable hilum or distal biliary obstructions. Computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), and even endoscopic ultrasound sonography (EUS) should be used to evaluate the stage and primary source of a malignancy ,10.Treatment plans for malignancies with different primary origins differ from one another when resectable biliary obstructive malignancy diseases are discussed. In general, routine endoscopic stenting has no obvious clinical benefits for patients with malignant distal biliary obstruction (MDBO) ,12,13,14For cholangiocarcinoma, the Bismuth classifications have beeFor hilum cholangiocarcinoma without distant metastasis, resectable tumors present the possibility of resection of the involved intra- and extrahepatic bile ducts as well as the associated hepatic lobes and caudate lobe. Some recent reports have shown excellent results after surgical resection in patients with Bismuth III and IV disease ,23, but Endoscopic stenting is the mainstream endoscopic management approach for malignant distal biliary obstruction of cholangiocarcinoma or pancreatic cancers, but most clinical studies ,24 and mIn ampullary neoplasms, EUS and intraductal ultrasound sonography (IDUS) can assess the depth of invasion as well as the intraductal extension. Importantly, surgical ampullectomy can reduce medical expenses yet have similar clinical outcomes for those that are achieved via pancreaticoduodenectomy for ampuEndoscopic biliary drainage with biliary stent placement is the treatment of choice for palliation in patients with distal malignant biliary obstruction that is caused by unresectable neoplasms, with a success rate of up to 95% ,29,30 anIn some situations, PTCD has been used as part of a rendezvous endoscopic approach. A comparison in 2016 between EUS-guided and PTCD rendezvous drainage after the failure of primary ERCP in MDBO showed that EUS rendezvous had a significantly lower success rate than the PTCD rendezvous . HoweverDifferent stent types are available for the treatment of MDBO. SEMS have a lEUS is a valuable diagnostic modality for the staging of hilum cholangiocarcinomas, particularly for the evaluation of unresectable perihilar cholangiocarcinoma for liver transplantation . PercutaSome evidence indicates that in cases of bilateral biliary opacification, bilateral drainage offers a better survival benefit when compared to unilateral drainage ,70. AfteThe evidence is still insufficient and no clear consensus has been reached regarding the benefits of unilateral versus bilateral drainage for hilar malignant obstruction, although the bilateral approach can be used by most experts using the SEMS stent-within-stent placement ,76 with Plastic stents and uncovered SEMS yield similar short-term outcomes in patients with malignant hilar strictures due to stent migration in SEMS . SEMS prEUS-guided biliary drainage via EUS-guided hepaticogastrostomy (EUS-HGS) is a good alternative for draining malignant hilar biliary obstruction following the failure of an initial ERCP. An EUS-guided rendezvous procedure with the conventional ERCP access ,86 is tyIn cases of malignant biliary obstruction, CT, MRI, MRCP, and EUS should be used for tumor staging and further drainage planning. For resectable malignant biliary obstruction lesions, routine endoscopic drainage or ERCP are not advised, except in cases of concurrent infection. Endoscopic drainage is the treatment of choice for unresectable biliary obstructions. PTCD and EUS-guided biliary drainage can serve as alternative approach methods. EUS-guided biliary drainage can provide equal clinical benefits without increasing complications in a high-tech endoscopy center. In addition, PTCD plays an important role in community hospitals, where the ERCP and/or EUS approaches are not available.For MDBO, single-stent insertion is adequate, and SEMS have better patency than plastic stents; however, the superiority of FCSEMS, PCSEMS, and UCSEMS remains under debate. For malignant hilar biliary obstructions, drainage of >50% of the liver volume should be achieved by either bilateral stenting or multi-segmental stenting, and SEMS\u2019 longer biliary patency when compared with plastic stents should be considered. The general approaches to malignant biliary obstruction are summarized in the flow chart presented in"} {"text": "The effects of retirement on cognition are still unclear and empirical evidence is conflicting. Especially for retirement from cognitively demanding jobs, positive as well as negative effects have been reported. Leisure activity engagement has been hypothesized to play an important role in explaining the mixed evidence. In this study, we examine the interplay between job demands before retirement and changes in leisure activities before and after retirement and their relation to post-retirement cognitive functioning. Using data from the HEalth, Aging and Retirement in Sweden (HEARTS) study, cognitive trajectories before and after retirement were modeled in a multi-level piecewise model (N = 2688 observations). Post-retirement memory and reasoning ability were predicted by self-reported work demands and changes in leisure activity engagement. Results imply a stable increase in memory over the retirement transition and less steep increase in abstract reasoning after retirement. Work demands and leisure activity participation were not related to post-retirement cognitive change. Job demands and leisure activity engagement may not play an important role for short-term post-retirement cognitive functioning. These findings support the conclusion that retirement, independent of prior work demands, does not affect cognitive functioning negatively."} {"text": "The purpose of our Geriatric Workforce Enhancement Program is to provide geriatric and primary care education and training to long-term care (LTC) providers and staff, health professions students and community members. Our LTC partners and the communities we serve are often very rural and travel to urban areas for training can be difficult. Therefore, we have developed four online training that are offered free to our partners and rural communities statewide. These programs are designed to integrate the aims of the Age-Friendly 4M\u2019s model . The LTC nurse residency program provides gerontological nursing and inter-professional leadership training , in a synchronous online environment. The asynchronous Alzheimer\u2019s Disease and Related Dementias training modules educate LTC staff and family caregivers about types, diagnosis and care of older adults with dementia (Mentation and Medication). The asynchronous Opioid Use in LTC modules were developed with partners to deliver live at LTC staff trainings about opioid stewardship (Medication). The LTC Learning Communities are monthly tele-health sessions for inter-professional LTC teams to discuss current issues and propose solutions . We have successfully leveraged different synchronous and asynchronous online modalities to increase educational opportunities for formal and informal caregivers, including those in rural areas whose educational opportunities are geographically limited. To date our programs have reached over 500 individuals across our state, increasing knowledge about geriatric concepts, communication and team leadership. Moving forward, we will continue to develop and refine educational programs that promote the Age-Friendly geriatric-focused health care."} {"text": "The widespread consumption of \u2018western\u2019-style diets along with sedentary lifestyles has led to a global epidemic of obesity. Epidemiological, clinical and preclinical evidence suggests that maternal obesity, overnutrition and unhealthy dietary patterns programs have lasting adverse effects on the physical and mental health of offspring. We review currently available preclinical and clinical evidence and summarise possible underlying neurobiological mechanisms by which maternal overnutrition may perturb offspring cognitive function, affective state and psychosocial behaviour, with a focus on (1) neuroinflammation; (2) disrupted neuronal circuities and connectivity; and (3) dysregulated brain hormones. We briefly summarise research implicating the gut microbiota in maternal obesity-induced changes to offspring behaviour. In animal models, maternal obesogenic diet consumption disrupts CNS homeostasis in offspring, which is critical for healthy neurodevelopment, by altering hypothalamic and hippocampal development and recruitment of glial cells, which subsequently dysregulates dopaminergic and serotonergic systems. The adverse effects of maternal obesogenic diets are also conferred through changes to hormones including leptin, insulin and oxytocin which interact with these brain regions and neuronal circuits. Furthermore, accumulating evidence suggests that the gut microbiome may directly and indirectly contribute to these maternal diet effects in both human and animal studies. As the specific pathways shaping abnormal behaviour in offspring in the context of maternal obesogenic diet exposure remain unknown, further investigations are needed to address this knowledge gap. Use of animal models permits investigation of changes in neuroinflammation, neurotransmitter activity and hormones across global brain network and sex differences, which could be directly and indirectly modulated by the gut microbiome. The worldwide prevalence of obesity has tripled since 1975, accompanied by a sharp increase in obesity among women of reproductive age . MaternaObservations regarding neurodevelopmental impacts of maternal obesity have emerged more recently, building on extensive evidence linking higher maternal body mass index (BMI) to adverse offspring metabolic and cardiovascular outcomes. This literature has been reviewed elsewhere and is not examined here ,8,9. RatHuman and preclinical studies of the impacts of maternal obesity and overnutrition on offspring behaviour can be categorised into three areas: cognition, affective states and psychosocial behaviour. Although human studies have shown associations between these domains and maternal body weight and diet on offspring cognition. One of the challenges in interpreting behavioural data regarding cognition is the heterogeneity in tests and test parameters employed across studies, as noted in a recent meta-analysis and systematic review which coIncreased proinflammatory signals including IL1\u03b2 and TNF\u03b1 were found in the whole brain of male and female mouse offspring of obese mothers at P0, with mixed effects seen at P7 and P21 . ElevateResults from several studies in humans indicate that maternal obesity alters affective states in children. For example, extreme maternal obesity (pre-pregnancy BMI \u2265 40) was associated with hyper-reactivity and affective changes in children, independent of demographic variables, prenatal factors or maternal anxiety and depression . A populBy contrast, preclinical studies using affective measures in rodents show mixed results, with maternal obesity found to increase ,39,41,53Although behavioural measurements differ between studies, preclinical studies have often sought to link affective changes to dysfunctional HPA axis activity, altered neuronal plasticity and increased neuroinflammation. The HPA axis regulates physiological stress responses and modulates behaviour in response to stressful stimuli, and its function is programmed by maternal obesity. An association between hyper- and hypo-active HPA axes and anxiety- and depressive-like behaviour, respectively, has been well documented . Two stuApart from differences in experimental research protocols one possible reason for the discrepancy between the results seen in human research and the mixed results from animal models might relate to methodological differences in reporting negative emotional states in humans and rodents. Human studies tend to use parental reports regarding child emotional states, whereas studies using rodents monitor anxiety- and depressive-like behaviour using ethologically relevant tests in the offspring themselves, such as forced swim, open field, elevated plus maze, dark-light box and sucrose preference tests, which cannot fully capture the breadth of negative affective states in human children. We argue that despite these challenges, the ability to associate behavioural outcomes with neurohumoral and molecular readouts in preclinical research has merit.The potential link between maternal obesity and Autism Spectrum Disorder (ASD) has been extensively investigated over the past decade or so. Several recent meta-analyses and reviews indicate an increased risk of ASD in children of mothers who were overweight or obese at the time of conception ,50. In aDespite growing interest in the link between maternal obesity and aspects of psychosocial behaviour in children in human studies, few studies have explored this relationship in animal models. Research to date has examined social interaction, anxiety and locomotor activity. Several studies have found evidence that neuroinflammation might contribute to impaired social behaviour in offspring of overfed dams: Kang et al. reportedObesity during pregnancy alters neuroendocrine, metabolic and inflammatory status and these exposures might affect foetal development, in turn influencing behaviour, emotion and cognition. In addition to neuroinflammation, altered neuronal plasticity and dysregulated brain metabolism likely contribute. Another mechanism attracting recent attention is changes in the composition of the gut microbiome, which contains trillions of bacteria, and plays a crucial role in health and disease of the host . In the Rodent models of maternal obesity have shown evidence of hypothalamic inflammation in offspring, characterised by elevated levels of TNF\u03b1, IL1b, and IL6 in adulthood, both in rats and miceAnother possibility is the involvement of glial cells. Glial cells such as microglia and astrocytes are essential for regulating immune responses and act as metabolic sensors . SeveralIn the context of maternal obesity and effects on offspring behaviour, an experimental study showed changes in glial cell proliferation and reactivity in mouse offspring of obese mothers, characterised by astrocyte proliferation and elevated levels of IL6 in the hypothalamic arcuate nucleus (ARC) and the supraoptic nucleus (SON) compared with offspring from normal weight dams . This evLactobacillus reuteri suppressed neuroinflammation by binding to a receptor expressed on astrocytes [L.reuteri produces gamma-aminobutyric acid (GABA) which has inhibitory effects on neuronal circuity [L.reuteri regulates social behaviour in mice via the vagus nerve pathway interacting with oxytocin in the VTA [Lastly, increasing evidence suggests an intriguing relationship between glial cells and the gut microbiome. Preclinical studies using conventional and germ-free mice showed that the gut microbiota indirectly regulate homeostasis and immune reactivity of microglia . Gut mictrocytes . Neurointrocytes . Notablycircuity . A recen the VTA . In summStudies in rodents and humans link maternal obesity to neurological changes in offspring. A recent human study reported a negative association between maternal BMI and hippocampal volume in male children at 7\u201311 years of age . FurtherRecent studies using functional magnetic resonance imaging technology indicate an association between higher pre-pregnancy BMI and altered white matter microstructure , neuronaDopamine is a neurotransmitter regulating motivational and reward-related functions. A recent preclinical study showed that consumption of cafeteria diets during pregnancy induced epigenetic changes in the dopamine receptor (DAT), dopamine transporter 1 (DRD1) and dopamine transporter 2 (DRD2) genes in the nucleus accumbens (NAc) and VTA, two key regions of the dopaminergic pathway . In the Perinatal exposure to maternal obesity and poor diet induces lasting effects on the central serotonergic system in female offspring . High faEvidence from animal models shows maternal obesity programs the rat offspring\u2019s health trajectory towards obesity by impaired lipid and glucose metabolism and appetite regulators ,94. InteMaternal overnutrition also alters the endocannabinoid system through impaired leptin signalling in the hypothalamus. Interestingly, only male rat offspring of HFD-fed dams exhibited impaired leptin signalling, with epigenetic changes in promoter regions of sex hormone signalling at birth . The sexThe adverse changes in brain metabolism in offspring from obese dams include altered mammalian target of rapamycin (mTOR) signalling in the rat hypothalamus and in tOxytocin is another brain hormone for which there is evidence of a relationship between maternal obesity and aberrant offspring behaviour. Oxytocinergic neurons in the PVN project to the amygdala, hippocampus, NAc and VTA, and peripherally project to the pituitary into the blood stream ,115. OxyThe \u2018gut-brain axis\u2019 describes the complex communication network between the gut and brain, comprising the enteric nervous system, sympathetic and parasympathetic branches of the autonomic nervous system, in addition to neuroendocrine signalling pathways, and neuroimmune systems . Emerginlactobacillus spp. abundance in the infant gut [Only limited evidence is currently available for an association between maternal diet and offspring gut microbiome composition in humans. Savage et al. showed a weak but positive association between maternal diet, characterised by high vegetable intake and low processed/fried food intake, and fant gut . A recenfant gut . Exposinfant gut . A caveafant gut . We havefant gut . Therefofant gut .Staphylococcus and Lactobacillus and lower numbers of Bifidobacterium bacteria relative to normal weight mothers [Lactation is another key period that shapes the offspring\u2019s gut microbiome, immune system and behaviour. Breast milk is comprised of non-nutrient components such as immunoglobulins, oligosaccharides, growth factors, and epithelial and immune cells, which could reflect maternal health, and DNA\u2014essential bioactive compounds that foster the development of the gastrointestinal, immune and neurological systems in offspring . Indeed, mothers . A recen mothers . What isThere is now broad evidence from human and animal studies indicating that maternal obesity, overnutrition and unhealthy dietary patterns induce adverse effects on behaviour and neurodevelopment in offspring. This review has identified possible underlying neurobiological mechanisms for these effects, which include neuroinflammation, disrupted neural circuitries and connectivity and dysregulated brain hormones. Dynamic interactions between these factors shape behaviour during gestation and lactation through the offspring\u2019s exposure to maternal obesity via the placenta, gut microbiome and breast milk. Future research should continue to examine behaviour and brain changes in maternal obesity models beyond the hippocampus and hypothalamus, given recent evidence from imaging studies suggesting that aberrant behaviour might be a result of dysregulated global network in the brain, in addition to region-specific dysfunctions. In addition, future research should be targeted at characterising the intriguing sex differences evident in many maternal obesity studies, given that current preclinical studies are still skewed towards males. Human studies using advanced imaging techniques could provide a useful resource to guide animal studies to further elaborate underlying mechanisms. Further, animal models need to incorporate experimental protocols that maximise translational relevance to align with human studies in terms of dietary components, feeding duration and behavioural tests, to allow behavioural and molecular outcomes to be systematically assessed longitudinally and compared across species where possible. Studies currently underway should yield more valuable data on the longer-term effects in humans."} {"text": "Diffuse gliomas, such as glioblastoma (GBM), represent the most common and aggressive form of brain cancer with an unfortunate dearth of treatment advances despite decades of ongoing research . PerhapsDespite this prospect, the aggressive biology and low incidence of gliomas make them poor candidates for conventional screening strategies. Case reports of serial neuro-imaging studies of GBM, with scans taken as few as 68\u2009days apart, show that even small cortical lesions can rapidly evolve into established disease within a very short clinical time frame (<\u20093\u2009months) . This shConsequently, when conceptualizing an effective screening tool for gliomas, brain health changes would need to be monitored over short intervals (days to weeks) using tools that could be practically applied to the general population. Herein lies the immense potential of using emerging non-invasive electroencephalography (EEG)-based biotracking devices to serve as agents that gather continuous health data from our nervous system Fig.\u00a0a. These With these exciting prospects in mind, several potential limitations at present are worth highlighting. Current EEG wearables, designed for niche application , only require a handful of sensors for their intended uses. The optimal quantity and spatial distribution of sensors for effective screening of central nervous system pathologies therefore still need to be defined. Additionally, the amount and timing of daily wear needed to detect subtle baseline changes would also need optimization and balance with enthusiasm to wear such devices. Despite these current unknowns, rapid and widespread acceptance of other smart wearables offers encouraging insights. For example, despite only debuting in 2015, Apple shipped >\u200940 million smartwatches in 2018 with the global wearable market expected to grow to >\u2009279 million users by 2023. This estimate of the wearable market alone could allow the detection of tens of thousands of brain tumors annually! With increasing possibilities and interest at the intersection between artificial intelligence and brain-machine interfaces , such devices may soon even become essential tools to intellectually compete in society. It is therefore possible that consumer demand for brain wearables may quickly mirror the rapid growth of their hardware manufacturers and extend far beyond current niche applications and existing smartwatch demands . Lastly,The ability of these devices to provide continuous longitudinal and personalized data, along with the advent of modern deep learning computational tools, could provide new solutions for the early detection and differentiation of various nervous system pathologies. Large-scale detection of incipient tumor formation could also provide new epidemiological insights of unappreciated risk factors and mechanisms of gliomagenesis. Deployment of these devices to existing brain tumor patients could also help monitor disease recurrence and understand treatment-related neurocognitive sequalae.Brain tumors such as GBM carry a dismal prognosis which has challenged conventional treatment paradigms for decades. Conceptualizing novel early detection-based approaches for these tumors may provide success in a patient population where conventional late-stage diagnosis and treatment have failed. While the role of early detection in the management of brain tumors is still unclear, recent innovations in personal brain wearables, artificial intelligence, and evidence for the benefits of aggressive surgery offer new opportunities to refine our clinical approach to these challenging clinical entities."} {"text": "Under physiological conditions, a balance between oxidants and antioxidants exists. Reactive oxygen species (ROS) are continuously generated by aerobic cells and eliminated through scavenging systems to maintain redox homeostasis. Disruption of redox homeostasis results in oxidative stress and altered ROS signaling. Higher ROS levels can lead to DNA mutation and genomic instability which can play causal role in cancer development and progression. These mutations coupled with distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation, and inefficient repair mechanisms.Cancer cells are energy intensive, owing to their high rate of proliferation. However, due to impaired TCA cycle and poor blood perfusion, cancer cells switch towards glycolytic pathway for energy generation termed as \u201cWarburg effect.\u201d Such pathways lead to a higher oxidative environment. The oxidative environment is also enhanced by tumor-infiltrating macrophages and neutrophils. Thus, cancer cells are used to a high ROS environment. This redox imbalance allows for protumorigenic cell signaling. In this issue, we explore the relation between ROS and cancer. The issue comprises of twenty original articles and comprehensive reviews.Reactive oxygen species (ROS) mediates cisplatin-induced cytotoxicity in tumor cells. However, when cisplatin-induced ROS do not reach cytotoxic levels, cancer cells may develop chemoresistance. Di Vito et al. reported the association of ferritin heavy subunit (FHC)-ROS axis with cisplatin resistance in ovarian cancer cells. Thus, implying that inhibition of FHC might be a potential approach for restoring cisplatin sensitivity of resistant ovarian cancer cells. The authors investigated whether the modulation of H-Ferritin might affect cisplatin-induced cytotoxicity in ovarian cancer cells. H-Ferritin knockdown strengthened cisplatin-mediated ROS increase and significantly restored sensitivity resistant ovarian cancer cells.via a ROS-dependent mitochondria-mediated pathway. H\u00e4m\u00e4l\u00e4inen et al. investigated the expression of redox regulator nuclear factor erythroid-2-related factor (NRF)1 and NRF2 in skin lesions like naevi and melanoma from 172 patients. NRF1 and NRF2 are transcription factors essential for maintaining redox homeostasis and coordinating cellular stress responses. The study found the association of redox microRNAs (miRs) with aggressive melanoma feature. This study opens up avenues to test these redox miRs as possible prognostic value in larger cohorts. The research article by Pires et al. described label-free mass spectrometry- (MS) based proteomics of breast cancer (BC) plasma to investigate the differences between circulating proteins between chemoresponsive and chemoresistant luminal A breast cancer. Protein-protein interaction networks were created utilizing using in silico tools. The study reports interesting findings on differences in inflammatory, complement system, and oxidative stress pathways in both BC phenotypes which holds potential clinical implications. Moreira et al. presented their findings about the antitumor effect of celastrol, a natural pentacyclic triterpenoid, in colon cancer cells with acquired resistant to cytotoxic drugs. Yang et al. have evaluated the anticancer and anti-invasive properties of alpha-lipoic acid (ALA) in gastric cancer cells. ALA is a naturally occurring thiol antioxidant which is known to exhibit antiproliferative and cytotoxic effects on several cancers. The study found that the Mucin 4 (MUC4) gene was strongly expressed in human gastric cancer tissues. ALA administration reduced the proliferation and invasion of human gastric cancer cells by suppressing MUC4 expression. Helfinger et al. reported expression of Nox4 in macrophages and the role played by them in determining the polarization and the phenotype of macrophages. In the report by Acheva et al., authors showed epithelial to mesenchymal transition (EMT) in lung cancer cells postexposure to oxidative stress of gamma radiation. The authors conclude that induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure to gamma radiation and that the presence of stromal component might enhance the effect through free radical production and accumulation.Studies by Zhao et al. in osteosarcoma cells found that metformin (drug for type 2 diabetes) suppressed the self-renewal ability of osteosarcoma stem cells (OSCs) and induced G0/G1 phase arrest by blocking the activity of cyclin-dependent kinases. Metformin triggered apoptosis in these cells, which promoted cell death Gao et al. investigated the association of nitric oxide metabolites and lung cancer incidence through a matched case-control study based on the German ESTHER cohort. The study deduced that subjects with high urinary nitrite/nitrate concentrations had an increased risk of lung cancer. Butturini et al. highlighted plant-derived Sesquiterpene as a potential for cancer therapeutics. The authors exhibited that the compound downregulated STAT3 signaling leading to an antitumor effect and correlated the anti-STAT3 activity with their ability to decrease GSH levels in cancer cells. These properties make them lead compounds for the development of a new therapeutic strategy for cancer treatment.In addition to these original works, Kim et al. listed a comprehensive report on the ROS-inducing strategy in anticancer therapy. The review by Xian et al. summarized the role of ROS in cutaneous carcinogenesis and skin cancer progression. Akanji et al. provides a comprehensive account of hypoxia-inducible factors (HIFs). In the review by Lv et al., the authors discussed recent understanding in the involvement of Glutathione (GSH) in cell death pathways such as apoptosis, necroptosis, ferroptosis, and autophagy. Goh et al. performed online literature search to identify studies reporting metabolic biomarkers of aerodigestive squamous cell carcinomas (ASCC). Akbari et al. have focused on the role of hydrogen sulfide in bladder, kidney, and prostate malignancies.In the review by Tataranni et al., the authors have addressed the therapeutic potential of dichloroacetate (DCA) in cancer therapy. DCA is a 150 Dalton, water-soluble acid molecule, analog of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. The authors have summarized recent reports suggesting the employment of DCA in cancer therapy, in combination with chemotherapy agents, radiotherapy, and other chemical or natural compounds showing anticancer properties. Paz et al. in their review have discussed the pharmacological effects and toxicogenetic impacts of omeprazole in context of cancer. This extensive report highlights that omeprazole therapy may induce genomic instability and increase the risk of certain types of cancer and hence advocates for taking adequate precautions, especially in long-term therapeutic strategies. The review by Fiocchetti et al. focused studies conducted on Neuroglobin (NGB), a globin primarily described in neurons as an oxidative stress sensor and cytoprotective factor against redox imbalance.Although ROS sustain tumorigenesis and cancer progression, these can also be efficient therapeutic tools to fight cancer. Oxidative stress-based therapies like radiotherapy, chemotherapeutic agents, and photodynamic theory increase ROS levels in the tumor niche and take advantage of the cytotoxic face of ROS for killing tumor cells by a nonphysiologically sudden, localized, and intense oxidative burst. Clinical efficacy of anticancer therapies is often subdued by multidrug resistance (MDR). Redox therapy by using redox-active drugs or inhibitors of inducible antioxidant defense in tumor microenvironment has reported to be effective against MDR tumors. Further insight into such redox biology will enable precisely targeted manipulation of ROS for effective medical therapies against carcinomas."} {"text": "Caenorhabditis elegans. We discuss how cell surface receptor complexes link to and modulate actin dynamics to regulate dendritic and axonal branch formation. The mechanisms of neurite branching are often coupled with other neural circuit developmental processes, such as synapse formation and axon guidance, via the same cell-cell surface molecular interactions. We also cover ectopic and sex-specific neurite branching in C. elegans in an attempt to illustrate the importance of these studies in contributing to our understanding of conserved cell surface molecule regulation of neurite branch formation.The high synaptic density in the nervous system results from the ability of neurites to branch. Neuronal cell surface molecules play central roles during neurite branch formation. The underlying mechanisms of surface molecule activity have often been elucidated using invertebrates with simple nervous systems. Here, we review recent advances in understanding the molecular mechanisms of neurite branching in the nematode An extensive neurite branching morphology is a fundamental aspect of neuronal structure. Each axon and dendrite contain numerous neurite branches that enhance neural circuit complexity by allowing for interaction with a large number of target neurons and non-neuronal cells. For example, a single neuron can synapse onto multiple target neurons due to the extensive branching of the axonal shaft. Dendrites have an extremely complex branching thereby producing a large dendritic field to receive synaptic or sensory inputs. These neurite branch networks allow for the formation of highly complex neural circuits that integrate and process information, thereby coordinating specific nervous system functions. Growing evidence suggests that dysregulation of neurite branching could underlie various neurological and neurodevelopmental disorders such as autism, schizophrenia, and Down syndrome or synaptic output functions of the posterior section of the body. These neurons extend elaborate dendritic branches throughout the body excluding the head , leading to defects in harsh touch response , an IgSF cell surface protein and their modifying enzymes , it also possesses 294 sex-shared neurons, some of which show notable sex differences in neuronal structure, branching pattern, and synaptic connectivity and regulated by conserved cell surface molecules , DD06 neurons , and PHC neurons (male-specific axon extension; Cook et al., Drosophila brain revealed several conserved, but previously unidentified, cell surface molecules that act as regulators of neural circuit formation (Li et al., Over the past decades, studies have identified numerous cell surface molecule interactions implicated in neural circuit formation processes including neurite branching. Most of these molecules possess conserved structural domains, such as LRR, Ig domains, and cadherin repeats, which mediate protein-protein interactions necessary during neuronal morphogenesis (De Wit and Ghosh, HJ and BK developed the concept. Both have written and edited the text.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Benevolence directed towards older adults can cross the line between respect and overaccommodation that undermines their physical and cognitive capabilities ; however, little research has examined the subtleties of the influence of benevolent ageism on older adults\u2019 ratings of their own functioning. Because stereotypes about older adults include the decline of mental abilities, this study examined whether their (N= 155) experiences with benevolent ageism, or overaccommodative offers of assistance and protection, influenced their own appraisals of memory abilities through their feelings of self-compassion. Older adults with fewer benevolent ageist experiences had higher rates of self-compassion, which in turn translated into better evaluations of their memory abilities. Future research should consider the potential pernicious influences that benevolent ageism has on older adults\u2019 self-evaluations and performance, consider self-compassion as a buffer in these relationships, and test whether these relationships have downstream consequences on well-being outcomes."} {"text": "This symposium will examine positive and negative aspects of older adults\u2019 relationships and their impacts on health and well-being. We will begin by reviewing the past decade of research on family gerontology. Seidel\u2019s meta-analysis of 995 articles will identify prominent theories and methods, as well as remaining research gaps. The subsequent presentations provide current, cutting-edge research. Marini examines how associations between rumination and sleep unfold within a social context. The findings highlight how spousal support protects older adults\u2019 sleep quality from rumination, whereas support from family and friends is vulnerable to rumination. Using an actor-partner approach, Novak investigates the dynamics of support and control on health among older gay couples. Results reveal the benefits of support and risks of control for partners\u2019 diet quality and depression. Ermer adopts a dyadic perspective to examine links between self-perceptions of aging and inflammation. Results highlight how wives\u2019 inflammation is sensitive to husbands\u2019 aging perceptions, particularly if marital strain is low. Finally, Wilson characterizes age-graded patterns of relationship narratives and their protective effects on emotional well-being. The findings demonstrate how older-adult couples\u2019 narratives are less self- and present-focused, which helps explain protective linkages between age and negative mood. The symposium will conclude with remarks from discussant Katherine Fiori, a GSA Fellow and internationally recognized scholar on older adults\u2019 social networks. She will synthesize the research and put forth her new theory about the importance of peripheral ties in later life to help direct the future of research on older adults within a social context."} {"text": "Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood\u2013brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke. Stroke is currently the fifth leading cause of death in the US, and someone dies of one approximately every 4 min. Stroke occurs due to the interruption of blood flow to the brain, and is typed as ischemic or hemorrhagic. Ischemic stroke makes up approximately 87% of total strokes. Ischemic stroke survivors may not fully recover and develop long-term disabilities ,2,3, sucCerebral functional insufficiency in chronic stroke might be due to pathological changes in brain areas remote from the initial ischemic lesion, for example, diaschisis. In this review, the BBB is implicated in subacute diaschisis. Additionally, BBB competence in chronic diaschisis using a transient middle cerebral artery occlusion (tMCAO) rat model is discussed as well. BBB alterations can be demonstrated in not only the ipsilateral hemisphere, but also the contralateral hemisphere, an area with remote brain structures not directly affected by ischemia. The microvascular damage in the subacute phase likely reveals ischemic diaschisis, and should be considered in the development of treatment strategies for stroke. The direct targeting of cell delivery into the injured vasculature might be a feasible approach for stroke treatment, and endothelial progenitor cells (EPCs) serve as a promising cell source for BBB restoration in stroke. The ability to preserve the mitochondria and increase these organelles\u2019 pinocytosis via cell-based therapeutics represents a new neurorestorative mechanism in BBB repair.Microvascular damage in ischemic stroke demonstrates ischemic diaschisis. In this review, the investigation of subacute diaschisis in ischemic stroke rat models exhibits stroke-induced pathological disturbances in ipsilateral and contralateral brain areas, and causes microvascular damage with BBB breakdown in remote brain microvessels. Additionally, widespread microvascular alterations in ipsilateral and contralateral brain hemispheres suggests continued BBB damage in chronic ischemic stroke. Because of the rampant pathological microvascular changes in remote brain areas in both subacute and chronic ischemic diaschisis, such vascular damage presents as a therapeutic target for stroke. The use of bone marrow-derived mesenchymal stem cells has been initiated to treat patients with acute ischemic stroke. Here, we discuss the potential use of EPCs as an effective cell source for BBB restoration in stroke by promoting neurovascular repair and preserving the mitochondrial morphology of the microvasculature.Following an ischemic stroke, substantial alterations in both cellular and molecular activity take place due to stroke-induced cerebral pathology ,6. StrokStroke pathology due to vascular injury is time-dependent and can be classified into three types: acute (minutes to hours), subacute (hours to days) and chronic (days to months). The acute and subacute stages of ischemic stroke can be grouped into one period, as secondary cell death following both phases drastically overlap ,6,8. NotIn-depth investigations into stroke pathology have brought about the phenomenon of diaschisis, an abrupt change in activity in regions of the brain far-off from the ischemic lesion generated by stroke-induced impairments. Transhemisphere diaschisis was first recognized through blood flow and metabolism alterations in unilateral and contralateral ischemic hemispheres in the brain . After iNevertheless, in the context of the subacute phase, BBB functionality and the associated pathology in distal brain regions have received less focus . A comprThe effects of subacute diaschisis on BBB stability and associated pathological mechanisms in contralateral regions of the brain were evaluated in focal ischemic stroke rat models . Using tMoreover, BBB impairment in distal cerebral microvessels and endothelial autophagosome build-up could be correlated with the injuries observed in the ipsilateral and contralateral brain regions spurred by focal ischemic stroke . ImportaBy utilizing a focal ischemic stroke rat model, subacute diaschisis could be explored ,29,36,37A major pathologic characteristic of subacute tMCAO involves BBB impairment in the ipsilateral and contralateral striatum and motor cortex ,29,36,37Parenchymal extravasation plays a role in secondary cell death following an ischemic stroke, and can be linked to diaschisis and BBB impairment. An in vivo study illustrated that EB extravasation was amplified in the MCAO group when compared to the control group, and could be associated with exacerbated BBB integrity . A high Autophagy in capillary ECs following ischemic stroke may heavily contribute to cell impairment and BBB alteration. It is still unknown whether enhanced autophagy is part of cell survival or death in an ischemic environment. Autophagosome accumulated in ipsilateral and contralateral capillary ECs following tMCAO. Autophagy plays a pivotal role in managing cell homeostasis by the degradation of cytosolic components via an autophagosomal\u2013lysosomal pathway . ExcessiAdditionally, reactive astrocytes and activated microglia populated in remote striatum, motor and somatosensory cortices 7 days post-tMCAO, potentially indicating an inflammatory response. Inflammation is a major event in ischemic stroke ,53,54. INeuronal pyknosis was also found in subacute ischemia in remote striatum, motor and somatosensory cortices. This post-ischemia damage potentially contributes to stroke pathology and inhibits recovery processes. Secondary neuronal damage and glial cell reactions were explored via two ischemic rat models . The resIn the ipsilateral hemisphere, diminished myelin was found in brain structures with neuronal damage. Decreased myelin was found in the contralateral hemisphere with reduced striatosome size. Communication between different regions of the brain is vital to normal brain function, making white matter damage harmful ,60. In oThe magnitude of the primary stroke lesion is important in predicting patient outcomes. However, the location of the lesion is also essential, especially during chronic stages. Motor recovery and functional outcome in hemiplegic stroke patients during the chronic stage had a stronger correlation with brain lesion size and location compared to that of only lesion size . Post-stAs noted in the preceding section, BBB pathological changes occur in both the ipsilateral hemisphere and contralateral brain regions, indicating the presence of subacute ischemic diaschisis . An assoChronic parenchymal extravasation was also revealed via electron microscopy imaging in ipsilateral and contralateral hemispheres ,74. The Excessive autophagosome production in both ipsilateral and contralateral striatum and motor cortex areas was observed in previous studies, primarily in subacute post-tMCAO settings, which was also exhibited in ECs in chronic stages due to the upregulation of Belcin-1 expression ,74. IncrThe analysis of vascular damage, such as BBB impairment, in cerebral brain structures represents a key pathological feature of chronic tMCAO at the ultrastructural levels ,74. AbnoAstrocyte reactivity in both ipsilateral and contralateral hemispheres displayed significant increases in glial fibrillary acid protein (GFAP) immunoreactivity in striatal areas of the ipsilateral hemisphere, while significant increases in GFAP expression were observed in the dorsal area of the contralateral striatum despite enhanced astrocyte reactivity in the striatum regions. The overexpression of bilateral astrocyte was only present in the dorsal striatum, but the causation of this phenomenon is unknown. Astrogliosis in the striatum may indicate spatial differences in astrocyte reactivity due to the structural location of the striatal area relative to the corpus callosum. Studies have demonstrated the degeneration of transcallosal fibers in subacute and chronic stroke settings using MRI . To explInvestigation of damaged BBB integrity in the cerebral hemisphere capillaries in chronic post-ischemic rats may reveal chronic diaschisis. Large autophagosome accumulation and astrocyte degeneration led to EC impairment, ultimately inducing extensive microvascular damage and neuronal degeneration in chronic ischemia. Chronic diaschisis should be included in stroke therapeutic strategies, primarily reviving endothelial and astrocytic integrity for BBB repair. Cell therapy is a possible stroke treatment option for BBB repair by replacing dysfunctional ECs through EPC transplantation. Combining cell therapy with pro-inflammatory inhibitors may prove to be a worthy stroke treatment.Currently, the only FDA-approved treatment for ischemic stroke is tissue plasminogen activator (tPA) for dissolving the blood clot and improving blood flow in the brain. When tPA is administered intravenously up to 4.5 h after stroke onset in patients with acute ischemic stroke, it reduces mortality and increases the rates of independent ambulation when thrombolytic treatment is given early . HoweverIn MCAO-induced rat models, various cell types including bone marrow stromal cells , umbilicA feasible approach for stroke treatment may involve directly targeting cell delivery into the injured vasculature. Since pervasive BBB impairment is an important factor in ischemic stroke pathogenesis, BBB repair might serve as a primary target for cell therapy development. An early study has shown that the intrastriatal transplantation of bone marrow stromal cells in MCAO rats restored local cerebral blood flow and decreased BBB permeability . AdditioThe ability of transplanted human bone marrow EPCs (hBMEPCs) to repair the BBB in adult Sprague-Dawley rats subjected to tMCAO can be evaluated via electron microscopy . When \u03b2-With intravenously transplanted \u03b2-gal pre-labeled hBMEPCs into rats 48 h after tMCAO, the rats experienced vascular repair in the brain structures of both hemispheres via transplanted cell engraftment into the vascular wall, which helped to re-establish BBB integrity post-stroke . BBB repAt 7 days post-tMCAO, BBB damage in the ipsilateral and contralateral striatum and motor cortex was observed , consistIntravenously transplanted hBMEPCs in tMCAO rats provide beneficial effects that are visualized by quantitative mitochondrial morphology analysis within ECs and perivascular astrocytes. Mitochondrial alterations can lead to cellular energy deficits and oxidative stresses that result in cell death, and mitochondrial dysfunction can occur after stroke which results in the reduced number and size of the mitochondria in astrocytes , neuronaIn cell-treated post-tMCAO animals, numerous pinocytic vesicles found solely in engrafted hBMEPCs were present . TypicalThe pinocytic vesicles were found only in engrafted hBMEPCs within the cerebral capillaries of cell-treated post-tMCAO rats, and represent a new line of investigation for cell therapy . AdminisAlthough intravenously transplanted hBMEPCs replaced post-stroke damaged ECs, it is possible that the administered cells were involved in capillary sprouting, or might have extravasated to the brain parenchyma via paracellular migration across cell\u2013cell junctions similarly to leukocyte diapedesis in various pathological conditions, given the new vessel formation ,127. TraAdditionally, transplanted hBMEPCs might not only exogenously but also endogenously enhance post-stroke vasculogenesis, via the secretion of angiogenic or growth factors. Local transplantation of the human EC cell line improved endogenous vasculogenesis and neurogenesis by the VEGF signaling pathway . SignifiIn conclusion, \u03b2-gal pre-labeled hBMEPCs intravenously transplanted into rats 48 h after tMCAO engrafted within the capillary wall at 5 days after its administration and closely participated in the vasculature repair of the BBB in subacute stroke . The anaStroke is a devastating disease, and further investigation regarding the underlying pathophysiological changes is warranted so as to unveil an effective neurodegenerative treatment. Acute and chronic microvascular damage, as a result of ischemia, may act as a potential mechanism to target when contemplating stem cell therapy . Similar"} {"text": "Sex and gender are important sources of variation in Alzheimer\u2019s disease and related dementias (ADRD) and associated caregiving. Women comprise 2/3 of ADRD cases and the majority of ADRD caregivers. Sex encompasses biological differences due to sex chromosomes, reproductive tract, and hormones, while gender constitutes socioculturally constructed psychosocial aspects of sex. Several lines of research have begun to interrogate sex differences, but less is known about the relation of gender and lesbian, gay, bisexual, transgender, and/or queer (LGBTQ) status with ADRD. In this symposium featuring both trainees and faculty we highlight novel research addressing these factors from multiple perspectives. Two presentations address how psychosocial characteristics and their strengths of association with brain health may vary by gender. C. Elizabeth Shaaban presents analyses testing whether gendered psychosocial factors explain sex differences in white matter hyperintensities, a neuroimaging marker of cerebral small vessel disease and risk factor for ADRD. Justina Avila-Rieger presents results testing region of birth-based spatial patterning of dementia risk among Black men and women. Next, Jason Flatt presents prevalence estimates of subjective memory problems and dementia and describe factors associated with dementia among LGBTQ older adults. Finally, gender may also impact perceptions of individuals with dementia. Shana Stites explores gender differences in AD stigma and discuss implications for who is willing to be an AD caregiver. Michelle Mielke, an expert in sex and gender differences in neurodegenerative and age-associated diseases will facilitate conversation about these results and place them in the context of current sex and gender-based ADRD research."} {"text": "Recent conceptualizations of depression and supporting empirical work suggests that elevations and allievations of depressive symptoms can be understood from a dynamic systems perspective. Specifically, depression is proposed to result from strong-feedback loops in a system comprised of highly interdependent component parts . Supporting this perspective, individual differences in emotional interia and strong connections across emotions at micro-level timescales have been consistently associated with individual differences in depressive symptomatology such that individuals with greater emotional inertia and cross-emotion relations show higher levels of depressive symptoms. Importantly, however, individual differences do not necessarily translate to intraindividual change. The present study explores whether emotional connectivity at the daily timescale differs within individuals across a ten-year span and how these associations relate to intraindividual changes in depressive symptomatology. The results of these individual-level analyses will help further a dynamic systems perspective of depression and help inform clinical interventions for depression."} {"text": "The SmartPrompt phone-based reminder application was designed according to neuropsychological theory and pilot testing to facilitate everyday functioning. A laboratory-based pilot of ten participants with MCI and mild dementia showed significantly greater task completion with significantly fewer checking behaviors when using the SmartPrompt versus a control condition. Younger individuals and those who engaged in more checking behaviors completed more tasks in the control condition, but these relations were not significant when using the SmartPrompt. After 15 minutes of training, caregivers achieved near perfect scores on a SmartPrompt configuration quiz. Participant and caregiver usability ratings were strong, even though participants reported relatively low computer proficiency and neutral/unfavorable attitudes towards technology. Piloting informed modifications of the SmartPrompt to enhance personalization and improved human-computer-interaction for in-home testing. Preliminary in-home test data on individually-owned smartphones and conclusions regarding barriers and facilitators to the effectiveness of the modified SmartPrompt will be discussed."} {"text": "Dear Editor:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder and affects up to 12 million individuals worldwide. Radiologic imaging is critical for successful management. Until recently, the treatments were only symptomatic but EMA in 2017 and FDA in 2018 approved Tolvaptan for ADPKD therapy. Renal imaging provide important diagnostic and management guidance in the monitoring of disease progression. In the past, standard radiographic imaging has not provided the accuracy necessary to reliably measure renal volume. With diagnostic advances, kidney volume growth is considered the principal surrogate marker predicting the decline of renal function in ADPKD; therefore the role of total kidney volume (TKV) has been investigated as surrogate endpoint in randomized clinical trials. TKV can be measured by ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) using manual, semiautomated, or fully automated data processing techniques.Using high-resolution MRI, the Consortium of Radiologic Imaging Studies of PKD (CRISP), observational cohort study of ADPKD subjects, investigated the ADPKD progression highlighting that MRI could accurately and reliably measure TKV cystic kidneys."} {"text": "This paper explored the effect of the type of health insurance on dentist visits among older adults in China. The data were drawn from the CHARLS-II (2013). The sample included older adults aged 60 and older =3272, n=3495). Multivariate logistic regression models indicated that in urban and rural places, respondents with a governmental/civil servants\u2019 insurance and those with an urban-employee insurance are more likely to visit a dentist in the survey year. Household registration status (hukou) does not play a significant role in dentist visits when insurance types are adjusted for. In other words, employment status, and the coverage of health insurance presented more significant effects on dentist visits. Differing from previous studies about urban-rural health disparities, this study disclosed substantial institutional influences on dental care access among older adults."} {"text": "Pulmonary vein stenosis or occlusion is a rare but one of the most devastating complications after catheter ablation for cardiac arrhythmias, and surgical repair is an option in severe cases. The sutureless technique, which avoids direct suture of vessel walls, was initially described for congenital pulmonary vein stenosis and has been widely performed due to its good restenosis-free rate.A 52-year-old male developed left pulmonary vein occlusion after catheter ablation for atrial fibrillation. The surgical repair with sutureless technique using the left atrial appendage was performed without any complications. Postoperative computed tomography demonstrated the revascularization of the pulmonary vein.The sutureless technique using the left atrial appendage is significantly reasonable particularly in case of left pulmonary vein stenosis or occlusion after catheter ablation for atrial fibrillation since it reduces the risks of restenosis and thromboembolism. Pulmonary vein (PV) stenosis occurs as a complication of catheter ablation for cardiac arrhythmia in 1\u20133% of patients [A 52-year-old male with AF underwent catheter ablation for two times. Eight months after the second maneuver for recurring AF, he presented with hemoptysis and exertional dyspnea. Computed tomography (CT) showed multiple consolidation in the left lung and ipsilateral pleural effusion Fig. . Three-dPV stenosis often develops as a congenital anatomical anomaly or anastomotic stenosis occurring after the repair of total anomalous PV connection, and several surgical repairs including endovenectomy, re-implantation of PV with direct anastomosis, or patchplasty have been described , 3. HoweThe sutureless technique using the LAA for the left PV stenosis or occlusion after catheter ablation for AF is a significantly reasonable procedure in terms of reducing the risks of restenosis and thromboembolism. Since the long-term outcome of this technique is still unknown, careful follow-up is required."} {"text": "Empathy for pain is a complex phenomenon incorporating sensory, cognitive and affective processes. Functional neuroimaging studies indicate a rich network of brain activations for empathic processing. However, previous research focused on core activations in bilateral anterior insula (AI) and anterior cingulate/anterior midcingulate cortex (ACC/aMCC) which are also typically present during nociceptive (pain) processing. Theoretical understanding of empathy would benefit from empirical investigation of shared and contrasting brain activations for empathic and nociceptive processing.Thirty-nine empathy for observed pain studies were selected by systematic review. Coordinate based meta-analysis (activation likelihood estimation) was performed and novel contrast analyses compared neurobiological processing of empathy with a comprehensive meta-analysis of 180 studies of nociceptive processing (Conjunction analysis indicated overlapping activations for empathy and nociception in AI, aMCC, somatosensory and inferior frontal regions. Contrast analysis revealed increased likelihood of activation for empathy, relative to nociception, in bilateral supramarginal, inferior frontal and occipitotemporal regions. Nociception preferentially activated bilateral posterior insula, somatosensory cortex and aMCC.Our findings support the likelihood of shared and distinct neural networks for empathic, relative to nociceptive, processing. This offers succinct empirical support for recent tiered or modular theoretical accounts of empathy. Empathy is a critical concept in human emotional and social experience. The ability to share in the affective states of those around us brings evolutionary advantages, enabling us to respond to the needs of others, predict their behaviour and support decision-making about our own actions and sociNociceptive (pain) processing is associated with wide-reaching patterns of neural activation which briefly encompass bilateral anterior, mid-and-posterior insula cortices, primary and secondary somatosensory cortex, inferior frontal gyri (IFG) and supramarginal gyri, as well as medial clusters in anterior cingulate/anterior midcingulate cortices (ACC/aMCC), thalami and brainstem .The Perception\u2013Action Model (PAM) of empathy , suggestHowever, current definitions of empathy suggest the involvement of automatic affective processing but also include aspects of higher order cognition. For example, empathy requires isomorphic sharing of feelings with another, but also necessitates awareness that one\u2019s state originates from observation of the target . In suppThe Russian-Doll model of empathy posits a tiered system with progressive levels of empathy from basic affective to higher order processes such as sympathetic concern and emotional perspective taking . SimilarNeuroimaging studies demonstrate a heterogeneous profile of activation foci for empathy for pain , as were supplementary and manual searches. Both authors were responsible for assessment of articles for inclusion, and decisions over article inclusion were determined by discussion, disagreements where resolved via discussion or presented to a third arbiter (A.S.). One author (N.F.) extracted the relevant coordinate data, which was cross-checked and confirmed by a second (C.R.). Studies that reported coordinates in the Talairach space were converted into MNI using GingerALE software for the purposes of analysis and reporting.P\u2009<\u20090.001 uncorrected voxelwise throughout the whole brain with at least P\u2009<\u20090.05 cluster level correction declared. We excluded papers which only reported ROI results.The criteria for inclusion were: (i) human fMRI studies published up until October 2019; (ii) original English language articles; (iii) published in a peer-reviewed journal; (iv) utilizing a paradigm including visual pain stimuli i.e. images, videos or animations of pain scenes or pain facial expressions; (v) employed an appropriate contrast with a suitable control stimulus ; (vi) coordinates were reported in the paper or supplementary material of the direct (pain > non-pain) contrast in either Montreal Neurological Institute was implemented followed by cluster-level Family-wise error (FWE) correction (P\u2009<\u20090.05) to identify relevant ALE regions as recommended in recent publications (P\u2009<\u20090.05) and a minimum cluster size of 200\u00a0mm3 as previously recommended middle frontal gyrus, and bilateral supramarginal regions .Contrast analysis comparing the ALE maps of concordant activations for each process pointed to significantly greater likelihood of activation during empathy for pain relative to directly perceived pain in 6 clusters encompassing bilateral supramarginal, IFG and occipitotemporal regions .The reverse contrast revealed six clusters indicative of increased activation likelihood estimates for directly perceived pain relative to empathy for observed pain. These regions encompassed two large bilateral clusters encompassing parietal opercular cortices (S2), posterior insula and S1. Right putamen was also evident for directly perceived pain relative to empathy. A right frontal cluster encompassing right prefrontal and dorsolateral prefrontal cortices was also elicited. Two medial clusters demonstrated increased concordance of activation in direct, relative observed, pain in aMCC .The findings of the ALE meta-analysis of empathy for pain revealed concordant activations to observed pain stimuli located in aMCC and bilateral AI which accords with previous investigations were also performed for the first time. Empathy, compared to direct pain experience, demonstrated preferential bilateral activation in supramarginal regions, which extended superiorly to the supramarginal gyrus. Although supramarginal activations are frequently reported in fMRI empathy literature, their specific relevance is often not subject to discussion or interpretation, particularly if the basic empathy contrast is not the primary aim of the research . This poContrast analyses also pointed to bilateral occiptotemporal activations that were more likely to be engaged during observed pain, but not direct pain experience. Previous fMRI research have explained these activations for empathic viewing in terms of enhanced visual processing or attenContrast analyses also revealed greater bilateral activation in ventral IFG during empathy for pain relative to direct experience of pain. The IFG is frequently activated during motor imagery or action observation type paradigms , it has ALE of directly perceived pain, compared to empathy, demonstrated preferential concordance of activation in bilateral S1, posterior insula and parietal operculum, right putamen, right prefrontal cortices and aMCC. Posterior insula and parietal opercular cortices represent the primary targets of nociceptors in the spinothalamic tract and the From a theoretical perspective, the patterns of ALE seen in conjunction and contrast analyses show alignment with a tiered theoretical understanding of empathic processing such as the Russian-Doll model or indepThe role of inferior parietal and occipitotemporal cortices for a broad range of social processing is a topic of considerable research, and a nexus of social processing extending from the angular gyrus of the TPJ anteriorly to supramarginal gyrus and posteriorly to occipitotemporal cortices was posited . Others The present study has some limitations. As mentioned, we focused on empathy for observed pain rather than more complex iterations of cognitive empathy such as paradigms which utilize learning to associate abstract cues with pain stimulation delivered to another person located outside of the scanner. The former design is more prevalent in fMRI research , allowinTo surmise the impact of the present study, elucidation of a rich functional brain network of empathy for pain, extending beyond AI and aMCC, is important for theoretical understanding of the phenomenon. The conjunction and contrast analyses reveal, for the first time, shared and distinct networks for observed and direct pain which supports the concept of tiered levels of processing of empathy as were previously theorized . The finTo conclude, the findings reveal concordance in an extensive bilateral network of brain regions for empathy for observed pain. This encompassed bilateral AI, supramarginal gyri, lateral occipitotemporal cortices IFG and aMCC, regions with functional relevance for interoception, pain processing, social cognition and self-other distinction. Utilizing novel contrast analyses for empathy for pain and direct pain experience, we demonstrated a broad network of shared brain representations which align to automaticity of response or emotional contagion, and empathy-specific activation patterns with relevance for higher order responses such as self-other distinction. Knowledge of these shared and distinct brain networks offers a novel insight into the neurobiological underpinnings of our subjective experience of empathy with relevance for theoretical, clinical and social applications.None declared.File013_nsaa090Click here for additional data file."} {"text": "Introduction: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in the United States. Preexisting chronic health conditions may be confer increased CVD risk, specifically fibromyalgia (FM), a chronic condition characterized by widespread pain, fatigue, stiffness, and concentration problems. CVD risk increases with normal aging; however, characteristics of FM are suggested to exacerbate health profiles in normal aging processes that may contribute to increased CVD risk. Method: The sample included 221 older adults and 55% reported an FM diagnosis. CVD risk factors were entered separately in a five-block hierarchical binary logistic regression model as predictors and included: cardiorespiratory fitness using the six-minute walk, BMI, standing and lying mean arterial pressure (MAP), and depression using the Beck Depression Inventory. Results: Logistic regression analyses revealed that poorer cardiorespiratory fitness , greater depressive symptoms and lower standing MAP were associated with higher odds of an FM diagnosis. However, no differences in lying MAP or BMI for an FM diagnosis emerged. Discussion: These data support the importance of examining the health profiles of persons with FM in the context of CVD risk. Experiences of FM may produce distinct health profiles with characteristics that serve as both protective and risk factors in the context of CVD."} {"text": "Some lower vertebrates such as zebrafish and axolotl have incredible cardiac regenerative potential while mammals have very limited ones. Comparative studies among species have revealed that cardiomyocyte polyploidy, endothermy, and injury-induced activation of certain transcriptional factors including AP1 complexes are critical for cardiomyocyte proliferation and heart regeneration during animal evolution. Gaining insights into these evolutionarily conserved mechanisms will likely lead to achieving heart regeneration in non-regenerative mammals including humans. Regenerative potential in the animal kingdom is a fundamental topic of regenerative biology and medicine. With the development of genome science and genetics technology, many investigators started to address how regenerative potential is lost or gained during the evolutionary courses of particular animal species. It is now documented that either whole-animal or organ regeneration is achieved by activating adult stem cells , by inducing Muller glia reprogramming into neurons in adult zebrafish retinas, or by promoting cardiomyocyte (CM) proliferation in adult zebrafish hearts, and neonatal mouse, rat, and pig hearts are mononuclear diploid CMs during development, but they become mostly polyploid CMs at late gestation or early postnatal stages. The appearance of CM polyploidy conincides with the loss of cardiac regenerative potential in mice, rats, and pigs increases CM proliferation and the percentage of MNCMs in neonatal and adult mice, and results in an evident improvement in cardiac function and fibrosis after myocardial ischemic reperfusion in adult mice. Consistently, exogenous application of thyroid hormone T3 inhibits heart regeneration with evident CM polyploidization and decreased CM proliferation in zebrafish. Thus, thyroid hormone signaling promotes CM polyploidy and decreases cardiac regenerative potential during animal evolution.Another elegant work has reported that the loss of cardiac regenerative potential is highly related with CM polyploidization via phylogenetic analysis of CM nucleation and polyploidy in a large collection of non-vertebrates and vertebrates, and the percentage of MDCMs inversely correlates with metabolic rate, body temperature, and serum total thyroid hormone T4 levels for regulating CM nucleation and polyploidization, as well as non-coding DNA elements (regenerative enhancers) and binding factors (AP-1 complexes) for regulating CM proliferation. These and future studies will likely reveal a network of transcription factors and enhancers for coordinating CM proliferation and heart regeneration. In addition to these critical factors and regenerative enhancers, the field will take advantage of genome editing and chemical biology approaches to identify factors and small molecules that are sufficient for promoting non-regenerative heart regeneration in the coming years."} {"text": "Of the estimated 16 million U.S. family members currently providing essential yet unpaid caregiving for persons with dementia (PWD), many will also make end-of-life (EOL) care decisions as surrogates, a process that can be fraught with uncertainty. Even with dementia death rates rising, many families delay advanced care planning (ACP) discussions, and surrogate decision makers often lack crucial information and support, implicating the need to further study this topic in aging. While decision aids (DA) serve as a support tool for caregivers, they can be less effective when failing to address unresolved decisional needs. Utilizing the Ottawa Decision Support Framework (ODSF), which asserts caregiver decision needs affect decision quality, this study sought to identify surrogate decision-support needs extending beyond general ACP. This mixed study used cognitive interviews and focus groups with family caregivers (N=13) and healthcare professionals (n=14) to assess their knowledge and understanding of hospice and artificial hydration and nutrition. Data were audio-recorded, transcribed verbatim, and analyzed with thematic content analysis. Three main themes were identified: DAs alone aren\u2019t enough to foster quality decision making for surrogates; individualized communication is necessary to clarify PWD and caregiver value priorities and disease trajectories; and clarification of the impact of care choices within situational contexts is quintessential. Further development is needed to create a practice protocol from these themes to inform professionals assisting surrogates in ACP at EOL. Practical implications from this study include highlighting the importance of individualized communication between PWD, providers, and caregivers in addressing EOL care decisional needs."} {"text": "Community-dwelling older adults often experience cognitive symptoms, and three common conditions that contribute to changes in cognition are dementia, depression and delirium. Despite the clinical inter-connectedness among these medical conditions, hereafter referred to collectively as cognitive vulnerability, little is known about the potential for success of clinical interventions that simultaneously address these conditions. From the perspective of older adults with cognitive vulnerability and their families, hospital admissions and emergency department (ED) visits are disorienting and often lead to declines in functional capacity and well-being, and significant family distress, threatening continued independent living. In this Symposium, we present details about an ongoing clinical trial testing a novel in-home, multidisciplinary team care management intervention for older adults with cognitive vulnerability and their families. This care management intervention led by nurse practitioners, called the3D Team care model, aims to help reduce ED visits and hospitalizations and achieve other health-related outcomes. The first presentation will provide study background and design features as well as characteristics of study participants. The next two presentations by the3D Team nurse practitioners will provide details about how the multidisciplinary team works, and how each team member provides interventions intended to address risk factors for adverse health outcomes. The fourth presentation by the3D Team community health educator will explain how needs related to social determinants of health are addressed. The Discussant will place this clinical trial within the broader context of multidisciplinary team care for older adults with cognitive vulnerability led by nurse practitioners trained in geropsychiatry."} {"text": "Background\uff1aGratifying the elderly health-care demands and promoting high-quality of nursing services are based on the effort of long-term care(LTC) nurses. However, the high turnover rate of LTC nurses has become very serious in China. What remains unclear is whether the organizational justice and job characteristics affect the LTC nurses\u2019 intention to stay. Objective: The aim was to investigate intention to stay among LTC nurses in relation to organizational justice and job characteristics. Method: A cross-sectional study was conducted with a convenience sample of 545 LTC nurses. Data collection was performed between July and November 2019. Data were analyzed using structural equation modeling. Results: Most of LTC nurses reported to stay in nursing or current work place, however they still had strong desire to leave if there were other job opportunities. Organizational justice and job characteristics were significant predictors of LTC nurses intent to stay. LTC nurses job characteristics partially mediates the relationship between organizational justice and intent to stay. Conclusion: This would suggest the importance of administrators/ managers understanding how to promote organizational justice, foster a justice climate and increase LTC nurses\u2019 perceived job characteristics. The organizational justice culture programs should be develop as LTC nurses retention strategy."} {"text": "Post-traumatic bronchobiliary fistulas (BBF) are extremely rare with high morbidity and mortality rates. Accurate and timely diagnosis of these entities is critical for appropriate treatment, which usually requires a multidisciplinary approach. We describe two post-traumatic cases using a multimodality approach including computed tomography (CT), magnetic resonance imaging (MRI)/Magnetic Resonance Cholangiopancreatography (MRCP), and hepatobiliary scintigraphy with specific emphasis on the imaging features for each modality. Management of hepatobiliary fistulas is complex, involving extensive diagnostic work up followed by a conservative and/or surgical approach. Bronchobiliary fistula (BBF) is communication of biliary system and bronchial tree. It was first described by Peacock in 1850 . Post-trCase 1A 16-year-old male with history of penetrating injury (gunshot) to the right upper quadrant and right lower hemithorax complicated by biliary leak, diaphragmatic injury, and bilomas. Initial contrast-enhanced CT demonstrated multiloculated fluid collections in the right subphrenic space and small pleural effusion Figure , 1B . ThCase 2A 40-year-old male and victim of gun violence with surgical history of laparotomy, left hepatectomy, cholecystectomy and removal of two foreign bodies. Six days later, he underwent an endoscopic retrograde cholangiopancreatography (ERCP) which revealed extravasation of contrast from the common bile duct and he returned to the operating room for drainage of intraabdominal abscesses and a Roux-en-Y hepaticojejunostomy.Since then over several months he suffered from many hepatic abscesses, bilomas, cholangitis, and gram negative bacteremia, primarily managed with percutaneous drains and antibiotics. His clinical course was further complicated by misplaced drains and a biliarycutaneous fistula.Multiple admissions were made for management of the biliarycutaneous fistula, a most recent CT of the abdomen and pelvis demonstrated loculated collection in the hepatic dome extending into the right subdiaphragmatic space Figure , 2B. ThiThere is paucity of large case series in literature since post-traumatic BBFs are extremely uncommon. Most of the publications consists of case reports and small series. A systematic literature review of 68 cases published in 30 years by Liao et al. revealed only seven cases 10.2%) secondary to trauma [% secondaA significant clinical symptoms in patients with BBFs is bilioptysis. Bilioptysis is presence of bile in the sputum and believed to be pathognomonic finding for BBFs. Other common symptoms include irritating cough, fever, and jaundice .Penetrating injuries rather than blunt traumas are reported in etiology of bronchopulmonary fistulas .\u00a0Both ofInitial evaluation usually starts with CT which is useful to demonstrate liver injury, abdominal and thoracic fluid collections, as well as abnormal lung findings. The widespread availability, decreased variability between operators, imaging speed, and relatively few contraindications make it ideal in immediate traumatic assessment ,8.\u00a0HowevConventional MRI of the abdomen with MRCP (Magnetic Resonance Cholangiopancreatography) can provide good anatomical information of the biliary system. However, contrast-enhanced magnetic resonance cholangiography using hepatobiliary contrast agents was reported to demonstrate bronchobiliary fistula since it depicts biliary excretion from injured ducts . UnfortuHepatobiliary scintigraphy, similar to MR cholangiopancreatography with hepatobiliary contrast agents provide functional information. Image acquisition may be obtained for a prolonged time to trace bile movement. The precise location of bronchobiliary connection could not be confidently determined with this method even when SPECT was performed in the past. SPECT/CT as a hybrid imaging technique combining the functional information of hepatobiliary scintigraphy and anatomical information of CT overcomes the shortcoming and may clearly define fistulous tract .Management of BBF varies from a conservative approach to definitive surgical management. The conservative approach is preferred in the initial management of bile leaks. Biliary decompression or diversion using endoscopic sphincterotomy, biliary stent placement, or nasobiliary drainage and percutaneous image-guided catheter collections alone may be successful. More definitive treatment would require surgical resection of the fistula with pulmonary segmentectomy, especially in the presence of lung injury -15. ReceA multimodality approach is critical for stepwise diagnosis of BBFs. Although CT is used in initial evaluation of BBFs, hepatobiliary scintigraphy can confirm biliary leaks and differentiate bilomas from other fluid collections. Bile excretion and movement may be traced by sequential dynamic imaging. SPECT and more recently SPECT/CT may reveal connections between the bile ducts, bilomas and other structures such as bronchial tree and may play an important role in management of complex cases. MR cholangiopancreatography with hepatobiliary contrast agents also allows dynamic biliary imaging. It is an alternative to hepatobiliary scintigraphy and SPECT/CT and may demonstrate fistulous communications of the biliary system with high accuracy."} {"text": "Motor impairments, including slow walking, are common in older age in the absence of prototypical Parkinson\u2019s disease (PD). The etiology of such disturbances is heterogeneous and multi-system in nature. Dopamine is a key neurotransmitter involving motor, cognitive and behavioral circuitry. Normal aging is associated with substantial dopaminergic losses in the brain. Dopaminergic vulnerability of aging can be augmented by genotypic changes that may further compromise dopaminergic signaling, such as polymorphisms in the COMT gene. These observations may augur dopaminergic pharmacotherapy studies to treat gait disturbances in older adults. Prior dopaminergic therapy studies have shown overall limited effects in non-PD older adults. A major limitation of these studies is the non-targeted selection calling for personalized medicine approaches. Recent dopaminergic treatment studies targeting specific sub-groups of non-PD older adults conducted by us and others will be discussed."} {"text": "In the coming years, inevitably growing numbers of older populations will yield more older Americans with extensive medical and long-term care needs. This will lead to an increasing need for long-term services and supports (LTSS) to assist older adults with routine daily activities . There is a growing interest in understanding how social and physical environments contribute to health outcomes and the provision of services and resources for older persons with disabilities requiring assistance from LTSS. Decisions about care and subsequent experiences are likely a result of factors that extend beyond personal preference or individual factors, such as neighborhood quality, housing context, and living situations among community-dwelling older adults. Given population aging and the shift of LTSS from nursing homes toward community settings, there is a pressing need for more information about contextual factors that might help better develop supports for vulnerable older adults. This symposium will feature four presentations that provide novel insight regarding social and physical contextual factors contributing to LTSS. Presentations leverage data from the National Health and Aging Trends Study (NHATS), a nationally representative survey of Medicare beneficiaries aged 65 and older, and will describe: 1) associations between individual and home environment risk-factors, neighborhood-level social deprivation, and falls; 2) the relationship between neighborhood-level social deprivation and caregiving intensity (number of hours of caregiving per week) among community-dwelling older adults; 3) associations between living in single-family vs. multi-unit housing and social networks; and 4) community tenure among homebound older adults."} {"text": "Novel technologies like navigation and robotic surgery are very costly and not easily available in all centres, especially in developing countries. We describe a simple method to assess the HKA alignment while performing coronal deformity correction around the knee using external fixator components which are commonly available with every centre.Coronal plane deformities of lower limb are often challenging and require a thorough pre-operative planning, accurate intra-operative assessment and execution. Intra-operative confirmation of correct restoration of lower limb alignment [Hip-Knee-Ankle (HKA) axis] is more often than not assessed by gross visual inspection, which can be fallacious. Various methods described in literature for intra-operative assessment include cable method, axis board, specialised alignment rods with a connector, computer assisted surgeries, etcApparatus required for assessment of alignment includes external fixator rods and tube to tube connector clamps . ConnectWe have shown the application of this method using external fixator set from Greens\u00ae Surgicals Private Limited. However, external fixators from any manufacturer can be utilised for this purpose. We believe this simple method can be easily used by any orthopaedic surgeon in any centre without any additional efforts or cost."} {"text": "Neural injury in mammals often leads to persistent functional deficits as spontaneous repair in the peripheral nervous system (PNS) is often incomplete, while endogenous repair mechanisms in the central nervous system (CNS) are negligible. Peripheral axotomy elicits growth-associated gene programs in sensory and motor neurons that can support reinnervation of peripheral targets given sufficient levels of debris clearance and proximity to nerve targets. In contrast, while damaged CNS circuitry can undergo a limited amount of sprouting and reorganization, this innate plasticity does not re-establish the original connectivity. The utility of novel CNS circuitry will depend on effective connectivity and appropriate training to strengthen these circuits. One method of enhancing novel circuit connectivity is through the use of electrical stimulation, which supports axon growth in both central and peripheral neurons. This review will focus on the effects of CNS and PNS electrical stimulation in activating axon growth-associated gene programs and supporting the recovery of motor and sensory circuits. Electrical stimulation-mediated neuroplasticity represents a therapeutically viable approach to support neural repair and recovery. Development of appropriate clinical strategies employing electrical stimulation will depend upon determining the underlying mechanisms of activity-dependent axon regeneration and the heterogeneity of neuronal subtype responses to stimulation. Following injury to the adult mammalian central nervous system (CNS), neural circuits are permanently disrupted as severed axons fail to undergo spontaneous regeneration. The limited regenerative response of injured CNS neurons is due to both intrinsic and extrinsic factors. These growth-restrictive mechanisms play a large part in the poor clinical outcomes following brain or spinal cord trauma; however, despite limited regenerative capacity, mounting evidence has shown extensive spontaneous sprouting of CNS axon collaterals in the injured adult CNS.The mammalian nervous system has an intrinsic capacity for structural and functional reorganization in response to a variety of stimuli during development, learning, or in response to pathological insults . This inRecent findings suggest that manipulation of neuronal activity can drive plasticity related growth mechanisms and augment collateral sprouting, thereby enhancing the functional effect of axonal remodeling . ElectriIn contrast to most CNS neurons, neurons of the peripheral nervous system (PNS) have a more robust regenerative response to injury . This owDespite the innate regenerative potential of PNS neurons after injury, recovery of function remains limited. Several factors can hamper recovery, such as age, extent of injury and disruption of endoneurium, perineurium, or epineurium, and neuroma formation. One critical factor is the slow rate of regeneration in the adult PNS of 1\u20133 mm per day . Axons nThe innate regenerative ability of adult mammalian PNS neurons has been used as a model to study the intrinsic mechanisms underlying the regenerative program. Primary sensory neurons are located in the DRG and extend axons into both CNS and PNS. Each axon exhibits a distinct response to injury in the adult. As described above, the peripheral axon retains the ability to regenerate following axotomy. In contrast, the CNS axon of the same cell will fail to regenerate after spinal cord injury. Intriguingly, the regenerative program activated by peripheral nerve injury conditions DRG neurons to mount an enhanced regenerative response to a second injury, whether in the peripheral or central axon . The proAnother important change after conditioning lesion is the transient increase of second messenger cyclic nucleotide cAMP levels. Artificial elevation of cAMP can support a limited amount of sensory axon regeneration in the injured spinal cord . DownstrActivation of the pro-regenerative transcriptional response in the somata of regenerating neurons requires a retrograde signal from the injury site. One candidate for this rapid signal is the early influx of calcium at the injury site . Rapid cin vitro injury stimulation . Nitric (CamKII) . Piezo-m in vivo . Further in vivo . Genetic calcium . Blockad in vivo .PTEN deletion from RGCs and other CNS neurons leads to elevated PI3K/mTOR signaling, enhanced phosphorylation of S6, and an increased capacity for axonal growth after injury by high-contrast visual stimulation or via chemogenetics approaches can enhance optic nerve regeneration . In contr injury . Alternadeletion .suppressor of cytokine signaling 3 (SOCS3) increases optic nerve regeneration have been largely defined as the coordinated and complementary genes activated by peripheral conditioning paradigms in PNS neurons. These include developmental growth-associated proteins , transcription factors , and signaling pathways . In muchWhile electrical stimulation activates many of the same molecular pathways as peripheral conditioning via crush injury, it does not fully recapitulate the growth-promoting effects of conditioning. Following a subsequent peripheral injury, previous exposure to low-frequency electrical stimulation enhances the initiation of regeneration, but does not increase the rate of peripheral motor or sensory axon regeneration . The limin vivo by low frequency (20 Hz) electrical stimulation, 20 Hz trains separated by 5 min intervals arrested neurite outgrowth of primary sensory neurons in vitro stimulation of the soleus muscle in the rabbit was used to shorten the time for recovery of soleus function after axonotmesis of the soleus motor nerve . This mod injury is likeld injury .trans-spinal direct current stimulation after cervical spinal cord injury results in a strengthening of novel connections in the spinal cord. Furthermore, this paired stimulation paradigm can support the recovery of dextereous forelimb movements that depend on corticospinal function is a non-invasive and painless neuromodulation strategy that augments motor and sensory function after SCI . CervicaAmong the different approaches that have been proposed to enhance post-lesion plasticity, extrinsic manipulation of neuronal activity by electrical stimulation is an attractive therapeutic approach. Electrical stimulation has been demonstrated to engage plasticity mechanisms in several central and peripheral neural circuits and has already shown feasibility in clinical settings. Development of appropriate strategies will likely depend upon the selective activation of desired neural subtypes in a temporally and spatially organized manner. Non-targeted electrical fields have been used to trigger population responses; however, it may be that distinct electrical stimulation parameters can selectively affect neuronal subtype responses and circuit-specific functional outcomes. Whether the molecular mechanisms activated by electrical stimulation are consistent across neuronal populations is unknown. The sprouting response of corticospinal axons to electrical stimulation contrasts with the elongation observed in stimulated PNS axons. These differences may arise from disparate stimulation parameters, discrete responses of these distinct populations to electrical stimulation, or from interactions of conserved stimulation-mediated molecular pathways with the intrinsic limitations of adult CNS neurons to axon elongation. Further studies will be required to identify whether CNS-tuned parameters of electrical stimulation can drive a regenerative response in transected corticospinal axons.In the context of SCI, preclinical and clinical studies have clearly demonstrated that the stimulation of local spinal networks can drive lasting functional improvements . CorticaJJ and EH wrote and edited the manuscript. SA created the illustrations. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "We summarize how older women face intersectional experiences that affect their retirement security. These include differential trends in aging, life expectancy, labor supply, work history, retirement savings, and poverty at old age. We also highlight research showing that older women experience significantly more age discrimination than older men. affecting the ability for older women to improve their retirement security by working longer. We demonstrate through examples that these differential trends and intersectional experiences of older women have important policy implications. We provide examples of how Social Security policies, such as increases in the full benefit retirement age and changes to the retirement earnings test, have differential effects on older women. We also discuss how age and gender employment discrimination law fails to protect older women from intersectional sex-plus-age discrimination. We conclude by urging policymakers to consider how older women experience different challenges and how policy should consider their unique experiences."} {"text": "High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas. Intracranial gliomas are the most common primitive malignant neoplasms of the central nervous system, accounting for approximately 24.1% of all primary brain tumors .,56.55,56"} {"text": "This pilot study assessed a novel intervention to enhance both walking and executive function in older adults. The primary hypothesis was that eighteen sessions of frontal lobe tDCS combined with walking rehabilitation would be feasible, safe, and show preliminary efficacy. Eighteen participants were randomized to one of three intervention groups: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking . Outcome measures included multiple tests of walking function, executive function, and prefrontal activity during walking as measured by functional near infrared spectroscopy (fNIRS). Of the three groups, the Active/Complex group demonstrated the broadest improvements across outcome measures including for prefrontal activity. The functional range of prefrontal activity in this group was increased considerably, as conceptualized by the Compensation Related Utilization of Neural Circuits Hypothesis. Frontal tDCS is a promising adjuvant to walking rehabilitation."} {"text": "Older adults\u2019 psychosocial factors, including personality, are correlated with driving performance and driving cessation. However, the relationship between personality and driving styles has been examined only among young and middle-aged drivers. This study examined the relationships of personality factors and self-reported driving styles among 72 healthy older drivers aged 65-85 using the Multidimensional Driving Style Inventory (MDSI) scale to measure reckless and careless, anxious, angry and hostile, and patient and careful driving styles. Personality was accessed with the Big Five Personality questionnaire. Correlational results indicated that less conscientiousness was significantly correlated with increased reckless and careless and less patient and careful driving styles; and lower agreeableness was significantly correlated with greater angry and hostile and less patient and careful driving styles. Being a man was associated with greater reckless and careless and angry and hostile driving styles. Age was not associated with driving styles. Accordingly, three regressions were tested. After controlling for gender, only lower conscientiousness was associated with greater reckless and careless driving style . Men had a higher risk of reckless and careless and angry and hostile driving styles. Our results highlight the relationship between personality traits and self-reported driving styles among older adults, and how gender may influence some of these relationships. Future research should further investigate the associations between gender and personality traits and older adults\u2019 driving mobility and safety."} {"text": "Certain emotion regulation (ER) strategies are often considered to be more or less demanding of cognitive resources. However, age-related differences in the perceptions of these demands are not yet understood. Older adults might perceive greater demands for certain strategies due to differences in cognitive ability and motivation to maintain emotional well-being. In the present study, we examined age and cognitive ability as predictors of perceived effort required to use ER strategies that span all families of the process model. A diverse sample of community participants (age 22-83) completed assessments of cognitive ability and perceived demands associated with ten ER strategies. Overall, response-focused strategies were rated as highest in demands whereas situation selection and savoring were perceived as least demanding. Older adults reported higher demands associated with situation selection, distraction, and detached reappraisal compared with younger adults. Cognitive ability was not associated with perceived demands for ER strategies traditionally viewed as cognitively demanding . Rather, higher cognitive ability only predicted lower perceived demands for strategies often considered low in demand: situation selection and savoring. Perceived ER success was not consistently associated with age or cognitive demands. Results suggest that older adults view some, but not all, ER strategies as more demanding than younger adults do. The role of cognitive ability in age-related changes in ER may be more complex than previously expected. Notably, the lack of findings with perceived ER success suggest effort requirements associated with ER may not impede ability to successfully regulate across adulthood."} {"text": "E. coli and quantify ppGpp within several strains using a recently developed analytical method. We find that although the inverse correlation between ppGpp and growth rate is robust across strains and analytical methods, absolute ppGpp concentrations do not absolutely determine RNA synthesis rates. In addition, we investigated the consequences of two separate RNA polymerase mutations that each individually reduce (but do not abolish) sensitivity to ppGpp and find that the relationship between ppGpp, growth rate, and RNA content of single-site mutants remains unaffected. Both literature and our new data suggest that environmental conditions may be communicated to RNA polymerase via an additional regulator. We conclude that basal ppGpp is one of potentially several agents controlling ribosome abundance and DNA replication initiation, but that evidence for additional roles in controlling macromolecular synthesis requires further study.The molecule guanosine tetraphophosphate (ppGpp) is most commonly considered an alarmone produced during acute stress. However, ppGpp is also present at low concentrations during steady-state growth. Whether ppGpp controls the same cellular targets at both low and high concentrations remains an open question and is vital for understanding growth rate regulation. It is widely assumed that basal ppGpp concentrations vary inversely with growth rate, and that the main function of basal ppGpp is to regulate transcription of ribosomal RNA in response to environmental conditions. Unfortunately, studies to confirm this relationship and to define regulatory targets of basal ppGpp are limited by difficulties in quantifying basal ppGpp. In this Perspective we compare reported concentrations of basal ppGpp in Escherichia coli, the small molecule guanosine tetraphosphate (ppGpp) is closely tied to growth rate control. However, due to the circumstances of its discovery, ppGpp is more familiar as a stress or starvation signal. ppGpp and guanosine pentaphosphate (pppGpp), collectively called (p)ppGpp, were first identified in E. coli as compounds produced in strains that inhibit stable RNA synthesis upon amino acid starvation, a phenomenon known as the stringent response (\u20131 for ppGpp) (E. coli (How might a bacteria cell measure its own growth rate? In the model bacterium response . The souresponse . The higr ppGpp) drive prr ppGpp) . The ove(E. coli we focusE. coli in the absence of stress (between 10 and 90 pmol OD\u20131). When growth rate is varied by nutritional quality, basal ppGpp correlates inversely with growth rate. Basal ppGpp is essential in minimal media as it is required to activate transcription of amino acid pathways ppGpp0] does not vary DNA replication initiation in response to growth rate, suggesting that ppGpp participates in regulating the DNA-biomass ratio like an emergency brake.The observation that high ppGpp concentrations inhibit biomass synthesis suggests that basal ppGpp concentrations might also directly regulate all biomass synthesis pathways during steady-state growth, in addition to regulating stable RNA synthesis. This hypothetical layer of regulation would complement control of rRNA transcription, which determines the maximum rate of is PurF, or transis PurF, or the fis PurF, . Basal pis PurF, , as highis PurF, . In thisE. coli controls growth. To further encourage the recent revival of interest in the mechanisms of steady-state growth regulation and homeostasis its low abundance; (2) its chemical instability; (3) the presence of environmentally sensitive enzymes that rapidly hydrolyze and synthesize ppGpp. This means the analytical method must both chemically stabilize ppGpp and immediately denature all enzymes that synthesize or hydrolyze ppGpp. Moreover, in order to study ppGpp dynamics relevant to the rapid ppGpp response (<5 s), the method must enable fast sampling.Actual ppGpp measurements are essential for determining which cellular processes are watching the growth rate speedometer. The rarity of basal ppGpp measurements is understandable as basal ppGpp is difficult to accurately quantify. The main challenges in measuring basal ppGpp Despite these difficulties, several (p)ppGpp measurement methods have been developed, including thin layer chromatography (TLC) , high peA survey of reported basal ppGpp concentrations combined with our own measurements indicateE. coli show an inverse correlation between growth rate and basal ppGpp (15\u201390 pmol OD\u20131) . Early sol OD\u20131) . Khan aned trend . Howevered trend .Reported ppGpp concentrations may differ perhaps due to differences in strains, turbidimeter calibration, or sampling method . InteresE. coli K-12 strains using LC-MS (rph+ but not isogenic with the MG1655 reported here) has been used to demonstrate correlation between the RNA/protein ratio and the growth rate artificially elevates ppGpp, inhibits rRNA synthesis and decreases growth rate. Data from ppGpp titrations using RelA\u2032 are compared in E. coli NCM3722 in both LB medium and glucose minimal medium yields a ppGpp-growth rate curve steeper than the curve obtained in nutrient-limited NCM3722 . Howeverincreases in parallel with growth rate. E. coli mutants unable to synthesize specific nucleotides [carAB- guaB(ts)]. When growth rate was titrated with pyrimidine and purine sources, the authors inverted the correlation between ppGpp and growth rate supply? First, uracil limitation does not activate ppGpp synthesis in wild-type strains , indicatE. coli glucose cultures. Pseudomonic acid causes accumulation of uncharged tRNA and increases ppGpp. High concentrations of pseudomonic acid abruptly increased ppGpp and rapidly arrested growth, consistent with the stringent response. Low concentrations of pseudomonic acid also triggered ppGpp synthesis (up to 60\u2013100 pmol OD\u20131) and an immediate but smaller decrease in rRNA synthesis. However, the instantaneous growth rate was not perturbed in the short term by small increases in ppGpp concentrations.Steady-state correlations such as the correlation between ppGpp and growth rate imply but do not establish regulatory connections. Hypotheses inspired by correlations must be tested by environmental perturbations. \u20131) do not seem to immediately inhibit biomass synthesis (with the exception of stable RNA). This undermines any notion that basal ppGpp directly regulates the instantaneous translation rate. Finally, two additional studies demonstrate that ppGpp and the rate of stable RNA synthesis can be transiently decoupled during nutritional upshifts, suggesting that additional signals may regulate rRNA synthesis retains regulation by basal ppGpp if its two ppGpp binding sites are disrupted, we measured basal ppGpp levels, growth rates and cellular RNA in mutants , 2016. ArpoZ(wt) rpoC R362A R417A K615A; rpoC N680A K681A; We transferred mutations that disrupt ppGpp binding site 1 [rpoC2- mutant in LB medium. At first glance, this is consistent with the notion that the RNAP mutants are less sensitive to ppGpp, as apparent from the slopes of cellular RNA content vs. ppGpp (P < 10\u20136). In other words, higher ppGpp concentrations may be required to inhibit RNA synthesis in these strains. While it might be expected that the cultures expressing ppGpp-insensitive RNAP thus contain a higher RNA abundance than wild-type, we found that for every medium aside from MOPS/acetate, both mutant strains exhibit equivalent or even less RNA per OD unit than does the wild-type deserve fuller exploration as they likely hint at poorly understood facets of ppGpp biology. Disrupting either individual ppGpp binding site of RNAP did not eliminate the correlation between growth rate, RNA content, and basal ppGpp concentrations. Despite compelling evidence for basal ppGpp control of rRNA synthesis, incorporating ppGpp into quantitative models of cell behavior requires a better understanding of both transcriptional and post-translational targets. In order to advance this goal, we suggest several questions for the field:1.What targets are responsive to basal ppGpp concentrations? As basal ppGpp varies with growth rate in parallel with all biosynthetic fluxes during balanced growth, it is tempting to overextend models of ppGpp control. Targets thought to be regulated during the stringent response may prove insensitive to basal ppGpp. Experiments that monitor ppGpp during growth transitions already suggest that small changes in basal ppGpp do not immediately affect instantaneous protein synthesis or total biomass production. Studies of basal ppGpp concentrations during growth transitions are essential for distinguishing what is influenced by ppGpp. We suggest experiments that monitor protein synthesis during small controlled variations in basal ppGpp (\u00b150 pmol OD\u20131).2.What establishes basal ppGpp concentrations? It is unknown which metabolic cues drive RelA and SpoT to generate basal ppGpp.3.What regulates stable RNA synthesis during steady-state growth, aside from basal ppGpp? Our observation that RNA polymerase mutants lacking either one of the two ppGpp binding sites still exhibit an inverse relationship between RNA content and ppGpp concentrations implies that other factors also regulate RNA content, as has been suggested would also determine whether basal ppGpp is an accurate growth rate speedometer.5.Do all species with RSH proteins also maintain basal concentrations of ppGpp (or pppGpp) during steady-state growth? As RSH proteins are widely distributed and defined media to enable comparisons between labs.We further recommend the use of common reference strains (preferably All datasets generated for this study are included in the article/NI and GB conceived and designed the experiments and wrote the manuscript. NI performed experiments and data analysis. NI, NB, and MN developed the LC-MS method. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "This study compared gait speed changes after CSF tap test in patients with idiopathic normal pressure hydrocephalus presenting with various gait phenotypes . All patients improved, except those with parkinsonian gait. Gait disorders are the hallmark feature of patients with idiopathic normal pressure hydrocephalus (iNPH) /[(gait speedpost-CSF tap test\u2009+\u2009gait speedpre-CSF tap test)/2]. Univariable linear regressions evaluated the relationship between gait speed changes and each gait phenotype . Multivariable linear regressions were adjusted for age, gender, comorbidities, white matter changes assessed by the age-related white matter change scale . Frontal gait was significantly associated with gait speed improvement after CSF tap test, even after adjusting on age, gender, comorbidities, white matter changes, and MMSE . Normal gait, parkinsonian gait, and other gait abnormalities were not significantly associated with gait speed improvement, after adjusting on age, gender, comorbidities, white matter changes, and MMSE .Clinical characteristics are presented in Table This study showed that gait improvement after CSF tap test varies across gait phenotypes: frontal gait is associated with the greatest gait improvement after CSF tap test, while patients with parkinsonian gait did not show any significant gait speed changes.p value\u2009<\u20090.001). Patients with frontal gait presented the lowest gait speed at baseline and, therefore, had the greatest potential of improvement, as previously described may be explained by the following reasons. First, patients were included at an early stage of the disease course, where clinical gait abnormalities may not be evident. Second, patients have been referred, because the suspicion of iNPH was solely based on cognitive impairment and/or urinary incontinence. Third, patients may complain of gait impairments in challenging situations or balance impairments that were not clinically evident in the secure setting of a gait laboratory. Fourth, they presented fewer comorbidities that may affect gait. These results suggest that CSF tap test could also be considered at the earliest stages of iNPH when patients complain about their gait, but no clinical gait abnormality is diagnosed by physicians.The variability of the gait phenotypes in our cohort of iNPH patients may be explained by comorbidities . However, the validity of the clinical examination is not perfect and prone to an interrater variability. Having a better quantification of neurological and non-neurological comorbidities would allow a better sense of the influence of comorbidity on each gait phenotype. A post-mortem pathological examination is missing and would be of interest, especially in this cohort including mainly patients with possible iNPH (87%), who may present either a comorbid neurological condition along with iNPH or present an iNPH mimic. Finally, future studies should confirm these results by evaluating the predictive value of clinical gait phenotypes after shunting.Among gait phenotypes, frontal gait in patients with iNPH is associated with the largest gait improvement after CSF tap test. This study suggests that a clinical classification of gait phenotypes in patients with iNPH may inform about the reversibility of gait disabilities. Future studies should include long-term clinical outcomes after shunt procedure to confirm that frontal gait in iNPH patients may present a good clinical outcome in comparison to other gait phenotypes."} {"text": "Calcifications play an essential role in early breast cancer detection and diagnosis. However, information regarding the chemical composition of calcifications identified on mammography and histology is limited. Detailed spectroscopy reveals an association between the chemical composition of calcifications and breast cancer, warranting the development of novel analytical tools to better define calcification types. Previous investigations average calcification composition across broad tissue sections with no spatially resolved information or provide qualitative visualization, which prevents a robust linking of specific spatially resolved changes in calcification chemistry with the pathologic process.Method: To visualize breast calcification chemical composition at high spatial resolution, we apply hyperspectral stimulated Raman scattering (SRS) microscopy to study breast calcifications associated with a spectrum of breast changes ranging from benign to neoplastic processes, including atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. The carbonate content of individual breast calcifications is quantified using a simple ratiometric analysis.Results: Our findings reveal that intra-sample calcification carbonate content is closely associated with local pathological processes. Single calcification analysis supports previous studies demonstrating decreasing average carbonate level with increasing malignant potential. Sensitivity and specificity reach >85% when carbonate content level is used as the single differentiator in separating benign from neoplastic processes. However, the average carbonate content is limiting when trying to separate specific diagnostic categories, such as fibroadenoma and invasive ductal carcinoma. Second harmonic generation (SHG) data can provide critical information to bridge this gap.Conclusion: SRS, combined with SHG, can be a valuable tool in better understanding calcifications in carcinogenesis, diagnosis, and possible prognosis. This study not only reveals previously unknown large variations of breast microcalcifications in association with local malignancy but also corroborates the clinical value of linking microcalcification chemistry to breast malignancy. More importantly, it represents an important step in the development of a label-free imaging strategy for breast cancer diagnosis with tremendous potential to address major challenges in diagnostic discordance in pathology. Calcifications associated with breast disease are critical to breast cancer screening as they are often the only discernible indicator of risk in mammography Despite their diagnostic and prognostic potential, the morphologic and chemical features of calcifications are poorly understood, in part due to technological limitations. Morphological features of calcifications identified by mammography are insufficient for accurate diagnosis and prognosis. In addition, smaller calcifications (<0.1mm) are undetectable using mammography Moving beyond morphology and distribution patterns in breast calcification, studies utilizing X-ray diffraction and electron microprobe analysis with scanning electron microscopy (SEM) have contributed to an earlier understanding of calcification chemical differences While offering information about calcification chemistry, most spectroscopic methods average calcifications within multiple ducts within a tissue section, irrespective of the heterogeneous pathologic processes among adjacent ducts. Spatially resolved methods such as FTIR imaging have limited resolution and throughput, prohibiting visualization of calcification composition variation within adjacent ducts and lobules. Moreover, tissue protein content is recognized to correlate with malignancy We utilize the high resolution and chemical specificity SRS offers to deliver an unprecedented level of detail when analyzing calcifications. Additionally, we incorporate second harmonic generation (SHG) which has been proven effective at visualizing collagen in the tumor microenvironment -1 for total of 90 frames per stack. For SHG, a dichroic mirror (Chroma 695dcxr) is placed before the objective to allow for epi-collection of SHG signal from the sample. The SHG signal is detected by a photo-multiplier tube (Hamamatsu H10770PA-40) using 485 nm long pass and 650 nm short pass filters.A broadband femtosecond dual-beam laser system (Insight DS + from Spectra-Physics) was used for SRS and SHG Figure . The detCalcium hydroxyapatite (HAP) and 10% carbonated hydroxyapatite (CHAP) were obtained from Sigma Aldrich and Clarkson Chromatography Products respectively. Both solid controls were ground using mortar and pestle. A total of five mixtures were prepared for calibration purposes . The calibration samples were placed between a coverslip and a microscope slide for SRS imaging.Breast tissue was obtained from 17 patient archival cases (including biopsy and resection) managed by Northwest Biotrust, Seattle, WA. The initial case selection was based on the pathology report . Slides were subsequently reviewed to confirm the histologic diagnoses . Formalin-fixed paraffin-embedded tissue blocks were retrieved from archives and sectioned at 4-microns and mounted on charged slides. One section was H&E stained to identify pathological process. The adjacent section was deparaffinized and coverslipped for SRS and SHG analysis. The areas of interest were identified in the bright field based on selected areas of interest on adjacent H&E stained slides. A total of 214 breast calcifications were imaged, including: 31 non-neoplastic calcifications , 27 fibroadenoma (FA) associated calcifications, 8 atypical ductal hyperplasia (ADH) associated calcifications, 36 ductal carcinoma in situ (DCIS) associated calcifications, 112 invasive ductal carcinoma (IDC) associated calcifications. -1) and phosphate (~960 cm-1) peaks corrected for background Calibration samples with 0%, 2.5%, 5.0%, 7.5%, 10% carbonate content in calcium hydroxyapatite mixtures were imaged using the hyperspectral SRS microscope described above. Using SRS intensities at carbonate (~1070 cm-1) was used to visualize tissue morphology of the FOV the average, for a given category , was calculated with the standard deviation reported as an error bar. The differences between categories were assessed using p-values calculated from Student's t-tests. The receiver operator curves (ROC) were calculated using R software to assess the sensitivity and specificity for each parameter. Maximum Youden's index was used to determine sensitivity and specificity values.Previously, the carbonate content in hydroxyapatite has been measured using RS Figures Breast tissue submitted for pathological examination often contains calcifications in multiple ducts, which may represent various pathologic processes. In previous spectroscopic studies, multiple ducts are frequently measured together, which can average calcifications associated with different processes. Isolating individual breast ducts and detailing the histopathology within the ducts allows for correlation of variation in carbonate content with local pathology.Here, we group calcifications by specific pathological processes and not by overall case diagnosis. In Figure Figure The two cases illustrate that calcifications in the same patient case can have differing chemical composition. Although ducts are present in the same tissue section, the carbonate content associated with individual ducts is markedly different and reflects underlying pathological process. The high spatial resolution of hyperspectral SRS imaging is important to resolve calcification heterogeneity within the same patient sample and to establish the relationship between chemical composition and pathological process.Previous studies using FTIR have demonstrated that breast calcifications with lower carbonate content of CHAP correlate with malignancy Figures The neoplastic progression from benign ducts to IDC is associated with an overall decrease in calcification carbonate content Figure F and 6G Although precise quantification of the spatial distribution of carbonate in large calcifications is challenging due to sectioning artifact, our findings suggest that the carbonate content decrease on the edges of the calcifications directly reflects the changing microenvironment (i.e. higher acidity) associated with neoplastic cells and necrotic debris -1) to phosphate (~960 cm-1) ratio is used to quantify protein content in calcifications and specificity (88%) when identifying benign and invasive processes. SHG data provides a parameter separating FA from IDC cases with high sensitivity (94%) and specificity (85%). Phenylalanine to phosphate ratio provides additional separation between DCIS and IDC. Together, spectroscopy and morphology can be utilized to better establish the malignant potential in cases with ambiguous morphology on H&E alone.CHAP is not the only microcalcification species that was identified in breast cancer. Although whitlockite typically accounts for a tiny percentage of breast calcifications -1 to 970 cm-1) Typically, whitlockite can be identified using Raman spectroscopy due to unique spectral features . This problem can be addressed in future studies by imaging either fixed tissue or fresh tissue, where calcifications remain intact.Besides carbonate content of calcifications, we have elucidated the unique features that distinguish chemical composition of calcifications between FA and IDC. For the first time, we demonstrate that SHG data confirms collagen in FA makes an organic matrix upon which hydroxyapatite accumulates. This matrix observed in FA calcifications is one of the main differences between FA and IDC. This collagen matrix enables robust differentiation of FA and IDC, which exhibit similar carbonate content.In conclusion, we imaged a diverse set of breast calcifications associated with benign processes, and a range of neoplastic processes including FA, ADH, DCIS and IDC. Our findings support previous reports of carbonate content decreasing on average with increasing malignant potential. Importantly, we showed that a detailed spatial map of calcifications and their complex underlying organic matrix is highly correlated with underlying neoplastic processes and could potentially be used for breast cancer diagnosis. Additionally, the spatial heterogeneity of carbonate content could potentially be a diagnostic indicator of malignancy. Calcification underlying organic matrix, visualized using SHG in conjunction with SRS, assisted in the diagnostic differentiation of patient lesions. Our study suggests that SRS imaging of calcification can be used as an important tool for breast cancer diagnosis. The diagnosis capability will be significantly improved when combined with stimulated Raman histology (SRH), a technique that has already been shown to provide H&E equivalent information in unsectioned tissue Supplementary figures and tables.Click here for additional data file."} {"text": "Recent changes in health care practices - shorter hospital stays, increased complexity of disease management, and greater management of chronic illnesses at home - have left family members increasingly responsible for medical tasks. Although these family caregivers represent the vital front line of care, they remain mostly excluded from the formal health care team. Based on interviews with multi-sector stakeholders representing patients/caregivers, providers, and payers, we identified several barriers to fully incorporating family caregivers into the health care team. They fall under five key themes: identification of caregivers; communication and information; time and resources; trust and cultural barriers; and Medicaid coverage. We discuss these barriers and potential solutions that could be undertaken by different stakeholder groups to improve family caregiver integration into the care team."} {"text": "The number of older populations raising their grandchildren has increased. Past research has indicated the distress custodial grandparents\u2019 experience is related to their family relationships . Family relationships are also influenced by a variety of factors such as social history, culture, family structure, and individual differences . The current study evaluated the influence of culture on the relationship between caregiver relationship quality and mental health by examining 885 children . This study also compared the difference in cultural impact between custodial grandparents-grandchildren and biological parents-children. Measures included the Network of Relationships Inventory, Hofstede Cultural Questionnaire, and Adult Behavior Checklist. Path analysis was conducted using AMOS 26.0 which resulted in an interaction between relationship closeness and collectivism to predict custodial grandparent depressive symptoms. Custodial grandparents who reported a lower level of closeness with their grandchildren in a higher collectivistic culture reported a significantly higher level of depression symptoms than those in a more individualistic culture, particularly for custodial grandmothers. However, custodial grandparents who reported a higher level of closeness with their grandchildren in a higher collectivistic culture reported significantly lower levels of depressive symptoms than those in a more individualistic culture. Furthermore, compared to biological parents, custodial grandparents reported significantly lower levels of depressive symptoms when reporting higher collectivistic culture. These findings will inform the need for more research to assess factors of cultural features that reduce psychological problems and support family relationships to adapt psychological therapies in older adults."} {"text": "This study examined the relationships between several attributes of living environment and attitudes towards aging among persons of age 75 years and older in Shanghai, China. The data were collected using self-administered surveys in a study of successful aging in 2018. Respondents included 139 persons of age 75 years and older living in 12 neighborhoods in Shanghai. Attitudes towards aging were measured by indices of happiness, time use and worry about the future. Using BaiduMap and GIS ArcPro, we quantified accessibility to neighborhood living resources as numbers of recreational facilities, medical facilities, parks, and grocery stores located within 500 meters of each respondent\u2019s home. The analysis found that more positive attitudes towards aging were correlated with less depressive symptom as measured by CES-D and greater numbers of neighborhood resources near home, especially greater number of grocery stores near home. In conclusion, accessibility to neighborhood resources may influence attitudes towards aging."} {"text": "As a consequence of the Affordable Care Act\u2019s enhancements of Medicare benefits, certain recommended clinical preventive services became available to Medicare beneficiaries without cost-sharing. We study the impact of these mandates on racial/ethnic disparities in the use of preventive services among traditional Medicare beneficiaries. We analyze nationally representative data on non-institutionalized Medicare seniors from the 2006-2016 Medical Expenditure Panel Survey . Our preventive services of interest include yearly receipt of cholesterol check, blood pressure test, flu shot, endoscopy, blood stool test, clinical breast examination, mammography and prostate exam. We estimate propensity score weighted difference-in-difference (DID) models to test for differences in preventive services utilization by race/ethnicity. Among traditional Medicare beneficiaries, we do not observe significant change in the use of most preventive services for Blacks and Hispanics compared to their White counterparts. However, Hispanics have significantly increased their use of blood stool tests relative to whites. Overall, we do not find major evidence to support a differential effect of reforms on race/ethnic minorities\u2019 uptake of preventive services following the mandates. Our results suggest that despite an overall benefit trough services expansion and cost-sharing elimination race/ethnic group differences persist. As such, disparities might continue and would require additional interventions. Reduction in disparities is a stated goal of US policy for many decades and achieving equity might require additional work and more varied and targeted interventions."} {"text": "Metastatic cancer patients undergo numerous treatment strategies with known cognitive side effects. It is unclear how medical decision-making capacity (MDC) is impacted by cognitive deficits in metastatic cancer. This study examines reliability of an objective measure of MDC compared with self-report. Participants with newly diagnosed metastasis to the brain and other sites were enrolled at the University of Alabama at Birmingham over seven years. At the study visit, participants completed a comprehensive neuropsychological battery including memory and executive functioning, and the Capacity to Consent to Treatment Instrument (CCTI) assessing medico-legal domains of MDC. The CCTI is a reliable and valid instrument containing two vignettes of hypothetical medical situations assessing four standards of consent. We examined reliability between the CCTI and self-reported MDC using Gwet\u2019s AC1 statistic. Participants with brain metastasis with impairment on the CCTI demonstrated significantly lower executive functioning and memory skills than those without impairment . There were no significant differences between intact and impaired participants with other metastases. Low reliability was observed between self-report and all medico-legal standards on the CCTI across both metastatic groups . Self-rating of MDC is unreliable in metastatic cancer patients. Patients with metastases (particularly brain metastases) may lack awareness of deficits in their MDC, so providers must affirm proper autonomy in their decisions."} {"text": "A paradoxical double challenge has emerged in the last decades with respect to nutrition and nutrition-related clinical conditions. Hunger-related undernutrition continues to represent an unacceptable burden, although its prevalence has been encouragingly reduced worldwide. On the other hand, the prevalence of overweight and obesity, defined as fat excess accumulation with negative impact on individual health, has dramatically increased due to increasingly pervasive obesogenic lifestyle changes. Undernutrition and obesity may coexist in world regions, Countries and even smaller communities and households, being referred to as double burden of malnutrition. It is however important to point out that fat accumulation and obesity may also induce additional nutritional derangements in affected individuals, both directly through metabolic and body composition changes and indirectly through acute and chronic diseases with negative impact on nutritional status. In the current narrative review, associations between fat accumulation in obesity and malnutrition features as well as their known causes will be reviewed and summarized. These include risk of loss of skeletal muscle mass and function (sarcopenia) that may allow for malnutrition diagnosis also in overweight and obese individuals, thereby introducing a new clinically relevant perspective to the obesity-related double burden of malnutrition concept. Natu2 \u20135. Indee2 , 7, 3, 4e groups , 6, 9.Based on the above observations, new complex nutritional challenges have emerged in recent times, with epidemiological shifts and coexistence of under- and overnutrition. The latter concept has indeed been recently described under the definition of \u201cdouble burden of malnutrition\u201d, indicating that both under- and overnutrition are commonly observed not only at global level but may indeed coexist in the same world regions and often in the same Countries and communities. Coexistence of seemingly opposite nutritional patterns may obviously partly reflect social and economic inequalities, but additional important reasons should be pointed out. In particular, enhanced life expectancy is increasing older adult population worldwide, and elderly individuals are commonly more prone to undernutrition due to multifactorial reasons that include psychological, social and health-related factors \u201312. EvenThe ongoing unprecedented shift in body weight paradigms is however posing larger dramatic individual, family, socio-economic and healthcare challenges . ObesityNegative obesity- and disease-related influences on skeletal muscle mass and function maintenance are summarized below. It is increasingly clear that profound alterations in skeletal muscle metabolism may occur in obesity with potential negative impact on whole body muscle mass and function , 26. Bodprimary metabolic abnormalities and insulin resistance: although a sizable portion of the obese population is not insulin resistant, a large majority of insulin resistant persons is either overweight or obese, or it presents with excess fat accumulation in the abdominal visceral compartment , 30. Subectopic muscle fat accumulation: muscle lipid accumulation commonly results in obesity from impaired adipose tissue expansion in the presence of excess lipid availability. Skeletal muscle fat accumulation is conversely closely associated with tissue and systemic insulin resistance , 48. Mecmitochondrial dysfunction: mitochondrial changes may not occur in obese individuals and become relatively common only in relatively late stages; their onset may however lead to excess ROS production resulting in oxidative stress and related complications that may exacerbate insulin resistance and directly favor muscle loss , 31, 44.stem cell dysfunction: altered muscle stem cell function with excess adipocyte differentiation have beeIntermediate and energy metabolism changes.metabolic complications: metabolic syndrome or overt type 2 diabetes and hyperglycemia are common in insulin resistant obese individuals and their onset may exacerbate pro-oxidative and inflammatory alterations as well as mitochondrial dysfunction. These enhanced abnormalities may further promote muscle loss and functional alterations , 48;chronic disease: chronic organ failure syndromes result in enhanced inflammation and oxidative stress through various mechanisms at tissue and systemic level, thereby also synergistically promoting muscle loss and damage . Obesitysurgery: bariatric procedures are becoming increasingly common and almost invariably lead to skeletal muscle catabolism at least in the initial rapid weight loss phase characterized by profoundly negative energy balance , 58; lowComorbidities and treatment.Lifestyle and physical inactivity: low physical activity levels play a key role in the onset of obesity and physical activity is commonly further progressively reduced with disease duration, aging and increased body weight, with direct negative impact on muscle protein turnover as well as muscle fitness . ObesityBased on the above observations, a multifactorial cluster of obesity-induced or obesity\u2013associated alterations leads to skeletal muscle loss and dysfunction with low muscle strength and endurance, that are likely caused at least in part by low muscle mass, mitochondrial dysfunction with altered bioenergetics and fat accumulation with reduced muscle density. These changes become progressively more likely in patients with longer obesity duration, complications and older age, that may be per se independently associated with muscle loss and dysfunction.Skeletal muscle changes in obesity have a profound clinical impact. Obese individuals with low muscle mass and function have higher risk of developing frailty and disability, and may generally present with poorer quality of life. Importantly, low or declining muscle mass is emerging as a negative prognostic factor associated with higher morbidity and mortality in obese patients with various chronic complications and diseases and in aging , 64, 65.The potential relevance of muscle mass maintenance as a priority therapeutic target in obesity is regrettably hampered by inadequate awareness. Definition and diagnosis of this condition are problematic. Definition of sarcopenic obesity may combine obesity with the geriatric concept of primary sarcopenia, a combination of low muscle mass and function (particularly strength) that almost invariably occurs in old age. While diagnostic criteria for aging-associated primary sarcopenia have been proposed , they arOverall, despite relevant practical limitations, recognizing skeletal muscle depletion or dysfunction in obese individuals by body composition measurement techniques, strength measurement or other functional tests should be a priority to alert clinicians to enhanced risk for negative outcome \u201378.Routine nutritional screening to identify patients at risk for malnutrition is recommended in most chronic and acute disease conditions and in hospitalized patients. Validated and widely utilized screening tools include Nutritional Risk Screening-2002 (NRS-2002) . ImportaMost importantly, major guidelines have started to take nutritional needs of obese patients into account with specific recommendations for nutritional support that may combine a limitation in calorie with high protein administration aimed at preventing loss of skeletal muscle mass and function , 86. PreIn conclusion, the ongoing obesity epidemics, along with population aging and increased chronic disease prevalence is profoundly modifying fundamental clinical nutrition and healthcare priorities worldwide. A true double burden of malnutrition exists beyond coexistence of obesity and undernutrition in Countries and communities. Indeed individuals with obesity may present with true malnutrition due to inability to preserve body composition and performance with loss of skeletal muscle loss and function that exert major negative influences on morbidity and survival. Recognition of this new double burden is a relevant priority in order to more effectively identify diagnostic and therapeutic tools."} {"text": "Isolated coronary Takayasu arteritis is a rare form of ischemic heart disease that typically appears as an aorto-ostial lesion. Although several vascular imaging modalities including ultrasonography, computed tomographic angiography, magnetic resonance angiography or catheter angiography, play crucial roles for diagnosing Takayasu arteritis, the intravascular ultrasound imaging of Takayasu arteritis is not well studied.A 55-year-old woman who was diagnosed with heterozygous familial hypercholesterolemia underwent coronary angiography due to effort angina, which showed ostial left anterior descending coronary artery (LAD) stenosis. Although directional coronary atherectomy followed by drug-coated balloon was successfully performed, 6\u2009months later restenosis occurred at the ostial LAD, and the ostial left circumflex coronary artery (LCx) progressed significantly. The intravascular ultrasound imaging in these lesions was noteworthy, in which the media was partly unrecognizable and an echo intensity similar to fibrotic intimal thickening traversed from the intima to the adventitia, thereby causing the whole image of the coronary artery to become unclear. Directional coronary atherectomy followed by drug-coated balloon procedures for both LAD and LCx lesions were performed again. Systemic examination of computed tomographic angiography found no other stenotic lesions except for those in the coronary arteries. Five months later, the LAD and LCx lesions progressed diffusely, therefore the coronary artery bypass graft was done. The histopathological findings of specimens of the coronary artery that were obtained during the bypass graft showed excessive fibrous thickening of the intima and adventitia, with granulomatous inflammation in the media, which led to the diagnosis of isolated coronary Takayasu arteritis. Systemic corticosteroid therapy was then started.We described an extremely rare case of isolated and non aorto-ostial Takayasu arteritis. The characteristic intravascular ultrasound images of diseased coronary arteries may help in the diagnosis of coronary Takayasu arteritis. Takayasu arteritis is an idiopathic chronic inflammatory arteritis characterized by stenosis, occlusion or dilatation of the aorta and its major branches, predominantly prevalent among young women . CoronarA 55-year-old woman was referred to our hospital because of chest pain on effort that had worsened in the last 3 months. The patient had no significant past medical history and was not on any medication. Family history revealed that her mother was diagnosed as having stable angina pectoris at 70. The patient had no evident physical findings of fever, lymphadenopathy, joint pain or left-right deference of blood pressure. Electrocardiogram showed regular sinus rhythm and no significant abnormalities Fig.\u00a0. The echPercutaneous coronary intervention with coronary plaque atherectomy using directional coronary atherectomy (DCA) catheter followed by paclitaxel-coated balloon was performed on the LAD lesion, and plain old balloon angioplasty was performed on the high lateral branch lesion Fig. c and d. Five months later, she suffered from chest pain on effort again and coronary angiography showed a restenosis of the ostial LAD, as well as a stenosis of the distal left main coronary artery (LMCA) and the ostial LCx Fig. e and f. Single photon emission computed tomography myocardial perfusion imaging at 6 months after the second coronary intervention revealed significant apical and lateral wall ischemia. Coronary angiography showed the restenosis of the ostial LCx and the diffuse stenotic progressions of the mid LAD and LCx was then started. Since the administration of corticosteroids, at the time of writing, the patient has been free from chest pain for 1\u2009year.Takayasu arteritis is an idiopathic chronic inflammatory arteritis characterized by stenosis, occlusion or dilatation of the aorta and its major branches, and is predominantly prevalent among young women . CoronarIVUS imaging of the lesion revealed intimal fibrotic thickening without lipid-rich plaque, in which the media was partly unrecognizable and the echo intensity similar to fibrotic intimal thickening traversed from the intima to the adventitia. The histopathologic characteristics of Takayasu arteritis are granulomatous inflammation of the media and adventitia with giant cells, diffuse productive inflammation consisting of lymphocytes and plasma cells infiltration, diffuse or nodular fibrosis accompanied by disintegration and loss of elastic fibers, and reactive intimal fibrotic thickening. These conditions caused marked intimal and adventitial fibrosis . The disDirectional coronary atherectomy is a useful method especially for bifurcated lesions . The comBoth Takayasu arteritis and familial hypercholesterolemia provoke arterial stenosis as a result of inflammatory disorder of the arterial wall; however, the correlation of these diseases is unclear , 14. TheWe here described an extremely rare case of isolated and non aorto-ostial coronary Takayasu arteritis, and IVUS images of coronary lesions in Takayasu arteritis. Characteristic IVUS images may help for diagnosing coronary arteritis."} {"text": "Avian influenza A viruses (AIVs), as a zoonotic agent, dramatically impacts public health and the poultry industry. Although low pathogenic avian influenza virus (LPAIV) incidence and mortality are relatively low, the infected hosts can act as a virus carrier and provide a resource pool for reassortant influenza viruses. At present, vaccination is the most effective way to eradicate AIVs from commercial poultry. The inactivated vaccines can only stimulate humoral immunity, rather than cellular and mucosal immune responses, while failing to effectively inhibit the replication and spread of AIVs in the flock. In recent years, significant progresses have been made in the understanding of the mechanisms underlying the vaccine antigen activities at the mucosal surfaces and the development of safe and efficacious mucosal vaccines that mimic the natural infection route and cut off the AIVs infection route. Here, we discussed the current status and advancement on mucosal immunity, the means of establishing mucosal immunity, and finally a perspective for design of AIVs mucosal vaccines. Hopefully, this review will help to not only understand and predict AIVs infection characteristics in birds but also extrapolate them for distinction or applicability in mammals, including humans. Avian influenza A viruses (AIVs) remain one of the important viral pathogens that cause respiratory tract infections in various animal species, such as poultry and humans, and aquatic birds are considered the primordial source of AIVs infecting other animal species . InfluenInfluenza viruses undergo antigen mutations through antigen drift and shift. Circulating AIVs evolve constantly, resulting in the occurrence of new strains with variable antigenicity. Particularly, mutations occurring in the HA or NA usually cause antigenic drift, subsequently leading to an escape from earlier immune responses. Besides, an antigenic shift can take place in AIVs. In this case, co-infection of a host cell with AIVs strains of different origins can lead to the generation of novel virus subtypes via induced genetic reassortment; a newly formed HA subtype of AIVs can transmit easily in immunologically na\u00efve individuals . To dateVaccination remains one of the most effective ways to control and prevent AIVs transmission in poultry. Current influenza vaccines are generally effective against antigenically matched strains. It has been demonstrated that the antigenic mismatch between the vaccine and circulating strains or inadequate vaccine protocols can cause an antigenic drift and failed vaccination ,14. AlthThe innate immune response constitutes the first line of protection from invading pathogens. AIV infection results in a recognition of viral conserved components called pathogen associated molecular patterns (PAMPs) by host pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs), retinoic acid inducible gene-I (RIG-I) receptors (RLRs), and NOD-like receptors (NLRs); the above recognition subsequently activates innate immune signaling and induces various proinflammatory cytokines as well as antiviral molecules ,19. ThenTLRs were identified as the first PRRs family that are expressed on either the plasma membrane or the surface of endosomes and lysosomes . To dateThe RLRs\u2014RIG-I and melanoma differentiation-associated protein 5 (MDA5)\u2014recognize the cytoplasmic viral non-self RNA and transcripts. RIG-I preferentially binds cytoplasmic single-strand 5\u2032-triphosphate RNA, while MDA5 is activated by long dsRNA species . Upon inThe roles of NLR signaling in bacterial infection have been broadly investigated . IAV infThe adaptive immune response comprising humoral and cellular responses at both systemic and mucosal levels constitutes the second line of defense against influenza viruses; this multifaceted immune response is complex 36]. In. In36]. Infection with influenza viruses initiates virus-specific cellular immune response involving CD4+ T and CD8+ T cells . Upon inDuring IAV infection, CD8+ T cells, a vital subset of immune cells, are activated after recognition of viral epitopes on DCs that migrate from the lung tissue to T-cell areas in the draining lymph nodes, resulting in their proliferation and differentiation into CTLs . CD8+ T The mucosal immune system plays a crucial role in controlling infection with influenza viruses in the URT . The URTAbs, particularly IgG and IgA, are the major immune components acting in the protective response to IAVs . IgG is In response to antigen stimulation, IgA class switching and IgA secretion occur in B cells stimulated by specific signals such as co-stimulatory molecules and cytokines and in Th cells via T-cell-dependent and T-cell-independent pathways . The aboAt present, the commercial vaccines against influenza available on the market mainly comprise inactivated influenza A virus (IIV) vaccine and recombinant influenza A virus (RIV) vaccine. Strains used in commercial influenza vaccines are selected based on the compositions of viruses from the surveillance, laboratory, and clinical observations . These vThe respiratory mucosa is the first target of influenza virus, constituting the first line of defense against the infection, which can effectively prevent the virus from entering . MucosalMoreover, it has been shown that mucosal vaccines induce cross-reacting Ab in the respiratory tract, providing cross-protection against heterologous virus infection. Inoculating the influenza HA vaccine together with cholera toxin B subunit (CTB) or B subunit of heat-labile enterotoxin (LTB) supplemented with cholera toxin (CT) intranasally enhanced anti-HA lgA and IgG Ab responses in nasal wash or serum, which protect mice against variant virus infection . OkamotoResearchers have been attempting to create universal influenza vaccines for providing broad and sustainable protection against diverse influenza viruses. In recent years, research on the prevention of influenza infection by nasal immunity has gained more and more attention. To effectively work in mucosal immunization, mucosal vaccines must be designed to possess the characteristics of mucosa and promote the specific immune responses to vaccine antigens in the mucosa. Currently, generating effective mucosal vaccines mainly involves the identification of efficient means for antigen delivery to the mucosal immune system and the development of safe and effective mucosal adjuvants or immunoregulatory agents.A growing number of pre-clinical studies and clinical trials have advanced our understanding of how live attenuated influenza vaccines (LAIVs) elicit mucosal antibodies via intranasal administration. Contrary to the wild-type forms, attenuated viruses have the capacity to replicate well at temperatures around 25 \u00b0C rather than at 37 \u00b0C, deterring their replication in the lower airway, including lung tissue, and the subsequent occurrence of influenza-like disease . The mosAmong developing live attenuated mucosal vaccines, the major class of vaccines, oral vaccines, are currently being assessed in clinical studies. Oral vaccines are classified into intranasal and sublingual vaccines that are developed for the control of influenza, rotavirus, norovirus and measles viruses . ExperimSuccessful development of LAIVs largely rests on the proper balance between attenuation and immunogenicity. It has been reported that serial virus passage in the host cells during vaccine development causes a decrease in the virulence of effective live attenuated vaccines for rotavirus . As a reAdjuvants can potentially increase the immunogenicity of mucosal influenza vaccines, while enhancing the efficacy of vaccines through modulating the quantity and quality of host immune responses. Commonly used adjuvants include a wide range of compounds . The comAdjuvants act via the following mechanisms: (1) a depot formation at the site of injection, which enables the vaccine agents to be slowly released and the host immunity to be constantly stimulated; (2) enhancement of the agent uptake via APCs and APC activation and maturation; (3) immune cell recruitment; and (4) innate immune receptor activation. Moreover, adjuvants can shape subsequent adaptive immunity for producing the most effective and protective responses to a given pathogen through targeting the subsets of innate immune cells and forming a unique cytokine milieu associated with Th1, Th2, and/or Th17.A number of adjuvants for inactivated influenza vaccines including TLR agonists are widely used to enhance the vaccine immunogenicity . StudiesDNA vaccines are capable of expressing immunogenic antigens in vivo, thereby inducing cellular and humoral immunities without causing host exposure to live viruses . ExtraceIt has been shown that intranasal administration of DNAs in mice leads to a fast and relatively even distribution of plasmid DNAs all over the body . DNA vacParticulate vaccines are capable of forming a close contact with the epithelial cells in the mucosa via included anchoring devices with adhesive properties or included immunomodulating factors ,121. TheRecombinant technology has been employed to engineer live vector vaccines to express target antigens. The vectors usually have minimal replicative ability to allow immune stimulation without causing infection. Delivery of vector vaccines via the mucosal routes mimics the natural infection, inducing strong mucosal, systemic, and cellular immunities against micro-organisms. Many candidate vectors. e.g., bacillus subtilis , FowlpoxAdministration of mucosal vaccines via the oral route is strongly recommended because it avoids an injection, is safe and painless, and does not require professionals for delivery. However, the efficacy of oral vaccination has proven less satisfactory due to the fact that vaccine degradation occurs in the harsh environment of the gastrointestinal tract, and mucosal tolerance suppresses immune responses to a foreign antigen. Thus, oral vaccination may require highly sophisticated formulations involving approaches for cell-specific targeting and immunomodulation. In the mucosal tissues, epithelial cells are coated by a viscous fluid called mucus containing a layer of glycoproteins (mucins). The layer of mucus serves as a physical barrier between the epithelium and invaded pathogens while harboring competitive binding sites for entrapping microbes and S-IgA Abs for binding to and neutralizing pathogens. Structurally, the intestinal epithelium formed by a single-cell layer constitutes the largest and most important barrier to the entry of foreign substances and functions as a selective barrier that only allows for nutrients and electrolytes to be absorbed while preventing the entry of intra-luminal antigens, toxins, and microorganisms ,134. TheThere exist continued efforts in developing oral live attenuated vaccines. However, compared with live-attenuated pathogen based vaccines with limitations in safety, recombinant subunit vaccines or non-living or non-infectious vector vaccines could be more attractive, albeit more difficult to deliver ,135. HenAs a major entering portal for pathogens, the nasal route becomes a promising option for mucosal vaccination due to its unique physiological and immunological characteristics. Intranasal vaccination is capable of stimulating immune responses in the nasopharynx-associated lymphoid tissue, eliciting systemic and mucosal immunities in the gastric mucosa and the respiratory and/or genital tract . Most soVaccination via the nasal cavity is the earliest mean of mucosal delivery, and nasal immunity can effectively prevent respiratory diseases. At present, mucosal immunity has made great contributions to human medicine from theory to practice, and various influenza vaccines such as LAIVs and cold-adapted influenza attenuated vaccines have been developed ,140. TheAvian influenza is a serious respiratory disease. Although currently used inactivated vaccines are effective, circulation of antigenically different strains could reduce the efficacy of vaccines due to the fact that almost all vaccines are administered via the i.m. route. The rate of antigenic variation of AIVs is accelerating, thereby increasing the risk of human infection and harm to the economy and society. Therefore, speeding up the research on AIVs vaccines and improving vaccine safety and reliability will have huge economic and social benefits. Mucosal immunity constitutes the first line of defense against AIVs; the mucosal delivery route elicits mucosal and systemic immunities simultaneously. Compared to inactivated vaccines, mucosal vaccines stimulate both cellular and humoral immunities and can be more effective in protecting against influenza variant strains, hence producing more cross-reactive and longer-lasting comprehensive immune responses. Overall, mucosal vaccines and delivery routes should play an irreplaceable role in remarkably reducing AIVs-caused burden."} {"text": "Examining the neural correlates underlying racial differences in cognitive functioning is necessary to help clarify mechanisms and to improve the generalizability of findings related to brain-behavior relationships. This systematic review aimed to determine whether there are racial differences in structural markers of brain aging among community-dwelling, neurologically healthy adults aged 18 and older. We identified studies from searches in Ovid Medline, Ovid PsychINFO, and Elsevier EMBASE published until February 13, 2020. We included original articles that examined structural markers of brain aging and neuropathology across individuals from more than one race or ethnicity. These measures included magnetic resonance imaging, positron emission tomography amyloid and tau, cerebrospinal fluid amyloid, tau, and neurofilament light chain and computed tomography. Two reviewers independently screened full-text articles. We will present ongoing results and discuss the current state of knowledge, quality of existing studies, and gaps in the literature and highlight potentially key next steps."} {"text": "Stem cells have improved the treatment of several diseases. Their efficacy has been widely debated over the last few decades, but their contribution to medical research has constantly increased .Recently, a pivotal study supported by the National Institute of Dental and Craniofacial Research (NIDCR), leaded by Prof. Yang Chai, investigated stem cell-based therapies for children with craniosynostosis. Authors demonstrated that Mesenchymal Stem Cells (MSCs) combined with hydrogel were able to regenerate functional cranial sutures previously undergone craniosynostosis, restoring not only skull anatomy but also neurocognitive functions in an animal model . This stSeveral research groups have worked on the role of genetic and epigenetic factors on craniosynostosis development, confirming a pivotal role of TWIST-1 gene mutations in Saethre\u2013Chotzen syndrome (SCS). The discovery of genetic and molecular pathways has increased attention on alternative treatments to surgery: the group of Prof. Stan Gronthos demonstrated that pharmacological targeting of Kdm6a/b genes activity may regulate aberrant osteogenesis by TWIST-1 mutant cranial suture mesenchymal progenitor cells via deregulation of epigenetic modifiers, thus preventing cranial prefusion and the related functional impairment . On the The use of stem cell therapy to reactivate functional sutures is a clinical breakthrough also in the light of the high incidence of resynostosis after complex cranial vault reconstruction. Nevertheless, an early combined surgical and regenerative approach to craniosynostosis, may reduce or definitely prevent several related dental and maxillofacial implications , in addiThe crosstalk among stem cell therapy and clinical outcomes has been investigated also in studies on muscular , neural Therefore, the results reached by Prof. Yang Chai and his group are a milestone that will promote novel less-invasive, stem cell-based therapeutic approaches that will benefit patients affected by craniofacial developmental disorder involving related brain and organs alterations. Overall, stem cell research has obtained an important achievement towards its future clinical application in minimally invasive therapeutic procedures."} {"text": "Emergency providers should recognize that pneumothorax is a rare but serious complication of shoulder arthroscopy that may require a unique approach to decompression.We present a case of a 60-year-old female who presented to the emergency department with right-sided facial swelling, voice change, and shortness of breath three hours after an elective arthroscopic right rotator-cuff repair and was noted to have a right-sided pneumothorax. We also describe a potential novel approach to chest tube decompression that maintains shoulder adduction in patients with recently repaired rotator cuffs.Although most cases of post-arthroscopy pneumothoraces are reported in patients who received regional anesthesia or have underlying lung pathology, it can occur in lower-risk patients as was demonstrated in our case. We also suggest considering an alternative anterior approach between the midclavicular and anterior axillary lines for chest decompression in select patients when a traditional approach is less ideal due to the need to maintain shoulder immobilization postoperatively. Over the past few decades shoulder arthroscopy has become an increasingly common technique to treat shoulder pathology. Proponents cite a decreased complication rate when compared to open procedures.A 60-year-old female presented to the ED with right-sided facial swelling, voice change, and shortness of breath three hours after an elective, arthroscopic, right rotator cuff repair. The outpatient surgery comprised a subacromial decompression, major glenohumeral joint debridement, and rotator cuff repair for right shoulder chronic impingement syndrome, intra-articular biceps tear, and full thickness rotator cuff tear. The surgery was performed in the lateral decubitus position under general anesthesia and without regional nerve block. The anesthesia report was reviewed and showed no major complications or episodes of hypotension or desaturation. The patient reported feeling well postoperatively; however, three hours later she developed right-sided face and neck swelling , voice cThe patient denied significant past medical history including any history of smoking or underlying lung or connective tissue disease. On arrival, her vitals were heart rate 92 beats per minute, blood pressure 135/80 millimeters mercury, respiratory rate 18 breaths per minute, and pulse oximetry was 96% on room air. Her physical exam was notable for predominately right-sided facial swelling, diminished right-sided lung sounds, and crepitus of the right neck, face, and chest. A chest radiograph showed a right-sided pneumothorax of approximately 70% with mediastinal shift and extensive subcutaneous emphysema .A pigtail catheter-type chest drain was placed in the fifth intercoastal space between the right midclavicular and anterior axillary line so as to not abduct or displace the patient\u2019s shoulder given her recent rotator cuff repair. Successful expansion of the lung was noted .On the third day of admission, the chest tube was removed and the patient was discharged home without further complications. At her two-week follow-up, her shoulder was healing well and she had no significant sequelae from her pneumothorax.Only a handful of case reports and case series describe an association between arthroscopic shoulder surgery and postoperative pneumothorax3CPC-EM CapsuleWhat do we already know about this clinical entity?Pneumothoraces have been reported as a possible complication of shoulder arthroscopy.What makes this presentation of disease reportable?We present a case of a rare complication of a common procedure and suggest a less common procedural approach to treating pneumothorax.What is the major learning point?Pneumothorax is a rare but serious complication of shoulder arthroscopy that may require a unique approach to decompression.How might this improve emergency medicine practice?This variation to traditional pneumothorax decompression technique could help avoid re-injury of the rotator-cuff repair site.Emergency providers have traditionally placed tube thoracostomy drains at the fourth or fifth intercostal space at the midaxillary or anterior axillary line11Limitations to this new approach include left-sided pneumothorax , obese patients, large area of breast tissue, or use of larger caliber chest tubes. Placing the pigtail catheter at the second intercostal space midclavicular line is a viable alternative in these casesEmergency providers should recognize pneumothorax as a rare but serious complication of shoulder arthroscopy. Although most cases reported are in patients who received regional anesthesia or have underlying lung pathology, it can occur in lower-risk patients as was demonstrated in our case. Patients may present with classical findings of pneumothorax including dyspnea, decreased breath sounds, and signs of tension including mediastinal shift. Postarthroscopy pneumothoraces nearly always present with crepitus on exam or subcutaneous air on imaging. The majority of these cases tolerate decompression without issues and patients are discharged within several days without complications. Providers may consider follow-up computed tomography imaging in patients without prior lung disease to assess for underlying lung disease or structural pathology including blebs. We also suggest considering an alternative anterior approach between the midclavicular and anterior axillary lines for chest decompression in select patients when a traditional approach is less ideal due to the need to maintain shoulder immobilization postoperatively; however, more research is needed to confirm safety and efficacy."} {"text": "Previous research has identified cancer and cancer-treatment related effects on survivors\u2019 mental impairment including memory and concentration. However, research has not systematically examined the relative impact of cancer in the context of age and other age-related health challenges common in later life. This paper compares the effects of cancer-related factors with other health challenges faced by 471 older adult long-term survivors from an NCI-funded study of a randomly selected tumor registry sample from a major comprehensive cancer center. Having had chemotherapy is associated with several cognitive outcomes including memory and concentration. Survivors who reported more cancer-related symptoms during treatment reported a greater number of cognitive symptoms even decades after treatment. Importantly, other comorbid health problems as well as social factors were found to be important in explaining symptoms of cognitive impairment in this older adult sample. These findings suggest that health care and mental health providers consider the range of health challenges, including those related to cancer and its treatment, as they provide patient centered care."} {"text": "This special issue includes seven articles. We have a brief review of mental health issues among Asian and Pacific Island (API) communities. Two papers examine non-biological factors that may be associated with mood disorders, using a nationally representative sample of Asian Americans (AA). These papers are particularly informative because they report disaggregated results across four AA subgroups. Another two articles examine different interventions and their efficacy to improve mood and quality of life among APIs. Finally, the case of a clinical encounter during COVID-19 was examined through the lens of Asian critical theory. Although these papers differ in their focuses and methodologies, collectively, they provide valuable information about mental health issues among the API community."} {"text": "Influenza viruses rapidly diversify within individual human infections. Several recent studies have deep-sequenced clinical influenza infections to identify viral variation within hosts, but it remains unclear how within-host mutations fare at the between-host scale. Here, we compare the genetic variation of H3N2 influenza within and between hosts to link viral evolutionary dynamics across scales. Synonymous sites evolve at similar rates at both scales, indicating that global evolution at these putatively neutral sites results from the accumulation of within-host variation. However, nonsynonymous mutations are depleted between hosts compared to within hosts, suggesting that selection purges many of the protein-altering changes that arise within hosts. The exception is at antigenic sites, where selection detectably favors nonsynonymous mutations at the global scale, but not within hosts. These results suggest that selection against deleterious mutations and selection for antigenic change are the main forces that act on within-host variants of influenza virus as they transmit and circulate between hosts. As influenza viruses replicate within infected hosts, they quickly mutate into genetically diverse populations. A small proportion of within-host variants transmit between individuals , and somSeveral recent studies have used deep sequencing to identify within-host mutations in hundreds of clinical influenza infections . HoweverHere, we compare the genetic variation of H3N2 influenza virus within and between human hosts to infer the fates of within-host mutations in the global viral population. Individual within-host mutations are challenging to track on a global scale, but by comparing large numbers of genetic variants identified within and between hosts, we can infer the evolutionary forces that act on different classes of mutations. We analyze within-host viral variation in 308 acute influenza infections from three deep-sequencing datasets , and we Evolutionary rates provide a simple, quantitative framework for comparing viral variation across scales. Under neutral evolution, we expect within-host and global evolutionary rates to be identical, and deviations from these neutral expectations shed light on how selection acts across evolutionary scales. For instance, HIV and hepatitis C virus both evolve more rapidly within than between hosts, probably because viruses acquire adaptations to specific hosts that often revert after transmission .We sought to calculate the within-host and global evolutionary rates of influenza virus. Influenza\u2019s global evolutionary rate is easily estimated from phylogenies of patient consensus sequences, which represent transmitted strains , but evoTo overcome these challenges, we developed a method to estimate rates of within-host evolution from deep sequencing of acute viral infections. In brief, we identified within-host mutations that were present in at least 0.5 per cent of sequencing reads to estimWe tested the sensitivity of this method to common technical considerations. Estimates of evolutionary rates can be influenced by the frequency threshold used to identify within-host variation . We focuIn calculating within-host evolutionary rates, we sought to limit the influence of outlier samples with unusually high within-host variation . This hiWe calculated rates of within-host influenza evolution from deep-sequencing data in three published studies that together represented 308 acute H3N2 influenza infections Dinis e. We estiTo assess sources of variation in our estimates, we calculated evolutionary rates separately for each deep-sequencing dataset . We alsoTo compare rates of evolution in acute and chronic influenza infections, we also calculated rates of influenza evolution in four chronic H3N2 infections that lasted multiple months Supplem. We findWhat kinds of mutations reach detectable frequencies within hosts? We compared how quickly synonymous, nonsynonymous, and stop-codon (nonsense) mutations accumulate within hosts. Differences in how quickly these three classes of mutations accumulate can reveal how selection acts within hosts. Most synonymous mutations are nearly neutral; many nonsynonymous mutations are deleterious; and premature stop codons are lethal. In the absence of selection, all three types of mutations accumulate at the same rate. However, purifying selection purges deleterious mutations, and positive selection increases the frequency of any beneficial mutations.We find that deleterious mutations are purged detectably but incompletely within infected individuals. Synonymous mutations accumulate about twice as quickly as nonsynonymous mutations within hosts, with some variation across genes . Stop-coHow do mutations that arise within hosts fare as they circulate between hosts? We compared rates of evolution within hosts and globally to determine how selection acts across different scales of viral evolution. Neutral mutations should have similar rates of evolution within and between hosts. Purifying selection that acts between hosts to eliminate deleterious mutations will decrease global evolutionary rates compared to rates within hosts. Conversely, positive selection that acts on a global scale will increase rates of evolution between hosts relative to their within-host expectations for beneficial classes of mutations.To calculate the global evolutionary rates of influenza virus, we analyzed H3N2 influenza sequences in the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database, where each sequence represents the consensus sequence of one patient infection . We usedSynonymous mutations accumulate at similar rates within hosts and globally . This coIn contrast, nonsynonymous mutations accumulate more slowly globally than within hosts in all six viral genes analyzed. In addition, while stop-codon mutations accumulate at appreciable rates within hosts, they never fix during global evolution. These discrepancies in evolutionary rates within and between hosts suggest that many nonsynonymous mutations that reach detectable frequencies within hosts are later purged by purifying selection as viruses transmit and circulate between hosts.An important exception to this trend occurs in the antigenic regions of the HA gene, which evolve more rapidly on a global scale than non-antigenic regions of HA Caton e. Within The previous section shows that nonsynonymous mutations are less common among mutations that fix globally than they are within hosts. This result suggests that purifying selection eliminates many nonsynonymous within-host variants before they fix in the global population of influenza viruses. However, it remains unclear from this analysis how quickly deleterious, nonsynonymous mutations that are generated within hosts are eliminated as viruses transmit and circulate between hosts.de novo mutations are expected to be nonsynonymous. However, purifying selection reduces the fraction of nonsynonymous mutations by removing deleterious mutations after they arise and before they fix. By examining when nonsynonymous mutations are depleted from circulating viral strains, we can identify where in the evolutionary process most purifying selection takes place . The fraction of nonsynonymous mutations is even lower among between-host mutations that reach higher frequencies, and eventually, fewer than 20 per cent of the mutations that fix in these genes are nonsynonymous. Previous work has shown that rare variants in global viral populations are dominated by transient deleterious mutations , so thisMore nonsynonymous mutations are present between hosts in the viral surface proteins HA and NA. Nonsynonymous mutations are especially enriched between hosts in antigenic sites of HA, which experience strong positive selection on the global scale Murphy,. In antiOur analyses show that transient deleterious mutations make up a large proportion of influenza\u2019s genetic variation within hosts. Deleterious variation is common at the between-host scale as well and can In this study, we quantitatively compared influenza virus\u2019s genetic diversity within and between human hosts. Our results show that although viral diversity may seem low within acute human influenza infections, it is sufficient to explain the virus\u2019s rapid global evolution. Synonymous mutations accumulate at similar rates within and between hosts, as expected for neutral genetic changes. Most nonsynonymous mutations that reach detectable frequencies within hosts are eventually purged between hosts, suggesting that within-host influenza diversity consists mostly of transient, deleterious mutations that are eliminated at transmission and global evolution. Antigenic sites of HA are the only region of the influenza genome where mutations are consistently favored between hosts beyond their frequencies within hosts.Our findings show how purifying and positive selection act on viral populations at different evolutionary scales. Influenza populations within hosts accumulate genetic variation as they expand during the first few days of an infection. However, most of this variation, which is deleterious, is purged as viruses circulate between hosts. One recent study estimates that influenza\u2019s transmission bottleneck consists of one to two viral genomes , and furin vitro mutations within hosts in each influenza gene . Random To calculate rates of viral divergence per day, we normalized per-site viral divergence by the timing of sample collection. Of the 308 H3N2 samples that we analyzed, 251 had metadata describing the number of days post-symptom-onset after which the sample was collected. For the remaining samples sequenced by For comparison, we calculated rates of evolution in acute patient infections through both the \u2018point\u2019 method described above, which averages rates of evolution calculated from each patient infection, as well as through linear regression . We perfTo calculate within-host rates of evolution in antigenic sites of HA, we used the antigenic sites defined by We downloaded all full-length H3N2 influenza coding sequences in the GISAID EpiFlu database collected from 1 January 1999 to 31 December 2017 . We randWe used a molecular-clock approach to calculate global evolutionary rates. We performed linear regression of the distances from a reference sequence by the timing of sample collection to estimate the rate of between-host evolution . MoleculWe previously deep-sequenced longitudinal samples of influenza from four chronic H3N2 influenza infections . We downTo calculate the fraction of mutations that are nonsynonymous within hosts, we tallied the total number of synonymous and nonsynonymous mutations in each frequency bin for each sample. Stop-codon mutations were counted as nonsynonymous mutations in this analysis. We then summed the variants in each frequency bin across samples. We calculated confidence intervals by performing 100 bootstrap resamplings of the viral samples and plotted the 95 per cent confidence interval from these bootstrap replicates .To calculate the fraction of mutations that are nonsynonymous between hosts, we must be able to determine when the same mutation has arisen multiple times in the global influenza population. We downloaded all full-length H3N2 influenza coding sequences in the GISAID EpiFlu database collected from 1 July 2015 to 30 June 2018, together representing the 2015\u20136, 2016\u20137, and 2017\u20138 Northern Hemisphere flu seasons . We grouhttps://github.com/ksxue/within-vs-between-hosts-influenza. Sequences downloaded from the GISAID Epiflu database are not available due to data-sharing restrictions, but acknowledgement tables for the sequences we analyzed are available at https://github.com/ksxue/within-vs-between-hosts-influenza/tree/master/data/GISAID/acknowledgements/H3N2.Raw sequencing data are publicly available from the NCBI SRA database for Bioprojects PRNJA577940 , PRJNA34Virus Evolution online.veaa010_Supplementary_DataClick here for additional data file."} {"text": "Older age has often, but not always, been associated with greater risk aversion. Some have suggested that age differences in risk may reflect age-related declines in cognitive abilities. This study investigated the robustness of age differences in risk aversion across three different risk-taking measures, after controlling for cognitive abilities. Community-dwelling younger and older adults completed self-report and behavioral measures of risk aversion and several measures of cognitive abilities. Results showed that older adults reported significantly greater risk aversion than young adults on the behavioral measure of risk , but not on the self-report measures (Framing Task and Choice Dilemmas Questionnaire). Greater risk aversion on BART was significantly associated with lower analytic thinking, slower processing speed, and worse shifting of attention. Therefore, we tested the relation between age and risk aversion on the BART while controlling for these three cognitive abilities. Age differences in risk aversion remained significant even after accounting for cognitive abilities. Our results suggest that the lack of consistent age differences in risk aversion in the literature may at least partly be due to measurement differences, which raises concerns about the construct validity of these measures of risk aversion. Moreover, cognitive decline may not explain age differences in risk. Further research is needed to understand factors that dampen and heighten risk aversion in people of diverse ages."} {"text": "The Latinx population is disproportionately affected by HIV-infection and older Latinx persons living with HIV (PLWH) are at greater risk for neurocognitive impairment (NCI). However, no studies have examined whether intersectionality increases NCI risk. This study investigated whether LGBT status increases NCI risk in 126 PLWH who completed a comprehensive NC battery. Domain average T-scores were based on demographically-corrected norms. Multiple regressions revealed that after accounting for covariates and other dimensions of intersectionality , LGBT status significantly contributed to NCI risk in attention/working memory and executive functioning . LGBT status, a key dimension of intersectionality, should be considered in NC assessment of PLWH. Future research is needed to identify factors that may confer increased NCI risk in this population."} {"text": "The vagus nerve-based inflammatory reflex regulates inflammation and cytokine release. Recent successful clinical trials using implantable bioelectronic devices to modulate the inflammatory reflex in patients with rheumatoid arthritis and inflammatory bowel disease have demonstrated the efficacy of targeting neural circuits as an efficient alternative to drug treatments. However, the optimal vagus nerve stimulation parameters to achieve efficacious symptomatic relief for inflammation are still unknown. In this issue of Bioelectronic Medicine, Tsaava et al. tested whether altering these electrical stimulation parameters would change circulating cytokine levels in healthy mice. They found that specific combinations of parameters produced significant increases in serum TNF while other parameters selectively lowered serum TNF levels, as compared to sham stimulated mice. These results have considerable implications for determining the optimal stimulation parameters to better treat common conditions and diseases that involve immune regulation. Recent successful clinical trials using implantable bioelectronic devices that modulate the inflammatory reflex have reported efficacy of vagus nerve stimulation in the treatment of inflammatory diseases. However, the optimal neurostimulation parameters to achieve significant cytokine changes are still unknown.In healthy mice without inflammation, specific combinations of pulse width, pulse amplitude, and frequency produce significant increases of the pro-inflammatory cytokine TNF but other parameters selectively lower serum TNF levels. Serum levels of the anti-inflammatory cytokine IL-10 were also significantly increased by selective parameters but remained unchanged with others.These findings provide guidance for design of future studies on the neural regulation of inflammation based on the selection of optimal parameters to relieve conditions and improve organ function.Bioelectronic medicine is based on neuromodulation of the nervous system restoring organ functions and health with less adverse effects than drugs, thus minimizing adherence issues (Olofsson and Tracey i) invasive with surgical implantation of an electrode around the left VN linked to a neurostimulator positioned under the collarbone or ii) non-invasive through transcutaneous cervical (on the path of the VN) or auricular stimulation, based on the innervation of the cymba conchae by the auricular branch of the VN (Peuker and Filler VN stimulation (VNS) is approved for the treatment of drug-resistant epilepsy and well tolerated vagal A-fibers are the largest and myelinated fibers and carry afferent visceral information and motor input, ii) vagal B-fibers are small and myelinated fibers carrying parasympathetic input, and iii) vagal C-fibers are small and unmyelinated and carry afferent visceral information. Antiepileptic property of VNS was supposed to be related to vagal C-fibers, but their destruction did not alter VNS-induced seizure suppression in rats (Krahl et al. Importantly, these results argue that serum cytokines may be controlled by specific fiber sets and firing patterns. The specific VN fibers mediating the inflammatory reflex are not known. The VN contains A-, B-, and C-fibers, defined in accordance to their conduction velocity, which, in myelinated fibers, is proportional to their size (Erlanger and Gasser Patients under VNS for epilepsy may experience improved seizure reduction by increasing the frequency and/or duty cycle of stimulation while VNS for heart failure is limited by the inability to activate the nerve fibers mediating therapeutic benefit without co-activation of side effect-inducing fibers (Musselman et al. The results of Tsaava et al. indicate"} {"text": "As the US population continues to age, it is important to gain a better understanding of factors that differ between independently living older adults and those that require assisted living. Accidental falls contribute to decreased quality of life for many older adults, and considerable research has been conducted examining measures of fall-risk and potential interventions. In this pilot study, we investigated fall-risk via assessment of spatio-temporal variables associated with gait in independent and assisted-living older adults aged 65+. Two gender-matched groups of participants were tested on seven gait variables utilizing Opto-Gait technology. Each group included sixteen participants. Independent living participants were recruited through word of mouth and flyers at local senior centers. Assisted living participants all resided in one local health care facility and were recruited via word of mouth and flyers posted in the facility. A one way ANOVA with an alpha level of .05 revealed significant differences between groups in contact time, foot flat, propulsive phase, and average speed. The independent living group performed better on each variable. These findings indicate that older adults living in assisted living facilities may be at much greater risk of accidental fall than their independent living counterparts. While this study identified several key factors related to instability among old adults, additional investigation is warranted to further examine the relationships among gait, fall-risk, and differentiators between independently living and assisted living older adults in these variables."} {"text": "This systematic review examines current randomized clinical trials of therapeutic agents to treat coronavirus disease 2019 (COVID-19). In this systematic review, we characterize the landscape of current COVID-19 trials to better quantify these potential issues.High-quality evidence generated by appropriately powered and controlled trials is needed to advance care for patients with coronavirus disease 2019 (COVID-19) and those who are susceptible to it.PRISMA) reporting guideline.3Institutional review board approval of this study was waived because it exclusively used publicly available data without any protected health information. Screening and trial selection adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses . Data analysis was performed in June 2020.We performed a data query of the ClinicalTrials.gov registry for interventional trials in any clinical phase regarding COVID-19 on June 8, 2020. Advanced search parameters included Our search yielded 674 trials after removing suspended and halted trials . Most we4We found a high rate of trial multiplicity, particularly with chloroquines, which are being tested in 143 studies. Although these overlapping trials may afford opportunities for replication and validation, the high degree of multiplicity also enhances the likelihood of finding a positive result through chance alone, potentially resulting in widespread use of an ineffective and possibly hazardous intervention.5 Because the projected participant accrual for US-only COVID-19 treatment trials is approximately 45\u2009942 participants , it seems unlikely that this target will be achieved given the intrinsic challenges of participant accrual during an active pandemic.The fragmentation of efforts could also lead to unnecessary competition for participants, which potentially compromises trial accrual and statistical power for all trials. This worrisome scenario has already occurred in China.Notably, our study is limited through the use of a single US-based clinical trials registry, potentially representing only a fraction of the worldwide COVID-19\u2013related trials portfolio. Furthermore, the ever-changing landscape of COVID-19 clinical research amid this pandemic may complicate future interpretation of this report.6 Together, these factors endanger the capacity to rapidly produce meaningful evidence that is vital during this critical time. Avoiding these pitfalls requires coordination of efforts. This could be achieved, in part, through makeshift cooperative groups to improve participant accrual and decrease duplicative efforts. Institutional review boards and regulators (including the US Food and Drug Administration) must also work together to responsibly ease roadblocks to coordinate pooled analyses across trials. These efforts should include synchronization and standardization of end points, focusing on the most meaningful and objective outcomes . It is hoped that these measures will expedite generation of high-quality prospective data to guide effective treatments while maximizing resource allocation.Although current trials have been initiated with the best intentions, the medical community must be mindful of the potential issues of incomplete participant accrual and publication bias that are introduced by enabling dozens of similar trials simultaneously."} {"text": "This is commonly accomplished by the timed addition of soluble signaling factors, in conjunction with cell-handling steps such as the formation of 3D cell aggregates. Interestingly, when stem cells at the pancreatic progenitor stage are transplanted, they form functional insulin-producing cells, suggesting that in vivo microenvironmental cues promote beta cell specification. Among these cues, biophysical stimuli have only recently emerged in the context of optimizing pancreatic differentiation protocols. This review focuses on studies of cell\u2013microenvironment interactions and their impact on differentiating pancreatic cells when considering cell signaling, cell\u2013cell and cell\u2013ECM interactions. We highlight the development of in vitro cell culture models that allow systematic studies of pancreatic cell mechanobiology in response to extracellular matrix proteins, biomechanical effects, soluble factor modulation of biomechanics, substrate stiffness, fluid flow and topography. Finally, we explore how these new mechanical insights could lead to novel pancreatic differentiation protocols that improve efficiency, maturity, and throughput.Insulin-producing beta cells sourced from pluripotent stem cells hold great potential as a virtually unlimited cell source to treat diabetes. Directed pancreatic differentiation protocols aim to mimic various stimuli present during embryonic development through sequential changes of Cell therapies involve the transplantation of human tissues or cells to treat illnesses that progressively damage or degrade functional tissues. These treatments are typically limited by access to a reliable and cost-effective cell source. For a successful transplant, allogeneic matching requires identification, procurement and transport of donor material; and variations in quality of the donated tissue may affect therapeutic potential. Therefore, the large-scale production of biological material for cell therapies is a rapidly growing area of interest. The primary goal of such research is to produce adequate quantities of functional therapeutic cells in a cost-effective manner.Treatment of type 1 diabetes by islet transplantation is one example of a currently approved cell therapy. Here, donor islets are used to replace the insulin-secreting functionality lost from the autoimmune destruction of pancreatic beta cells. The Clinical Islet Transplantation Consortium trial (CIT-07) reported that 87.5% of patients were free from severe hypoglycemic events and achieved normal or near normal glycemic control at the 1 year end point . As with+ cells (in vivo (in vitro (The production of insulin-secreting beta-like cells from pluripotent stem cells (PSCs) is a potential solution to the donor supply issues of islet transplantation. The first report of stem-cell derived insulin-producing cells via spontaneous differentiation was almost two decades ago and reported only 1\u20132% insulin+ cells . However+ cells . Therefo+ cells . More re 20 days . One of 20 days and subs 20 days . Since teptide+) . Howevereptide+) . Maturat interactions , which cin vivo. Studies of developmental mechanobiology are challenging, and these parameters are often not considered as it is unclear what mechanics are present during human embryogenesis. Furthermore, the complexity of the in vivo microenvironment makes it difficult to control these biomechanical signals and to delineate their effects on differentiation from other correlated stimuli. Therefore, the field relies mainly on studies of biochemical pathways with in vivo mouse models or in vitro human models for information.Embryonic development is guided via highly dynamic signals from the surrounding cell microenvironment with remarkable precision and robustness. As cells differentiate, they relay different signals to neighboring cells by secreting soluble factors and matrix proteins. The soluble signaling cues associated with pancreatic differentiation have been well-studied using animal models and include the Wnt, Activin/Nodal, fibroblast growth factor (FGF), bone morphogenetic protein (BMP), retinoic acid, and sonic hedgehog (Shh), and Notch signaling pathways . HoweverCells respond to mechanical stimuli through mechanotransduction mechanisms, in which biomechanical stimuli are converted into biochemical signals . ReciproResident cells communicate with their neighbors during development by secreting soluble signaling molecules which can bias differentiation . The devin vivo cellular microenvironment is much more intricate than can be modeled by current in vitro systems. Although directed differentiation protocols that focus solely on the timed addition of soluble signaling factors can generate insulin-producing cells perhaps due to improved paracrine signaling and cell\u2013cell contacts . Paracricultures . In theiskeleton .In vitro, larger non-vascularized islets may develop central necrosis due to high metabolic demand and low oxygenation , thus retaining ECM proteins composition. Utilizing decellularized pancreas matrix scaffolds in bioartificial pancreas designs could also be a fruitful strategy to improve islet functionality by retaining pancreas stiffness and matrix architecture . HydrogeIn addition to the combinatorial effects of individual ECM components, the composition of the ECM is dynamically changing during development. While one composition may promote early pancreatic differentiation, the same composition may hinder downstream differentiation stages. During hESC differentiation, ECM and MMPs are secreted which remodels the exogenous ECM on the culture substrate . PSCs cuin vivo, a recent successful strategy has been to target specific mechanotransduction-associated pathways during directed differentiation to promote pancreatic differentiation and thus improve the capacity to produce insulin-secreting cells. Such factors include H1152 (a ROCK II inhibitor) , vertepohibitor) , and lathibitor) . Nuclearhibitor) . Timed ihibitor) . Depolymhibitor) . AltogetCells interact with ECM proteins by binding with integrin receptors spanning across the cell membrane. These receptors can then activate downstream integrin-related signaling pathways that alter cell function and bias cell specification. In pancreas development, integrin-ECM signaling regulates collective cell migration and function . When plThe surrounding ECM matrix also propagates stress which al+ endocrine progenitors, fibronectin promotes high cell spread area while laminin-coated surfaces were associated with lower spreading or stiffness (MMP-mediated degradation or UV-based) could better accommodate the constantly changing requirements for beta cell differentiation. Finally, as our knowledge progresses, increasingly complex co-culture systems involving defined compositions of PSC-derived endothelial, islet endocrine cells, and other cells present during development, may be the route to a functional cell source for islet transplantation.To address these questions, some technologies that could be used to specifically identify the effect of these factors are highlighted in Overall, better understanding the mechanobiology of pancreas development could lead to new strategies to more efficiently produce functional glucose-responsive, insulin-secreting cells for cell therapies. Interdisciplinary approaches combining advances in materials science and developmental biology could accelerate the development and scale up of culture systems tailored for diabetes cell therapy.RT conducted the literature search and drafted the manuscript in consultation with CM and CH. All authors contributed to writing the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Most studies of middle-aged adults find blacks have higher levels of psychological distress compared to whites but have lower risk of common psychiatric disorders. For instance, there is evidence of lower rates of depressive and anxiety disorders among blacks relative to whites despite large disparities in stress, discrimination and physical health in midlife\u2014commonly referred to as the black-white mental health paradox. We examine evidence of the black-white paradox in anxiety and depressive symptoms among older adults. Data come from 6,019 adults ages 52+ from the 2006 Health and Retirement Study. Unadjusted models show older blacks report more anxiety and depressive symptoms than whites. After adjusting for socioeconomic factors, everyday discrimination, chronic conditions, and chronic stress, there are no black-white differences in anxiety and depressive symptoms. Findings suggest the black-white mental health paradox only extends into older adulthood for blacks living under similar stress and health landscapes as whites."} {"text": "Initially described as pneumonia of unknown aetiology in December 2019 in populations of Wuhan (China), the coronavirus disease (Covid-19) rapidly disseminated around the world . They alActually, nearly three billions people are confined at homes or in quarantine around the world. Brooks et al. in a recently published review including studies comparing psychological outcomes between people quarantined and not quarantined, found that quarantine had negative psychological effects such as post-traumatic stress symptoms, confusion and anger . All theShanghai government organized psychological care in four levels. At the first level, an onsite psychological support is provide to patients with severe symptoms of novel coronavirus pneumonia (NCP) by front-line medical staff, Centre for Disease Control researchers or administrative staff . The secThe current Covid-19 pandemic has tremendous consequences on population health around the world, with various degrees of mental health repercussions. Actual strategies are mainly targeting Covid-19 patients and healthy general populations, and are chiefly based on clear and secured communication as well as continuous onsite and online psychological support by appropriates professionals. However, these strategies should be disseminated to all countries, especially sub-Saharan African ones, and approved by concerned governments. Also, adequate psychological care policies have to be developed for health care workers fighting against this pandemic. All these measures would help to maintain optimal care of Covid-19 patients and prevent deleterious mental health outcomes including suicides.All authors declare no competing interests."} {"text": "Dear Editor, Recently, Wu and colleagues published a study about hepatobiliary organoids generated from human induced pluripotent stem cells . For thSeveral studies have used human stem cells including hiPSC and reported that differentiation via definitive endoderm resulted in hepatocyte-like features associated genes, potentially limiting hepatocyte maturation, which could be investigated by monitoring TWIST and SNAIL transcription factor activity. It should be considered that hepatocytes in vivo are arranged in sheets along sinusoids is that19 is thaal., 2019). The usal., 2014; Hoehme al., 2014; Reif etin vitro systems for toxicity tests . Also, al., 2018), althouThe author declares no conflict of interest."} {"text": "Creutzfeldt-Jakob disease (CJD) is a rare prion disease characterized by rapidly progressive dementia.A 76-year-old woman exhibited pronounced signs and symptoms of dressing apraxia for about seven weeks before the disease progressed and probable CJD was diagnosed supported by imaging and CSF findings.Dressing apraxia as the initial manifestation of CJD has been sparsely reported. This remarkably focal syndrome should be considered with view on movement and neuropsychological disorders in early CJD. Creutzfeldt-Jakob disease (CJD) is a rare prion disease mainly characterized by rapidly progressive dementia. Neuropsychological disorders however frequently occur in the initial phase of the disease with amnesia, impaired attention and frontal lobe syndrome as the most frequent . RecentlA 76-year-old woman developed difficulties in dressing. She had progressive problems dressing herself. In particular, she had difficulty handling buttons and arranging her clothing articles on her body. Dressing became more and more prolonged, and she began to manipulate her clothes incoherently until finally needing support from her husband. Her medical history included stable plasmocytoma, atrial fibrillation and residual effects from a minor stroke, and she was orally anticoagulated with phenprocoumon. Her neurological examination on admission revealed a slight right-sided motor impairment with finger tapping and slight dysarthria, which resulted from the previous minor stroke. Neuropsychologically pronounced signs and symptoms of dressing apraxia were found whereby performing simple gestures and pantomiming object use were preserved. Otherwise, there were no signs of constructional and limb ataxia, optic ataxia and visual disturbances. The MoCA test showed 28 of 30 points with slight impairment in the visuospatial items. Her family history was unremarkable. She had not had any previous neurosurgical procedures or corneal transplants [Her first cranial magnetic resonance images (MRI) showed marked cortical restriction of diffusion bilaterally (positive \u201cribbon sign\u201d), most prominent in the parietal regions Figure . A cerebWith this case report, we wish to complement the observations on neuropsychological disorders in CJD for three reasons. First, dressing apraxia as an initial and for a certain time exclusive symptom of CJD has sparsely been reported . Most re465810"} {"text": "This study enhances the existing literature on the role of trust and online perceived risk in shaping consumer purchase decision-making in social commerce. The aim of this article is to investigate consumers\u2019 purchase decision-making process, the determinant components of social commerce purchase intentions and attitudes, the effect of perceived risk on intention to go shopping in online settings, and consumer trust and buying behavior on online retailing platforms. The insights obtained from our research extend current knowledge as regards determinants of consumer attitudes and intentions toward online purchases, consumers\u2019 perceived shopping risk and repurchase behavior when buying products online, and perceived consumer online trust and purchase decisions. Limited research has considered consumers\u2019 decision-making processes on social commerce platforms by investigating how their perceptual attitudes, behavioral intentions, and immediate gratifications affect the purchase of products and services online. Our study addresses this gap and extends prior research by focusing on the relationship between online consumer purchase intention, social commerce adoption behavior, and consumers\u2019 trust together with risk factors affecting online buying decisions, in light of the characteristics of source credibility. Our findings point toward important avenues of research on psychological determinants of consumer engagement in social media, decision mechanisms lying behind evaluation of prices, the types of perceived risk incurred, and online repurchasing behavior and intention on social commerce platforms. Subsequent directions should clarify whether adoption of mobile payment services may shape online consumers\u2019 impulsive buying behavior and decision-making, especially under the influence of online product reviews. Our study cumulates evidence that consumers\u2019 decision-making process is a dynamic performance , but thaUsing exclusively empirical sources published recently (2017\u20132019) in Web of Science- and Scopus-indexed journals, our paper fills the gap in the literature by elucidating consumers\u2019 evaluation, commitment, and choice throughout online decision-making, insisting on their cognitive processing behaviors and on how expectations shape their pre-purchase and post-purchase satisfaction.On Wu J. et al. (2017)\u2019s reading, trust is the essential component of consumer purchase intention when buying things on peer-to-peer temporary rental platforms where both hosts and renters do not know each other. The empirical evidence we reviewed supports the belief that social platform users\u2019 purchase intentions can be constituted taking into account the relationship between online trust and perceived risk. Limited research has considered consumers\u2019 decision-making processes on social commerce platforms by investigating how their perceptual attitudes, behavioral intentions, and immediate gratifications affect the purchase of products and services online.Our study addresses this gap and extends prior research by focusing on the relationship between online consumer purchase intention, social commerce adoption behavior, and consumers\u2019 trust together with risk factors affecting online buying decisions, in light of the characteristics of source credibility. As limitations in the present article, our findings point toward important avenues of research on psychological determinants of consumer engagement in social media, decision mechanisms lying behind evaluation of prices, the types of perceived risk incurred, and online repurchasing behavior and intention on social commerce platforms. Subsequent directions should clarify whether adoption of mobile payment services may shape online consumers\u2019 impulsive buying behavior and decision-making, especially under the influence of online product reviews.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Medicare is the primary insurance provider for approximately 51 million older adults, including those who seek mental health care. Medicare provider eligibility was last updated in 1989, and approximately one-third of the graduate-level mental health workforce is excluded from Medicare, despite these professionals participating in Medicaid, TRICARE, the Veterans Administration, and private insurance plans. This Medicare mental health coverage gap (MMHCG) raises concerns about older adults\u2019 access to mental health care, resulting in a policy misalignment between Medicare\u2019s provider regulations and a growing number of older adults seeking mental health care. However, little is known about the precise impact of the MMHCG. To better understand how the MMHCG impacts older adults, we interviewed 17 Medicare-insured individuals about their experiences accessing mental health services. Using a phenomenological framework to analyze our data, we found that Medicare recipients described several consequences, such as: 1) a detrimental impact on their mental health and well-being; 2) concerns about having to start over with new providers due to commencing mental health treatment only to have services interrupted once the provider is no longer Medicare-reimbursable; and 3) relying on pro bono services from Medicare-excluded providers with uncertainty about the long-term sustainability of these arrangements. The presenters will describe how these findings fit within the current Medicare mental health service context, including the direct impact on older adults\u2019 mental health. Discussion will also focus on policy implications of the findings and possible solutions for addressing the MMHCG."} {"text": "Pathogens and pests are one of the major threats to agricultural productivity worldwide. For decades, targeted resistance breeding was used to create crop cultivars that resist pathogens and environmental stress while retaining yields. The often decade-long process of crossing, selection, and field trials to create a new cultivar is challenged by the rapid rise of pathogens overcoming resistance. Similarly, antimicrobial compounds can rapidly lose efficacy due to resistance evolution. Here, we review three major areas where computational, imaging and experimental approaches are revolutionizing the management of pathogen damage on crops. Recognizing and scoring plant diseases have dramatically improved through high-throughput imaging techniques applicable both under well-controlled greenhouse conditions and directly in the field. However, computer vision of complex disease phenotypes will require significant improvements. In parallel, experimental setups similar to high-throughput drug discovery screens make it possible to screen thousands of pathogen strains for variation in resistance and other relevant phenotypic traits. Confocal microscopy and fluorescence can capture rich phenotypic information across pathogen genotypes. Through genome-wide association mapping approaches, phenotypic data helps to unravel the genetic architecture of stress- and virulence-related traits accelerating resistance breeding. Finally, joint, large-scale screenings of trait variation in crops and pathogens can yield fundamental insights into how pathogens face trade-offs in the adaptation to resistant crop varieties. We discuss how future implementations of such innovative approaches in breeding and pathogen screening can lead to more durable disease control. R genes) e.g. fungicides, insecticides) Feeding the world population requires a stable production of safe food, which is threatened by factors such as climate change, land degradation and diseases. Pathogens and pests cause significant reductions in agricultural productivity worldwide, and control strategies remain ineffective for many pathogens Sustainable agricultural management practices critically rely on an understanding of the biology and evolutionary potential of the major crop pathogens. Emerging or re-emerging pathogens can only be contained by investigating their origins and migration routes, as well as their potential to counter-adapt to deployed control measures. Advancements in genomics, transcriptomics and proteomics have been instrumental to elucidate these questions and unravelled a broad range of molecular mechanisms governing host-pathogen interactions leading to more effective control strategies 1.1e.g. appressoria) i.e. temperature, pH, humidity) to thrive, changes in the environment can alter the pathogen's ability to cause damage 2 and ozone can affect plant disease severity e.g. wash-off of fungicides following strong rainfall). Hence, the challenge to contain pathogen damage in agriculture is to predict the emergence of virulent strains and the rise of fungicide resistance.Major crop diseases are caused by pathogens including fungi, bacteria and viruses . In addii.e. biotrophs) can feed on plant nutrients for a long period without causing apparent infection symptoms Given the possibly severe consequences, the early detection of resistance breakdowns in crops or loss of sensitivity to pesticides is critical. Detection early in the growing season and identifying previously uncharacterized pathogens remain major challenges. Classic plant disease diagnostics usually relies on visual symptom scoring by trained individuals categorizing disease severity on linear scales e.g. leaves, Disease symptoms may include any range of changes in the color, shape or functioning of the plant as it responds to a pathogen and can be visualized at specific wavelengths A. Depend1.2e.g. GF-1 from China or SPOT from Europe, can provide time-resolved phenotyping of individual fields at the meter scale Technologies suitable for screening plant diseases even in early infection stages have become widely deployed 1.3Proximal phenotyping is mostly deployed in greenhouse experiments or in well-controlled field experiments. Sensors covering a broad range of spectra can be mounted on stationary platforms or, for outdoor use, on suspension cables, robots and tractors i.e. qPCR) are often required to clearly establish what is likely to cause a disease. Interesting developments to overcome these limitations are e.g. the differential reflectance spectra (400\u20131050\u00a0nm) of sugar beet leaves, which helps distinguish three different fungal pathogens including Cercospora beticola, Erysiphe betae, and Uromyces betaeOidium neolycopersiciCorynespora cassicola and bacterial spot caused by Xanthomonas perforans on tomato in the asymptomatic phase. The multi-spectral imaging approach was successful both under laboratory and field conditions. Such robust phenotyping methods could make it possible to detect infection foci in the field. Emerging infections could then be isolated and treated individually by the deployment of specific fungicides.Current plant phenotyping technologies and image processing algorithms struggle to reliably differentiate disease symptoms originating from multiple or unknown pathogens Plant phenotyping technologies have generated data to populate public image databases with a fluorescent readout sensitive to changes in gene expression or subcellular localization. The main goal of the technology is to accelerate drug discovery by screening large antimicrobial compound libraries at a rate of thousands of compounds per week. Efforts are as well made in the development of high-throughput approaches to generate mutated versions of drug targets in vitro screening of diverse pathogen population scans is very informative about possible standing resistance, which can prevent rapid efficacy failures under field conditions High-throughput phenotyping platforms for microbial organisms have dramatically advanced in automating cell culturing, liquid handling, spotting on culture medium as dense arrays and integration of fluorescence measurements and microscopy The wealth of information on phenotypic trait variation in pathogen species combined with low-cost sequencing can be exploited for GWAS 1.5etc.) influence the outcome of infections. The complexity arises in part from complex pathogen infection cycles starting from initial host contact to transmission to new hosts The application of imaging combined with computational techniques enabled enormous progress in breeding resistant crops and detecting the emergence of new pathogen threats. To reduce complexity, most studies until now focused either on variation on the plant or the pathogen side. However, the nature of host-pathogen interactions can vary across space and time omics datasets to build biological networks (e.g. gene co-expression or protein\u2013protein interaction networks) has become a powerful approach to unravel genetic factors controlling biological interactions Arabidopsis thaliana - Xanthomonas arboricola interaction, Wang et al. Z. tritici, a large set of loci associated with pathogen virulence and reproduction on different hosts were identified Botrytis cinerea and 90 plant genotypes of eight species revealed a highly polygenic architecture of pathogen virulence and host specialization e.g. blackleg in canola) or at different growth stages. Bigger sample sizes in both host and pathogen will also improve heritability estimates (e.g. as shown in human studies Integration of different 1.6Plantago lanceolata-Podosphaera plantaginis interactions C. beticola have shown that resistant isolates have significantly lower virulence and spore production than sensitive isolates Ralstonia solanacearum mutants lacking the gene for synthesizing an exopolysaccharide virulence factor show increased growth rates compared to the wild-type strain Z. tritici. Performance of a global strain collection on twelve wheat varieties and in various abiotic conditions revealed a broad pleiotropic control of pathogen performance on and off the host How successful pathogens cope in diverse environments depends on life-history trade-offs, which arise from resource allocation dilemmas and antagonistic gene actions. A trade-off indicates that an increase in one trait is associated with a decrease in another trait. Such trade-offs are typically dependent on the host genetic background and abiotic conditions. Some pathogen strains have evolved specialization on certain hosts or climatic conditions to maximize their performance. Classic examples include the wild pathosystem of 2Technological progress in assessing susceptibility of large collections of crop plants to pathogen damage is crucial for modern resistance breeding efforts. A variety of image capture techniques allow to monitor plant damage at the cellular, leaf, whole plant or field level. Most applications focus on the visible spectrum but hyperspectral imaging platforms have recently gained the ability to detect pathogen infestation even before the appearance of symptoms. A major area of going research is to improve image analyses algorithms to detect and classify pathogen damage. Variation within individual pathogen species can be highly informative about the rise of new virulence or pesticide resistance. Robotics applied to automate the culturing of thousands of pathogen strains enables screening for metabolic variation, drug susceptibility and production of secondary metabolites improving our understanding how pathogens cope with the agricultural environment. Both high-throughput plant and pathogen phenotyping efforts can be combined with genome sequencing and GWAS applications. Unraveling the genetic basis of host resistance helps to speed up breeding efforts through marker-assisted selection. Analysis of pathogen populations can be informative about possible trade-offs in the emergence of virulence or pesticide resistance.Future directions of research should focus on a set of complementary research areas.- Create efficient pipelines merging imaging and molecular assays for pathogen detection. Such integrated systems could help farmers deploy appropriate counter-measures in the field prior to widespread damage and reduce overall pesticide application.- The susceptibility of crop cultivars to major pathogens should be re-assessed continuously to detect changes in the virulence profile of the prevalent pathogens. Rapid evolution in pathogens can lead to catastrophic resistance breakdowns and must be detected early enough. High-throughput imaging systems capturing disease symptoms should be combined with machine learning to effectively recognize changes in virulence profiles. The lack of curated and open access disease image databases is currently slowing progress.- Regional monitoring efforts of resistance breakdowns or the loss of pesticide efficacy can be achieved by high-throughput genomic screening of infected leaf material. Efficient genotyping assays focusing on major genes are likely to scale well to broad applications. Bioinformatic procedures for such genomic data analyses are largely in place. A successful implementation of such genomic monitoring will also help to detect the arrival of new pathogens early enough to deploy resistant cultivars or implement changes in pesticide application regimes.- The systematic identification of trade-offs faced by pathogens adapting to pesticides and resistant crop cultivars could lead to more durable control measures.Nikhil Kumar Singh: Conceptualization, Writing - original draft, Visualization. Anik Dutta: Writing - original draft, Visualization. Guido Puccetti: Writing - original draft, Visualization. Daniel Croll: Conceptualization, Writing - original draft, Supervision, Funding acquisition.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} {"text": "Intracortical bone pins are introduced as gold standard for analysing skeletal motion because of eliminating soft tissue artefact. However, excluding this methodological error might be in cost of intervening movement pattern by local anaesthesia and pain of external tool within body. The purpose of this study was to examine whether intracortical bone pins alter shoulder joint kinematics or coordination. Three subjects were analysed during arm elevation/depression in frontal and sagittal planes. Retroreflective skin markers captured the motion in two sessions, before and after inserting bone pins (SKIN and PIN sessions), respectively. Thoracohumeral and scapulothoracic kinematics and scapulohumeral rhythm (SHR) were compared between two sessions. Thoracohumeral exhibited lower elevation and internal rotation in PIN session especially close to maximum arm elevation. The highest differences were observed for scapulothoracic kinematics, with higher retraction during abduction as well as higher posterior tilt, lateral rotation and retraction during flexion in PIN session. In addition, no systematic changes in SHR between subjects was found. Statistically significant lower SHR in PIN session was observed over 87-100% of thoracohumeral elevation/depression cycle in frontal plane and over 25-61% in sagittal plane. Further studies should treat carefully toward the clinical validity of shoulder joint kinematics after inserting bone pins. Retroreflective markers mounted on either skin or intracortical bone pins are used to highly accurately capture shoulder motion and evaluate the shoulder dynamics represents any changes in scapulothoracic/scapulohumeral movement and their coordination at 300 Hz.Data collection was performed in two sessions in a single day, for each participant. For session 1 (SKIN), 22 skin markers were attached to the left clavicle (5), scapula (4), humerus (7) and thorax (6) based on the model introduced by Jackson et al. . Their lAnatomical and relaxed static positions were primarily recorded for each person per session. Thereafter, each participant was asked to perform movements in SKIN session and repeat these movements in PIN session. The movements included functional motion tasks and main tasks. Functional motion tasks were arm flexion, rotation, and circumduction performed in each session to find functional joint centres and axes. Main tasks involved 10 trials of arm elevation/depression in frontal plane (abduction/adduction) and sagittal plane (flexion/extension). In S4, the location of the scapula\u2019s pin interfered with the skin markers which had to be repositioned more laterally. The post-surgery skin markers on the scapula were quasi-collinear. This resulted in the impossibility of accurate kinematics calculations. S4 data were removed.t-tests using statistical parametric mapping (SPM) were implemented, during elevation and depression separately, to determine whether any significant differences exist between SKIN and PIN sessions. The open-source SPM1d toolbox (http://www.spm1d.org) in MATLAB was used for our SPM analysis.The systems of coordinates and sequences were defined based on International Society of Biomechanics (ISB) recommendations , while thoracohumeral kinematics just altered slightly. In fact, the subjects reduced their axial rotation and the plane of elevation after inserting pins. These alterations are consistent with findings of previous studies about shoulder abnormalities. Mell et al. showed aThe changes in joint kinematics before and after pin insertion , Table 1n = 3) in our cross-comparison study, we compared the kinematics of each subject separately between SKIN and PIN sessions. In addition, the obvious differences in SHR between subjects might be due to individual movement strategies rather than different compensatory mechanisms. It is recommended that validation studies which mount both skin markers and bone-pin markers on the body estimate how they will interact with each other before data collection. Otherwise, repositioning skin markers because of interference with bone pins would deteriorate the kinematic results. In our study, one of our four available subjects was excluded due to this issue. A well-organized protocol especially for such invasive studies with small sample sizes will help in minimizing the between-subject differences derived from methodological errors. While only kinematics were assessed in the present study, electromyography and/or muscle force estimation may provide additional information about the effect of pin insertion on the upper-limb biomechanics. However, the estimation of muscle forces at the shoulder remains challenging due to co-contraction and the complex trajectories of (multi-articular) muscles (Behm et al. In addition to joint rotations, SHR was selected to look at the effect of inserting bone pins, since it can represent the movement quality index for shoulder complex for several reasons. The most important reason is that kinematic redundancy enables the central nervous system to generate a specific shoulder motion with different contribution of bony structures (Yang et al. Our results showed that inserting shoulder bone pins dominantly deteriorates the pattern and RoM of scapulothoracic joint rather than thoracohumeral joint. It was also observed that SHRmight be partially reproduced after pin insertion. Eliminating methodological errors from soft tissue artefacts using intracortical pins would not necessarily add more clinical value to the kinematic results, while the approach remains relevant to model/algorithm validation."} {"text": "Public mental health response to coronavirus disease is essential. After reviewing systemic and local efforts in China, we found efficient coordination and human resources. We recommend better symptom assessment, monitoring of organizations, and basic needs protection. This recommendation can inform how other countries can overcome mental health challenges during this pandemic. The coronavirus disease (COVID-19) outbreak and quarantines have caused major distress in China and psycCoordination and resource allocation were compiled from local efforts at the Wuhan epicenter . On JanuThe MoE and CPS recruited professionals and volunteers across China, which suggests adequate resource allocation (The Inter-Agency Standing Committee calls for assessment of mental well-being and program evaluation of psychsocial support effectiveness (CPS published a list of approved hotline organizations based on survey evaluation of organizations (Although COVID-19 does not cause intentional harm, there are human rights issues on access to basic needs (Our review suggests that China has overcome resource shortages with coordination and resource allocation in its mental health response. The government, universities, and academic societies provide coordination, and independent organizations provide local support. We recommend integration of assessment in direct support, monitoring of organizations, and advocating for affected persons. These recommendations can inform how other countries can overcome shortage of mental health resources when facing this pandemic.Additional information on review of mental health response to COVID-19, China."} {"text": "Zostera marina). Sampling seawater along transects extending alongshore outward from eelgrass beds, we demonstrate that eDNA provides meter-scale resolution of communities in the field. We evaluate eDNA abundance indices for 13 major phylogenetic groups of marine and estuarine taxa along these transects, finding highly local changes linked with proximity to Z. marina for a diverse group of dinoflagellates, and for no other group of taxa. Eelgrass habitat is consistently associated with dramatic reductions in dinoflagellate abundance both within the contiguous beds and for at least 15 m outside, relative to nearby sites without eelgrass. These results are consistent with the hypothesis that eelgrass-associated communities have allelopathic effects on dinoflagellates, and that these effects can extend in a halo beyond the bounds of the contiguous beds. Because many dinoflagellates are capable of forming harmful algal blooms (HABs) toxic to humans and other animal species, the apparent salutary effect of eelgrass habitat on neighboring waters has important implications for public health as well as shellfish aquaculture and harvesting.Seagrass beds provide a variety of ecosystem services, both within and outside the bounds of the habitat itself. Here we use environmental DNA (eDNA) amplicons to analyze a broad cross-section of taxa from ecological communities in and immediately surrounding eelgrass ( Seagrass species are ecosystem engineers throughout the world\u2019s coastal zones , generatIn addition to these broad ecological and chemical functions, such habitats demonstrate important antimicrobial properties. Seagrass meadows have been shown to reduce exposure to bacterial pathogens affecting humans and marine life, relative to areas lacking such meadows . AdditioZostera marina) is the dominant seagrass along temperate coasts of the Northern Hemisphere or ostrich (genus Struthio) tissue. We selected these organisms because they are absent from the sampling sites and common molecular biology reagents, but amplify well with the universal primer set used in this study. Additionally, they can be used to identify possible cross-contamination: reads from other taxa that appear in these positive control samples allow us to estimate and account for the proportion of sequences that are present in the incorrect PCR reaction (see \u201cBioinformatics\u201d below). We also amplified negative controls (molecular grade water) in triplicate alongside environmental samples and positive controls, and verified by gel electrophoresis that these PCR reactions contained no appreciable amount of DNA.Finally, we generated amplicons with the same replication scheme for positive controls, comprised of extractions from either kangaroo . We then performed sequencing on an Illumina MiSeq platform in four different sets of samples: two MiSeq V.2 runs and two MiSeq V.3 runs. We processed each batch separately through the initial bioinformatics analysis (see below). We employed hierarchical clustering on transects containing six PCR replicates sequenced across two different runs and found that these samples were each other\u2019s nearest neighbors ; thus seWe followed updated versions of previously published procedures for bioinformatics, quality control, and decontamination . This pr11), false-positive rate (P10) and commonness (psi) in a Bayesian binomial model. We then used these parameters to estimate the overall likelihood of occupancy (true presence) for each ASV; those with low likelihoods (<20%) were deemed unlikely to be truly present in the dataset, and therefore culled. 25 million reads from 3143 ASVs survived this step.To address possible cross-sample contamination , we subtLastly, we removed samples whose PCR replicates were highly dissimilar: we calculated the Bray\u2013Curtis dissimilarity amongst PCR replicates from the same bottle of water and discarded those with distance to the sample centroid outside a 95% confidence interval. Of 84 bottles of water collected, 3 technical replicates survived QC in 72 cases (86%), two replicates in 9 cases (11%), one replicate in 2 cases (2%), and zero replicates in a single case (1%) . The finPRJNA606519).All bioinformatic and analytical code is included in GitHub repositories , and proe-values of 10\u221230 (culling limit = 5), and reconciling conflicts among matches using the last common ancestor approach implemented in MEGAN 6.4 .Our analysis revealed strong habitat associations for dinoflagellates and not for other taxa (see \u201cResults\u201d). To examine patterns specifically within the phylum Dinoflagellata, we further refined our annotations for these ASVs. Specifically, we considered the geographic range of taxa involved (restricting possible annotations to those taxa known from the North Pacific) and assigned taxonomy conservatively to the level of family only in cases of >95% sequence identity between the subject and query sequence; ASVs we could not confidently assign to the level of family we excluded from further analyses. Multiple dinoflagellate sequences with identical amino-acid translations occurred within To confirm the spatial resolution of our eDNA communities, we used non-metric multidimensional scaling (nMDS) ordination of eDNA indices for all ASVs within each technical replicate . To deriTo examine the relative abundance of phyla in eelgrass habitat relative to bare substrate, we determined eDNA indices for the sum of sequences within each phylum at the two transect extremes (within-eelgrass versus bare), calculating a relative eDNA abundance measure by subtracting the mean eDNA abundance index over bare substrate for each site-month combination from the corresponding mean eDNA abundance index in the eelgrass habitat. Positive values of this measure thus denote higher abundance in eelgrass, while negative values of this index indicate higher abundance over bare substrate. To assess the statistical significance of these phylum-level differences between habitat types, we compared the distributions of mean eDNA abundance indices for individual phyla in samples taken from eelgrass relative to their counterparts taken over bare substrate, using a paired Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons.k-means function of the R stats package . Next, to determine whether dinoflagellate abundance measures at intermediate alongshore transect samples were more closely associated with eelgrass habitat or bare substrate, we additionally performed Gaussian mixture modeling with two groups . We thenWe assigned over 3,000 unique ASVs to 13 eukaryotic phyla comprising a diverse set of single- and multicellular taxa including Arthropoda (arthropods), Annelida (annelid worms), Bacillariophyta (diatoms), Chlorophyta , Chordata (chordates), Cnidaria (cnidarians), Dinoflagellata (dinoflagellates), Echinodermata (echinoderms), Heterokonta (stramenopiles), Mollusca (molluscs), Nemertea (ribbon worms), Ocrophyta and Rhodophyta . This represents a broad\u2014although by no means comprehensive\u2014survey of eukaryotic communities in and around our sampled eelgrass beds.Ordination via nMDS revealed consistent differentiation between eDNA communities across transects within a sampling site and date; technical replicates consistently clustered together. An example plot of samples gathered along the transect from eelgrass to bare substrate at Willapa Bay in July shows thR2 = 0.186, p = 0.001), month , and transect distance each explain a significant portion of the variance in the dataset. Thus, despite strong effects of location and time, these results confirm that we can consistently distinguish nearshore eDNA communities (as sampled by our primers) at spatial scales of meters for each site and month of sampling. Moreover, we see a highly significant effect of proximity to eelgrass on the complement of organisms present.PERMANOVA apportioned the variance in Bray\u2013Curtis distance among samples as follows: site . Other single-celled microalgae such as diatoms (Bacillariophyta) and green algae (Chlorophyta) have no significant relationship with eelgrass.To determine the habitat preference of major taxa in our dataset at a coarse spatial scale, we classified ASVs to the level of phylum and plotted an index of their relative sequence abundance in eelgrass versus bare positions . Positivk-means clustering) to define a set of high- and low-abundance transects for each dinoflagellate sequence across all sites and months .In this subset of high-abundance transects, the negative interaction of eelgrass and dinoflagellates is taxonomically universal. The taxa represented include two unique variants from the genus species . All arep < 0.02; p > 0.85).After demonstrating a preference of all dinoflagellate taxa towards the bare substrate extreme (when highly-abundant), we then characterized their patterns as a function of distance from the edge of the contiguous eelgrass beds, using data from entire transects . ExaminiIn a broad-spectrum eDNA survey of the organisms living in and near to eelgrass, we track the relative abundance of a diverse group of taxa from thirteen phyla. We demonstrate the ability of eDNA to distinguish communities represented in samples taken only meters apart, and to reveal a significant axis of variance based on proximity to habitat type, despite strong influences of geography and time across sampling events. One major and significant pattern emerges in our analysis: dinoflagellate taxa are more common over bare substrate than within eelgrass beds when highly-abundant, and this effect extends at least 15 m beyond the edge of the contiguous beds themselves. Because ours was an observational field study, rather than an experiment, we cannot rigorously distinguish among plausible mechanisms for the observed dinoflagellate distributions. Instead, we use the patterns in our own data as well as the relevant scientific literature to evaluate a number of potential hypotheses.One plausible mechanism is that of an ecological edge effect acting in nearshore zones at the interface between eelgrass and non-eelgrass habitat. \u201cEdge effects\u201d are changes in the distribution or abundance of a species at a boundary between habitats , such tA third possibility is that predatory taxa exist in greater abundance within eelgrass beds and thereby consume dinoflagellates in larger quantities within this habitat , and is mediated locally by a variety of strains of eelgrass-associated algicidal and growth-inhibiting bacteria, particularly from Erythrobacter, Teredinibacter, Gaetbulibacter and Arthrobacter genera causes paralytic shellfish poisoning via production of saxitoxin produce yessotoxins (YTXs), whose effects on human consumers of contaminated shellfish are complex and unclear (reviewed in Alexandrium) are intensifying with recent ocean warming in the North Pacific gigas, in particular, has recently been shown to lessen the effects of eelgrass wasting disease on Z. marina , transect direction , transect position , month, technical replicate, and sequencing run.Click here for additional data file.10.7717/peerj.8869/supp-2Supplemental Information 2Click here for additional data file."} {"text": "Cross-sectional findings showed that education differences in memory performance were moderated by frequent cognitive activity . The present study examined whether frequent cognitive activity could compensate for lower education when focusing on change in cognitive performance across nine years. The study also explored whether cognitive activity can slow down declines in retired adults as previous research suggested that retiring is associated with an increased risk of cognitive decline . Longitudinal data from the MIDUS study included N = 3,325 middle-aged and older adults. Outcome variables were two factors of cognitive performance: Episodic Memory (EM) and Executive Functioning (EF). Independent variables were years of education, work status (working vs. retired), and frequency of cognitive activity. The results suggest that cognitive activity moderated the effect of educational attainment on change in EM. Individuals with both higher education and cognitive activity showed the smallest declines in EM. Individuals with lower educational attainment but high cognitive activity had less decline in EM compared to their low education counterparts. Those who increased their cognitive activity over time showed less decline in EF. In terms of work status, working adults had less decline in EM and EF compared to retired adults and retired adults who did not maintain their cognitive activity declined more in EF. The results emphasize the importance of frequent engagement in cognitive activity across the lifespan, which can attenuate cognitive declines especially among those who have lower education or have retired."} {"text": "Tropical rainforest disturbance and conversion are critical drivers of biodiversity loss. A key knowledge gap is understanding the impacts of habitat modification on mechanisms of community assembly, which are predicted to respond differently between taxa and across spatial scales. We use a null model approach to detect trait assembly of species at local- and landscape-scales, and then subdivide communities with different habitat associations and foraging guilds to investigate whether the detection of assembly mechanisms varies between groups. We focus on two indicator taxa, dung beetles and birds, across a disturbance gradient of primary rainforest, selectively logged rainforest, and oil palm plantations in Borneo, Southeast Asia. Random community assembly was predominant for dung beetles across habitats, whereas trait convergence, indicative of environmental filtering, occurred across the disturbance gradient for birds. Assembly patterns at the two spatial scales were similar. Subdividing for habitat association and foraging guild revealed patterns hidden when focusing on the overall community. Dung beetle forest specialists and habitat generalists showed opposing assembly mechanisms in primary forest, community assembly of habitat generalists for both taxa differed with disturbance intensity, and insectivorous birds strongly influenced overall community assembly relative to other guilds. Our study reveals the sensitivity of community assembly mechanisms to anthropogenic disturbance via a shift in the relative contribution of stochastic and deterministic processes. This highlights the need for greater understanding of how habitat modification alters species interactions and the importance of incorporating species\u2019 traits within assessments.The online version contains supplementary material available at 10.1007/s00442-020-04829-z. Habitat modification via selective logging and forest conversion to agriculture is widespread across the tropics , and interactions with other species that are characteristic of anthropogenic disturbance . The majority of the concession (~\u200990%) has been selectively logged, primarily between the 1970s and 2008 across two rotations of logging logging concession in eastern Sabah, Malaysian Borneo across all four habitats]. Each site consisted of one line transect for bird sampling and two-line transects (a minimum of 500\u00a0m apart) for dung beetle trapping (see below for further methods). Sampling for birds and dung beetles occurred at the same sites across the forested habitats and at three of the oil palm sites, however the fourth oil palm site, for each taxa, was sampled in different locations due to logistical reasons (Online resource 1a). Sampling within oil palm was restricted to mature plantations (10\u201315\u00a0years old). The environmental conditions across sampling years remained similar . Primary forests are heterogeneous in structure with a dense canopy, extended vertical strata, and an open understorey with low densities of lianas when compared to logged forests . Sampling effort was equalised across habitat types for dung beetles and birds ; Online Resource 1c; following Edwards et al. Dung beetles (Coleoptera: Scarabaeidae: Scarabaeinae) were sampled using standardised baited pitfall traps across all habitats [nMicrosites\u2009=\u2009192 ; Online Resource 1c; following Edwards et al. Unlimited-radius point counts were used to sample birds across all habitats [Functional traits that reflect the key functional roles of dung beetles and birds were assessed for use with trait assembly null models described below. We combined both behavioural and morphological (body size and bill structure) traits to capture a greater proportion of the variation across species as per Edwards et al. to creatTo assess how functional traits and species abundances influence community assembly, we used a null model approach to test for trait divergence or convergence across our disturbance gradient and landscape (n\u2009=\u20094) scale (Online resource 1), and tested whether SESRaoQ values were significantly different from zero (indicating a random trait distribution) using a student\u2019s t-test.To then be able to assess community assembly patterns across our disturbance gradient we compared the deviation of observed RaoQ from the expected null distribution, using the standardised effect size (SES) (SES_RaoQ), taking the approach of Gottelli and McGabe . SESRaoQnMicrosites\u2009=\u200940 per habitat; birds: nMicrosites\u2009=\u200948 per habitat) and landscape (nSites\u2009=\u20094 per habitat) scales. Therefore, for any given subset of the community (see variations of community subsets below), four models were run for each taxa. All null model randomisations were run with 10,000 permutations and with abundance data, which has been shown to maximise detection power . This model has the effect of removing any relationship between the traits and abundances of species co-occurring at a sampling site while maintaining the sample species richness and the total sample abundance . Importantly, this maintains the link between species abundances and traits (thus differing from model 1), while also maintaining species frequencies and total abundances, but allowing sample abundance and richness to vary . Habitat specialists were defined as those species that were unique to either oil palm or forested habitats . We analysed both subsets of species using the same null models at both the local and landscape scales. To ensure our definition of habitat association was not influenced by rare species , we re-analysed these models with singletons removed. The results mirrored those from the full community; we, therefore, present only the full community results in the main text and provide both model outputs in the supplementary material (Online resource 5).To explore whether any changes in co-occurrence patterns related to changes in interactions determined by species\u2019 habitat associations, we tested whether assembly mechanisms differed between those species shared across all habitats and those that were not (non-shared). Habitat generalists were defined as those species found in all four habitats described in the Elton Trait database, which are based on the summed proportion of five individual diet components for each species , at the local scale dung beetle communities varied considerably. Random trait assembly was found in primary and twice-logged forests, while trends in once-logged forest indicated trait convergence (t-test: P\u2009<\u20090.01) and in oil palm trait divergence (t-test: P\u2009<\u20090.01) , we found no evidence of non-random trait assembly for dung beetle communities at either spatial scales .Nesting guilds of dung beetles indicated uniform trait-based assembly across habitats for rollers, which displayed trait convergence at both scales using model 1. Insectivore communities indicated strong trait convergence across all habitats and scales .Dominant avian feeding guilds showed variation in trait-based assembly patterns using We explored the manner in which tropical land-use change influences species co-occurrence patterns to infer community assembly mechanisms in two indicator taxa. To our knowledge, this is the first assessment of dung beetle co-occurrence patterns, and the first multi-taxon, multi-spatial scale analysis of co-occurrence in relation to anthropogenic habitat change. In revealing evidence of non-random assembly at local scales in dung beetles, and variation between trait convergence and random assembly in birds across the disturbance gradient Fig.\u00a0e\u2013h, our Model 1, which can detect limiting similarity, varied across the disturbance gradient, whereas model 2, which reliably detects environmental filtering and conversion . Critically, we highlight the potential hidden effects of land-use change beyond altered community structure Below is the link to the electronic supplementary material."} {"text": "The successful implementation of antiretroviral therapy (ART) in women living with HIV (WLWH), either for their own health or for prevention of mother-to-child transmission (MTCT), has reduced MTCT risk of HIV to <5% . Yet, inIn addition to the risk of HIV infections that occur early in life via breastfeeding, sexual transmission during adolescence and adulthood also represents a significant and ongoing mode of infection . A pediaSeveral recent studies have indicated that the early life immune system may present some advantages for elicitation of HIV-specific antibody responses. The purpose of this review is to summarize these studies and highlight the unique ability of the early life developing immune system to mount robust and durable immune responses against HIV, compared to adults. Additionally, the potential of harnessing neonatal immune ontogeny to develop an effective earlylife HIV vaccine is emphasized.Owing to maturational differences in the early life and adult immune systems, the ability of infants to generate vaccine-specific immune responses has traditionally been considered as impaired [reviewed in ]. AdditiNeonatal nonhuman primate (NHP) studies have provided encouraging results regarding the ability of infants to mount durable immune responses against HIV or simian immunodeficiency virus (SIV) vaccines \u201319. In fTo date, only a few pediatric HIV vaccine trials have been completed . While nAlthough the induction of cross-clade bNab is 1 of the major goals of any HIV vaccination strategy ,37, so fWhile elicitation of bNabs remains a priority of HIV vaccine development, a combination of neutralizing and non-neutralizing effector responses might be crucial for an efficacious vaccine. A recent study has indicated that polyfunctional antibody responses are predictive of bNab development , suggestNewborns transition from a relatively sheltered intrauterine environment to an environment with multiple antigenic exposures. To obtain survival benefits during the period of immune maturation, newborns establish a highly tolerogenic environment and exhibit a distinct immune profile than adults [reviewed in ]. TherefWhile alum has been the standard adjuvant of choice for commercial pediatric vaccines, HlV pediatric vaccine trials have reported the superiority of MF-59 adjuvant in mounting potent and durable antibody responses when compared to alum. In PACTG 230 trial, the MF-59-adjuvanted vaccine formulation was associated with durable anti-Env IgG responses, which was associated with higher breadth and durability as compared to the alum-adjuvanted counterpart . This inEmerging evidence suggests that an individual\u2019s microbiome can influence immune responses to vaccination . TherefoNeonates and infants possess unique immunological characteristics that promote the development of protective immunity via immunological and molecular pathways distinct from those of adults. Therefore, a deeper understanding of the infant immune system is needed to develop novel HIV immunization regimens tailored to the infant\u2019s immune landscape. The fact that the most recent adult HIV vaccine trial HVTN 702), done in South Africa, which tested a canarypox vector-based vaccine (ALVAC-HIV) with HIV subtype C gp120 protein adjuvanted with MF-59, was recently discontinued due to lack of efficacy highligh2, done iThe pediatric HIV vaccine protocol HVTN 135 is currently in development to assess the safety and immunogenicity of HIV CH505 transmitted-founder (T/F) gp120 adjuvanted with the TLR4 agonist GLA-SE in HIV-exposed infants. This Phase I trial will use the CH505 T/F protein that is currently being tested in an adult HIV vaccine trial, and the results from HVTN135 will determine if this vaccine is safe to be used in infants. Additionally, this trial will indicate whether infants develop a distinct immune response to this vaccine as compared to adults, hence providing valuable information for the design of future pediatric HIV vaccine trials. Ultimately, additional clinical trials will be required to assess if immunization at birth can protect infants from vertical HIV transmission during infancy and against sexual HIV transmission during adolescence."} {"text": "Using a stress process framework model, this study is the first to comprehensively examine the role that religious/spiritual struggles play in the lives of informal dementia caregivers. A convenience sample of 156 informal dementia caregivers completed a scale measuring six domains of religious/spiritual struggles, as well as other measures of primary stressors, background/contextual variables, and mental health outcome (depression). Overall levels of religious/spiritual struggle were low, but 26 percent of the sample were classified as possible cases of clinically significant religious/spiritual struggle for at least one of the six domains. Of this group, 49 percent acknowledged struggles with ultimate meaning. Religious/spiritual struggles predicted greater self-reported depression over and above number of care recipient problem behaviors (primary stressor), caregiver sex, and caregiver personality . Although no individual domain of religious/spiritual struggle emerged as most salient, caregivers reported significantly more ultimate meaning struggles than demonic or interpersonal struggles. These findings support the growing body of research suggesting that religious/spiritual struggles serve as a secondary stressor, adding predictive power to background/contextual factors and to primary stressors for informal dementia caregiver mental health outcomes. Further research in this area may advance efforts to better equip both secular and religious professionals to provide evidence-based counsel to informal dementia caregivers."} {"text": "Excellent pulmonary function is one of the strongest predictors of longevity across animal models and human populations. Unfortunately, none of the major age-associated pulmonary diseases \u2013 obstructive lung disease, pulmonary fibrosis, and increased susceptibility to pneumonia \u2013 have strongly effective disease modifying therapies. There is growing evidence that normal age-associated decline in pulmonary function and major age-associated pulmonary diseases are linked to the hallmarks of aging including senescence, nutrient signaling dysregulation, mitochondrial dysfunction, and telomere disorders. This presents opportunities for collaboration between gerontologists and pulmonologists to unravel age-associated developmental mechanisms and design novel treatments. In this symposium, leaders in pulmonary aging research will present novel data on links between aging and pulmonary health and geroscience-based interventions under study. Dr. Sanders will provide an overview of the scientific and clinical space and present epidemiologic associations between aging biomarkers, early pulmonary fibrosis, and mortality. Dr. Le Saux will discuss senescence and specifically how eicosanoid biology may explain organ-specific patterns of senescence-associated fibrosis. Dr. Thannickal will discuss age-associated perturbations in metabolism and mitochondrial function and targeting these pathways to improve lung function and treat pulmonary diseases. Dr. Newton will discuss mechanisms and clinical applications of telomere biology to pulmonary aging. Symposium attendees will (1) be poised to generate collaborations between gerontologists and pulmonologists to address existing knowledge gaps in mechanisms of pulmonary aging, and (2) develop a better understanding of translational opportunities to design geroscience-based diagnostics and therapeutics to improve pulmonary health with aging."} {"text": "Ovarian cancer, cervical cancer and endometrial cancer are three relatively common malignant cancers of the female reproductive system. Despite improvements in female genital tract cancer detection and development of new therapeutic approaches, there are still poor prognoses and some do not respond to therapeutic patterns, displaying low survival and high frequency of recurrence. In an era of personalized medicine, novel therapeutic approaches with greater efficacy for these cancers represent an unmet need. One of the actionable signaling pathways is the fibroblast growth factor receptor (FGFR) signaling pathway. Several mutations and alterations in FGF/FGFR family members have been reported in human cancers. FGF/FGFR signaling pathway has become a new target for cancer therapy. This review will summarize the role of FGFR pathway and the genetic alterations of the FGF/FGFR related to female reproductive system cancer. We will describe the available inhibitors of FGFR pathway for potential treatment of female reproductive system cancer. Furthermore, we will discuss FGFR-targeted therapies under clinical development for treatment of female reproductive system cancer. Endometrial cancer, ovarian cancer and cervical cancers are three relatively common malignant tumors of the female reproductive system. Endometrial cancer that accounts for more than 95% of cases of uterine cancer is one of the most prevalent forms of gynecological cancers. It is thought to be caused by increasing estrogen levels relative to progesterone in the body. Endometrial cancer at stages I and II responds well to surgical interventions, but the disease at stages III and IV has poor prognosis with low survival rates. Ovarian cancer is the third leading gynecological malignancy worldwide and carries the highest mortality. Most ovarian cancers initiated from epithelial cells and are thus composed of poorly differentiated epithelial cells in vitro and in vivo tumor models harboring FGFR aberrations, an increasing number of researchers have selected FGFRs as targets for anticancer drug development Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinase (RTKs) encoded by four different genes FGFR1-4), among them, FGFR1-FGFR3 generate two major splice variants of immunoglobulin-like domain III, referred to as IIIb and IIIc, which are essential determinants of ligand-binding specificity , among tSome of the most striking clinical findings regarding FGFRs relate to how these receptors are implicated in female genital tract cancers. In this article, we describe recent advances of FGFR signaling pathway in endometrial, ovarian and cervical carcinogenesis and progression. Moreover, we highlight the genetic variations (including somatic mutation and gene amplification) of FGF or FGFR family members and summarize the FGFR-targeted therapies under clinical development for treatment female genital tract cancers.FGFRs in response to fibroblast growth factors (FGFs) transmit signals. The FGF family belongs to a large family of growth factors with significant expression profiles in the female reproductive tract and potentially important roles on fertility. This family is composed of 18 secreted proteins that are grouped into 5 subfamilies according to sequence homology Figure 1).Notably, dysregulation of the FGFR pathway is associated with various human cancers and is considered as an oncogenic signaling pathway FGF/FGFR signaling governs fundamental cellular processes such as cell survival, proliferation, migration, differentiation, embryonic development, organogenesis, tissue repair/regeneration, and metabolism Figure 2). Recent study suggested that the fibroblast FGF/FGFR family could interact with PI3K/AKT pathway and subsequently involve in the carcinogenesis of ovarian cancer. In endometrial cancer cell lines, loss of PTEN has been suggested as apotential mechanism of resistance to FGFR inhibition Genetic variations, especially SNPs, and genomic alterations, such as gene amplification, chromosomal translocation, and point mutation, are involved in the transcriptional upregulation of FGFR mRNAs and the functional activation of FGFR proteins during carcinogenesis . The main challenges have included (i) determining optimal diagnostic procedures for FGFR molecular alterations, and standardizing the definition of FGFRs amplification; (ii) detecting rare-frequency fusion genes involving various partners; (iii) discriminating between passenger and driver alterations; (iv) integrating the available information within a specific cellular and tumor heterogeneity context.In clinical, although anti-FGFR therapy represents a promising targeted cancer treatment, early phase clinical trials have had mixed success, with response to therapy dependent on several factors, including cancer type, tumor histology, and presence or absence of certain biomarkers Cervical cancer is the fourth most common female malignancy worldwide. Each year, more than half a million women are diagnosed with cervical cancer and the disease results in over 300,000 deaths worldwide et al. The oncogenic significance role of the FGFRs has been elucidated in cervical cancer. Choi et al. Ovarian cancer is the leading cause of death from gynecologic cancers in vitro and in vivo have shown that silencing FGFR4 and inhibiting ligand-receptor binding significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells, suggesting that FGFR4 protein expression is a new therapeutic modality for this disease and will improve its survival in clinical trials FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian cancer. Experiments In vivo experiment has shown that FGFR inhibitor decreased the growth of FGFR2-mutated endometrial cancer xenograft models Endometrial cancer is the most common gynecologic malignancy among women in developed countries, with an estimated 63,230 new cases in 2018 et al. Table The FGF/FGFR signaling pathway is frequently deregulated in human cancers. Over the last years, several mutations and alterations in FGF-FGFR pathway have been reported in cancer et al. et al. Previous studies of germline FGFR mutations indicate that point mutations can result in differential localization and signaling et al. Besides FGFR aberrations, a number of studies have also shown that genetic variations of FGF are associated with the disease. Take FGF2 for example, our group previously found that the polymorphisms of FGF2 gene are significantly associated with obesity and osteoporosis in Chinese population Since FGF/FGFR signaling plays a crucial role in cancers, a variety of small molecule FGFR inhibitors target FGF/FGFR signaling pathway have been developed and shown significant therapeutic effects in pre-clinical and clinical studies Actually, the most clinically advanced compounds are non-selective TKIs, such as brivanib, dovitinib, lenvatinib, ponatinib, nintedanib, and cediranib. Most of these inhibitors target ATP binding pocket in the TK domains of FGFRs through reversible or covalent bonds To date, the most clinically advanced FGFR TKIs in FGFR targeted treatment is dovitinib (TKI258), which is now being tested in endometrial cancer patients with FGFR2 mutation (NCT01379534). Brivanibis another dual TKI against FGFRs and VEGFRs, which was found to be effective in metastatic solid malignancies resistant to standard therapy and is currently being developed as an anti-angiogenic agent in Phase II clinical trials AL3818 (anlotinib) is a receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors , stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFA), and fibroblast growth factor receptors . This study evaluates the efficacy of AL3818 studying tumor regression in endometrial cancer model Table 2).Several other TKIs are also summarized in Table in vitro and in vivo models of endometrial cancer characterized by FGFR activation due to genetic alteration Table 3). Phase II trials with genomic enrichment are ongoing. A number of clinical trials use AZD4547 in cancer. One recent finding revealed that combined treatment of BGJ398 and rapamycin may be a promising therapeutic strategy in the treatment of patients with ovarian cancer AZD4547 is a famous selective TKI that specific target for FGFRs (FGFR1-3) Table 3). Pre-clinical cancer models with genetic aberrations in the FGFR pathway, including FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039 mediated tumor inhibition Anti-FGFR mAbs as well as small molecules acting as traps for the ligands of the FGFR family might represent a new strategy for the treatment of tumors. Based on the identification and characterization of FGF ligands, FGF ligand traps have allowed the development of promising FGF-targeting molecules with potential implications for the therapy of FGF-driven tumors Figure A large effort to develop FGF/FGFR inhibitors as anticancer treatments is underway. The most clinically advanced anti-FGFR drugs are small-molecule TKIs, some of them are monoclonal anti-FGFR antibodies and FGF-trapping molecules. Those anti-FGFR drugs that have entered the clinical phases of development are summarized in The cancers of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Undoubtedly, in the past decade, FGF/FGFR signaling therapies are under development for the treatment of gynecologic malignancies as well as in many other solid tumors. Therefore, dissecting canonical FGF/FGFR signaling pathways is still valuable. Deregulation of the FGF/FGFR signaling axis is observed in a wide variety of human cancers In conclusion, targeting FGFR is a promising strategy in the treatment of female reproductive system cancer. It is plausible to hope that in the following years the research efforts in pre-clinical and clinical fields allow to establish an optimal treatment strategy in FGFR-addicted female reproductive system cancer population."} {"text": "Preparedness of residents in long-term care (LTC) in the face of hurricane emergencies is a contested and largely unanswered question. Our prior work involving the U.S. Gulf Coast hurricanes of 2005-08 showed that exposure to various storms on nursing home (NH) residents resulted in significantly more deaths than reported by health care officials. This work also highlighted that evacuation of NH residents, compared to sheltering in place, was independently associated with morbidity and mortality. Hurricane Irma struck Florida on Sept. 10, 2017, prompting the evacuation of thousands of NH and assisted living community (ALC) residents. This symposium will discuss the effects of Hurricane Irma on vulnerable older adults residing in NHs and ALCs using mixed quantitative and qualitative methodologies. The first presentation will discuss morbidity and mortality of NH residents exposed to Hurricane Irma and will stratify by long stay/short stay status and hospice enrollment. The second presentation will discuss improvements and continued barriers to NH preparedness based on interviews with 30 administrators following Hurricane Irma. Using a novel methodology to identify residents of ALCs using secondary data sources, the third presentation will document AL resident morbidity and mortality risk following Hurricane Irma. The final presentation will highlight results of interviews with 70 stakeholders from small and large ALCs concerning the hurricane experiences of residents, including those with dementia. This symposium offers a multi-faceted view of a disaster\u2019s effects on LTC residents across Florida, including novel data from the NH environment and lesser-examined ALCs."} {"text": "Background: Preterm infants with hemodynamically significant patent ductus arteriosus (HsPDA) are exposed to low cerebral tissue oxygen saturation (rScO2) values. Additionally, infants requiring surgical ligation are at risk of further changes in cerebral oxygenation and postligation cardiac syndrome (PLCS). Previous studies have assessed the effect of PDA ligation on rScO2 with variable results.Cases description: In this report we analyse near-infrared spectroscopy (NIRS) and echocardiographic findings of two patients who underwent ligation of PDA and presented low cardiac output. Literature on regional tissue oxygenation saturation (rSO2) before and after PDA ligation was briefly reviewed.Discussion: Cerebral oxygenation values before and after PDA ligation may be influenced by gestational age, vasopressor use, ductal shunt volume, time of exposure HsPDA, chronological age and the presence of cerebral autoregulation. PLCS complicates 28\u201345% of all PDA ligations and is associated with higher mortality. Cerebral and somatic NIRS monitoring in the postoperative period may enhance the identification of PLCS at early stages.Conclusion: Cerebral oxygenation in the perioperative period of PDA ligation may be influenced by numerous clinical factors. Early detection of PLCS using multisite NIRS after ligation could prevent further alterations in cerebral hemodynamics and improve outcomes. A decrease in somatic-cerebral difference and/or a significant drop in somatic NIRS values may precede clinical signs of hypoperfusion. NIRS values should be interpreted as trends along with echocardiographic findings to guide goal directed interventions. After PDA ligation, a significant reduction (>20%) in rSrO2 and somatic-cerebral difference concurred with low LVCO in both cases in the absence of hypotension, oliguria and/or delayed capillary refill. In case 1, cerebral oxygenation decreased significantly at the end of measurement period compared to preligation baseline values (60 vs. 80%). In case 2, rScO2 remained unvaried.In the aforementioned cases, rSrOEarly detection of PLCS using multisite NIRS after ligation could prevent further alterations in cerebral hemodynamics and improve outcomes. A decrease in somatic-cerebral difference and/or a significant drop in somatic NIRS values may precede clinical signs of hypoperfusion. Further studies are needed to investigate the applicability of somatic-cerebral difference in preterm infants. Our report has many weaknesses. Firstly, we describe only two cases and no conclusions can be drawn regarding our findings. Secondly, somatic-cerebral difference although physiologically founded, has not been used in preterm infants. We consider that continuous and long lasting NIRS recording is a strength of this report, as well as the review of literature on NIRS findings before and after treatment.A prospective cohort study is recommended to evaluate the utility of two-site NIRS monitoring in the detection of PLCS. NIRS values should be interpreted as trends along with echocardiographic findings to guide goal directed interventions.Written informed consent was obtained from parents of both patient for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Diurnal cortisol slopes are stress-sensitive HPA-axis biomarkers implicated in cardiometabolic health outcomes and disparities. This study used two longitudinal cohort studies (CREATE and TRIAD) with harmonized variables to comprehensively examine what types of exposure to stressors are most salient for cortisol dysregulation in later life, and whether the characteristics of stressor exposure accounts for Black-White disparities in cortisol dysregulation . Black participants reported greater stressor exposure than Whites along some dimensions but comparable exposure in others . Stressor exposure measures that captured psychological components and pervasiveness were more closely related to cortisol dysregulation than more objective measures . Everyday discrimination was associated with racial disparities."} {"text": "This study aimed to identify accelerometer measured daily physical activity patterns and to examine how they associate with health-related physical fitness among 258 participants from the Finnish Retirement and Aging Study. Wrist-worn ActiGraph accelerometer was used and health-related physical fitness measures included body composition, cardiorespiratory fitness and muscular fitness. Based on latent class trajectory analysis, six different patterns of daily physical activity was identified on workdays and two on days off. Having low activity throughout the workday was associated with poorest health-related physical fitness, whereas a combination of low or moderate activity during working hours and increase of activity level in the evening was associated with most favorable body composition and better physical fitness compared to the other trajectories. In conclusion, a large variation in the workday physical activity patterns and health-related physical fitness was observed among aging workers."} {"text": "Opioid overdose risk is particularly high in immigrant communities partly due to limited English proficiency . Previous studies reported that social determinants of health (SDH) have been associated with risk for opioid overdose . The current study examines the association between SDH and literacy of opioid overdose risk among the immigrant population living in a rural area. Specifically, we examine the association in various age groups including young adults (aged 20 to 34), middle-aged (aged 35 to 49), and older adults (ages 50 to 75). Data were drawn from a sample of Korean American immigrants residing in rural Alabama (N=225). The participants administered the Brief Opioid Knowledge (BOOK) Questionnaire . Multiple regression analyses were conducted for three age groups to identify predictors of opioid literacy. Overall, older adults had lower levels of opioid literacy relative to their younger counterparts. Among young adults, low English proficiency, more chronic conditions, and greater depressive symptoms were significant predictors of limited opioid literacy. For the middle-aged adults, lower levels of health literacy and more pain symptoms were associated with limited opioid literacy. Among older adults, women, those with higher English proficiency, and lower health literacy had lower levels of opioid literacy. The findings demonstrated a greater vulnerability of older immigrants to limited opioid literacy. Different predictors based on SDH of limited opioid literacy across age groups have implications for tailored health promotion strategies to reduce opioid overdose risk."} {"text": "Background: Surgical root canal retreatment is required when peri-radicular pathosis associated with endodontically treated teeth cannot be treated by non-surgical root canal therapy (retreatment), or when retreatment was ineffective, not feasible or contraindicated. Endodontic failures maybe happen when irritants remain within the confines of the root canal, or when an extra-radicular infection cannot be eradicated by orthograde root canal treatment. Following enhanced microsurgical techniques in the last years, the success rates of surgical root canal retreatment have improved considerably.Objective: The aim of this systematic review is to gather updated data in regard to the surgical root canal (retrograde) retreatment to heal the periapical lesions.Materials and methods: The electronic databases PubMed and Google Scholar were searched in this review using specific inclusion and exclusion criteria. The search was performed in June 2019 and updated in November 2019. Among 3900 studies, 10 studies satisfied the eligibility criteria and were included in the review to be analyzed.Results: The 10 studies showed the importance of surgical root canal retreatment as a treatment option in removing infections within the root canal system and its efficiency in periapical tissue healing. These studies investigated different aspects of healing of periapical lesion after surgical (retrograde) retreatment including success rates, follow-up duration, and updated studies in surgical (retrograde) retreatment.Conclusions: Surgical root canal (retrograde) retreatment demonstrates its efficiency in reducing the period needed for healing of the periapical lesions in short-term follow-up compared to conventional orthograde retreatment. Periapical lesions are one of the common pathological conditions affecting periradicular tissues . The micThe preliminary purpose of all endodontic procedures, especially cleaning and shaping, is to eliminate necrotic tissue and infective bacteria . Large pThere are several studies that were conducted to discuss the healing of periapical lesion after nonsurgical (orthograde) retreatment or surgical root canal treatment. However, few studies have investigated the healing of periapical lesion after surgical (retrograde) retreatment. Consequently, the aim of this review was to collect all updated and available studies including imperative information concerning the surgical root canal (retrograde) retreatment to heal periapical lesions.Material and methodsThis review has been compiled according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.Research QuestionThe following was the research question for the systematic review: \u201cThe best endodontic treatment option for the healing of periapical lesions: is it surgical retrograde retreatment or conventional orthograde retreatment?\u201d.Literature SearchWith respect to the question of the study, we searched the literature and identified relevant studies. The literature search was formulated in June 2019 and then updated in November 2019. A web search was done through PubMed (2009-2019) and Google Scholar (2009-2019) with MesH terms and/or in various combinations .Relevant articles had been read and assessed by the introduction of the close meaning ideas by the study reviewers. Full articles were obtained for most of the titles and abstracts that met the inclusion criteria, the full text was accessed. From each included article, study design, interventions, and findings were extracted. Articles used were categorized into two main groups (free and restricted). Free ones have been downloaded directly by the URLs generated from the database. The restricted group has been downloaded by the institutional access of the King Abdulaziz University (KAU) library. Even though some articles did not match the main idea, they have been reviewed again & decided to be either relevant or irrelevant.Inclusion Criteria1. Native research released in the English language.2. Time framed articles released within 10 years (2009 - 2019).3. Studies carried out on human subjects only.Exclusion Criteria1. Articles that described healing of periapical lesion with management techniques excluding the surgical root canal retreatment.2. Articles that discussed healing of periapical lesion after surgical root canal retreatment by percentages and samples taken from animals.3. Review articles.Critical AppraisalEligible studies were independently analyzed by all reviewers according to the eligibility criteria as well as PRISMA guidelines. Any disagreement between the reviewers was resolved using discussion.Data Extraction and PresentationThe search strategy using the keywords and MeSH of the databases like PUBMED and Google Scholar yielded a total of 3,900 studies, of which 3,580 were either unrelated or duplicate topics. Among the potential 140 studies, the eligibility criteria were applied and ten studies were included in this systematic review. The summary of the search flow chart for this systematic review has been depicted in retreatment including success rates, follow-up duration, and updated studies in surgical root canal (retrograde) retreatment. The studies included in this systematic review were one randomized controlled trial study, two prospective studies, one retrospective study, and six case reports -19,20-25DiscussionThe systematic review presents a comprehensive compilation of evidence taken from ten articles which included original studies. The sample size was up to 376 subjects seeking endodontic retreatment by the use of surgical retrograde retreatment. All included studies confirmed faster treatment time by surgical root canal (retrograde) retreatment Table . The recAlso, Del Fabbro et al. in 2007 and Torabinejad et al. in 2009 have compared the success rates of non-surgical orthograde and surgical retrograde endodontic retreatment ,28. TheySurgical root canal (retrograde) retreatment is defined as an important invasive procedure that permits fast treatment options minus the necessity of the extensive traditional method. Surgical retrograde retreatment demonstrates its efficiency in reducing the period needed for healing of the periapical lesions and suggests benefits that will result in better recognition among patients seeking faster results in short-term follow-up, but on the long-term follow-up\u00a0showed not significant difference for healing of periapical lesions compared to conventional orthograde retreatment. However, more clinical trials are encouraged to inspect the results of surgical retrograde retreatment on the healing of periapical lesions."} {"text": "The Long Life Family Study (LLFS) has longitudinally measured key aging phenotypes on 4,953 participants (539 pedigrees) in the USA and Denmark selected for exceptional familial longevity. On average, both generations of the LLFS sample are healthier than average for their age/sex, for many phenotypes. However, the pedigrees are heterogeneous, with different families showing familial clustering of protection for different phenotypes. Linkage analyses identified extremely strong genetic linkage peaks for many cross-sectional as well as longitudinal trajectory rates of change phenotypes. These peaks are NOT explained by GWAS SNPs (either measured or imputed). Pedigree specific HLODs and preliminary deep sequencing suggests that these peaks are driven by rare, protective variants running in selected pedigrees. Whole Genome Sequencing, a third longitudinal visit, and extensive OMICs will help us resolve the mechanisms behind these protective genetically linked variants, and could illuminate new biology and enable new therapeutics."} {"text": "The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced. The amygdala is a telencephalic group of diverse, interconnected nuclei in the brain receptors preferentially activated by NGF (nerve growth factor), TrkB receptors activated by BDNF as well as NT-4/5 (neurotrophin-4/5) and TrkC receptors by NT-3 (neurotrophin-3) Barbacid .While many findings regarding BDNF/TrkB signalling in cellular aspects of learning were initially reported for hippocampal and cortical circuits, BDNF/TrkB pathways in the amygdala emerged soon thereafter to be prominently involved in fear learning (see below). TrkB receptor as well as BDNF mRNA and protein were detected at moderate to high levels in various amygdala subnuclei , the posterior intralaminar nucleus (PIN) and the suprageniculate nucleus (SG) or Y515 (Shc) phosphorylation site of the TrkB receptor, respectively , which drives the expression of Met-BDNF and leads to decreased activity-dependent BDNF secretion were unaffected or impaired when assessed by skin conductance response or fear-potentiated startle, respectively from tones not paired with the aversive US (CS\u2212) in a discriminative fear learning task (Meis et al. Interestingly, chronic BDNF reduction to about 50% of wild-type levels in BDNFThe LA is highly interconnected with the BA (Pitkanen et al. AR\u03b11 subunits in amygdala cell cultures, which was supposed to elicit a transient hyper-excitability in the amygdala, thereby contributing to cellular mechanisms of memory consolidation (Mou et al. +/\u2212 mice displayed neither impaired basal synaptic GABAergic transmission nor altered inhibitory synaptic plasticity in the LA. However, positive modulation of interneuron activity by noradrenaline was significantly decreased by chronic BDNF reduction (Meis et al. Beside glutamatergic synaptic transmission, BDNF/TrkB signalling also regulates GABAergic neurotransmission (Gottmann et al. Beside the basolateral amygdala, the central nucleus is now considered as an important site of associative plasticity involved in fear memory (Ehrlich et al. In conclusion, BDNF/TrkB signalling increases excitatory synaptic transmission in different subnuclei of the amygdala and enables LTP. At GABAergic synapses, acute BDNF/TrkB signalling may lead to reduced inhibition and elevated excitability necessary for memory formation, while chronic BDNF reduction results in impaired interaction of GABAergic synaptic transmission with modulatory transmitters like noradrenaline and serotonin.After fear learning, repeated exposure to the conditioned stimulus alone leads to diminished fear responses (Myers and Davis +/\u2212 mice display an age-dependent deficit in extinction learning (Psotta et al. Val/Met or BDNFMet/Met mice as well as human Met allele carriers were impaired in extinguishing a conditioned fear response, associated with abnormal fronto-amygdala activity in humans (Soliman et al. +/\u2212 mice but was mimicked by overexpression of BDNF in the BLA from the end of extinction training onward (Karpova et al. A critical contribution of BDNF signalling in extinction was recently demonstrated. BDNFNeurotrophins are at first synthesized as precursor proteins, which are processed to the mature form by proteolytic cleavage (Lessmann and Brigadski Conflicting results are available about the distribution of TrkA receptors in the amygdala. While initially neither TrkA receptor mRNA nor immunoreactive cells for TrkA receptors were detected (Gibbs and Pfaff While neither NT-3 mRNA nor immunoreactive neurons were found in the amygdala (Phillips et al. Accumulating evidence indicates that BDNF/TrkB signalling in the amygdala plays a pivotal role in fear learning and memory as well as fear extinction. In the amygdala circuitry, BDNF/TrkB signalling contributes significantly to synaptic plasticity, which is widely accepted as a cellular mechanism underlying fear memory learning. In addition, downstream molecular signalling pathways triggered by TrkB activation are well documented. However, actions of BDNF/TrkB signalling in amygdala synaptic processes involved in fear extinction learning are far less understood. While behavioural studies suggest a significant contribution of BDNF signalling within the amygdala in extinction learning, analysis of the underlying cellular mechanisms warrants further studies."} {"text": "Filial caregivers are a part of the growing number of family caregivers in midlife and late adulthood. The responsibilities that filial caregivers navigate in midlife and late adulthood may expose them to multiple types of discrimination that may decrease their physical health, though this relationship has been understudied. As numbers of family caregivers grow, it is important to examine the potential vulnerability of younger and older filial caregivers\u2019 physical health in the context of discrimination. Informed by the life course perspective, this study compares the physical health of younger (aged 34-64) and older (aged 64-74) filial caregivers who experience discrimination. Filial caregivers from the Midlife in the United States (MIDUS-II) Survey reported on demographics, family caregiving, daily discrimination, self-rated physical health, and chronic conditions via questionnaires and phone interviews. Regression analyses showed no differences between younger and older adults\u2019 self-rated physical health or average chronic conditions. However, moderation analyses revealed that younger filial caregivers who experienced greater discrimination reported poorer self-rated physical health than their older counter parts as well as younger and older filial caregivers who experienced less discrimination. Additionally, younger caregivers with greater discrimination exposure exhibited more number of chronic conditions as compared to other caregivers. The study results highlight the impact of the intersection between filial caregivers\u2019 age and discrimination on physical health. Findings have the potential to inform programs that could promote the health of filial caregivers in the face of discrimination."} {"text": "Although nonalcoholic fatty liver disease (NAFLD) is more prevalent in older individuals, the underlying mechanisms by which aging processes accelerate NAFLD are not fully understood. NAFLD can progress to nonalcoholic steatohepatitis (NASH), which in turn can lead to the development of cirrhotic liver disease and hepatocellular carcinoma (HCC). Since NAFLD, NASH, and HCC are rapidly increasing in the aging population, understanding the mechanism of how NAFLD progresses to NASH is crucial. NASH is emerging as the leading cause of chronic liver disease and the most rapidly growing indication for liver transplantation worldwide, with liver fibrosis being the most important predictor of liver failure in NASH . HoweverCRMertk) mouse model, the authors further showed that all-trans retinoic acid (ATRA)\u2013induced ADAM metallopeptidase domain 17 (ADAM17)\u2013mediated MerTK cleavage decreased the levels of MerTK receptor on macrophages and suppressed NASH fibrosis. ATRA is a major active metabolite of retinol stored in quiescent HSCs in healthy liver. In damaged liver, as HSCs are activated, they release retinol. Livers of subjects with NASH show lower levels of retinol than livers of subjects with simple steatosis [in vivo. However, given that MerTK is critical for maintaining tissue homeostasis in other settings, including atherosclerosis and myocardial infarction [Liver fibrosis is driven by the activation of hepatic stellate cells (HSCs) that produce collagen and other types of extracellular matrix. It has been widely reported that liver macrophages, including resident Kupffer cells and infiltrated monocyte-derived macrophages, can activate HSCs through releasing growth factors including TGF\u03b2 and PDGF . Howeverteatosis . Consistfarction , global In summary, Cai et al. uncover a previously unrecognized function of macrophage MerTK in NASH fibrosis and provide constructive insight on the potential therapeutic targeting of MerTK. However, this study opens up new questions worth exploring. Since MerTK is often seen as a protective regulator for tissue homeostasis, why doesn\u2019t MerTK signaling trigger beneficial effects, including efferocytosis, dampening of inflammation, and resolution of inflammation in the context of NASH? Moreover, some studies have shown that Kupffer cells are protective in non-NASH liver injury models. However, Kupffer MerTK is detrimental in NASH. Does MerTK express in a unique subset of Kupffer cells that promote NASH progression? Finally, what are the mechanisms of decreased liver ATRA and increased GAS6 during NASH?"} {"text": "Coastal wetlands provide many critical ecosystem services including carbon storage. Soil organic carbon (SOC) is the most important component of carbon stock in coastal salt marshes. However, there are large uncertainties when estimating SOC stock in coastal salt marshes at large spatial scales. So far, information on the spatial heterogeneity of SOC distribution and determinants remains limited. Moreover, the role of complex ecological interactions in shaping SOC distribution is poorly understood. Here, we report detailed field surveys on plant, soil and crab burrowing activities in two inter-tidal salt marsh sites with similar habitat conditions in Eastern China. Our between-site comparison revealed slight differences in SOC storage and a similar vertical SOC distribution pattern across soil depths of 0\u201360 cm. Between the two study sites, we found substantially different effects of biotic and abiotic factors on SOC distribution. Complex interactions involving indirect effects between soil, plants and macrobenthos (crabs) may influence SOC distribution at a landscape scale. Marked differences in the SOC determinants between the study sites indicate that the underlying driving mechanisms of SOC distribution are strongly system-specific. Future work taking into account complex interactions and spatial heterogeneity is needed for better estimating of blue carbon stock and dynamics. It points to the necessity of incorporating these indirect effects for better understanding the mechanisms underlying carbon stock in coastal ecosystems. It also calls attention to spatial heterogeneity and system specificity for estimating blue carbon stock and dynamics.By comparing between two inter-tidal salt marsh sites with similar habitat conditions in Eastern China, we observed minor differences in SOC storage and a similar vertical SOC distribution pattern across the soil depths of 0\u201360 cm. Despite these similarities, we found strongly different effects of biotic and abiotic environmental factors on SOC density distribution between the two study sites. Complex interactions involving indirect effects between soil, plants and macro-benthos (crabs) can provide important additional explanatory power to the models explaining SOC distribution, suggesting that these interactions may underpin SOC distribution at a landscape scale. Marked differences in the SOC determinants between the study sites indicate that the underlying driving mechanisms of SOC distribution are strongly system-specific. Future work, taking into account spatial heterogeneity and system specificity, is needed for improving the accuracy of estimates of blue carbon stock and dynamics."} {"text": "The current pandemic due to the coronavirus disease 2019 (COVID-19) outbreak has forced physicians to review their current clinical practice and guidelines. Although elective procedures using assisted reproductive technologies (ART) should be preferably canceled or postponed at this time, this does not always apply to urgent procedures such as those in patients with cancer. A complete oncofertility counseling balancing the benefits and risks of undergoing fertility preservation before commencing gonadotoxic therapies (chemotherapy and/or radiotherapy) should also be provided during the COVID-19 outbreak. This article briefly highlights what patients, oncologists and fertility specialists need to keep in mind during oncofertility counseling at the time of the COVID-19 outbreak. Some anticancer treatments can affect fertility , 2. OncoPatients face hurdles that can be as basic as getting to the tertiary hospital that offers both cancer care and fertility preservation treatments to more complex emotional thoughts dealing with the fear of both the known and unknown risks of complications from COVID-19 during cancer treatment and the additional fertility preservation treatments involving further hospital visits, potential surgery and in some units additional costs relating to COVID-19 testing and personal protective equipment (PPE) gear. Moreover, the anxieties from the fear of contracting the virus during hospital visits leading to isolation and quarantine are real enough for some to even consider opting out of fertility preserving treatments whilst fighting their most basic desire to procreate. For healthcare providers, the novel challenges of providing safe and optimal care while dealing with the undefined risks remain.Nonetheless, where resources allow, with extra caution and strict adherence to the COVID-19 safety protocols and local guidelines, oncofertility is a feasible option, giving hope for young patients with cancer.Newly diagnosed eligible cancer patients should discuss before commencing treatment with their oncologist and oncofertility specialists the wish to have children to see if it is possible to safely balance this option without compromising their cancer care and further increase the risk of infections by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Outline various fertility preservation procedures that can be undertaken safely with the precautions recommended by various national and international organizations including having protected pathways.For male patients, sperm banking before starting anticancer treatments is standard of care.For female patients, embryo/oocyte cryopreservation before starting anticancer treatments is the first option to be discussed .Ovarian tissue cryopreservation in patients that cannot wait 2-3 weeks before starting anticancer treatments can be discussed .Ovarian transposition can be considered before starting pelvic radiotherapy .Temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) during chemotherapy is an available option to protect ovarian function during treatment .Detailed oncofertility counseling should clearly discuss the additional concerns during the COVID-19 outbreak whist defining all the established safety protocols in place to minimize these risks.Triage patients for SARS-CoV-2 testing in accordance with local guidelines before starting any of the ART procedures.Train additional members of the team on how to refill the liquid nitrogen tanks in case the lab staff is quarantined.If local resource allocation allows, consider having two teams working by rota. An alternate team can take over in case one team comes in contact with an infected patient .The advances in oncofertility have given a lot of hope on preserving future fertility to cancer patients. Hence, we urge oncologists and fertility specialists to consider oncofertility counseling (which includes COVID-19-related safety concerns at this time) and work as a dedicated team to support young cancer patients optimizing their future fertility and reproductive health even during this pandemic. Let us not allow the COVID-19 outbreak to sidetrack us on this important issue.Tanya Buckshee Rohatgi has no conflicts of interest. Bhawna Sirohi has received honoraria from Bayer and Roche outside the submitted work . Matteo Lambertini acted as a consultant for Roche, and received honoraria from Theramex, Takeda, Roche, and Lilly outside the submitted work.No funding was received for this work."} {"text": "Salmonella (NTS) enterica subspecies enterica is associated primarily with a self-limiting diarrhoeal illness, invasive bacterial infections were also reported. Human outbreaks of NTS were reported in several countries all over the world including developing as well as high-income countries. Conventional laboratory methods such as pulsed field gel electrophoresis (PFGE) do not display adequate discrimination and have their limitations in epidemiological surveillance. It is therefore very crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological characterisation and outbreak investigation.Salmonellosis is one of the most common foodborne diseases worldwide. Although human infection by non-typhoidal Salmonella Typhimurium and Salmonella Dublin that occurred in 2013 in UK and Ireland respectively.Here, we used different whole genome sequence (WGS)-based subtyping methods for retrospective investigation of two different outbreaks of Salmonella Typhimurium genomes revealed well supported clades, that were concordant with epidemiologically defined outbreak and confirmed the source of outbreak is due to consumption of contaminated mayonnaise. SNP-analyses of Salmonella Dublin genomes confirmed the outbreak however the source of infection could not be determined. The core genome multilocus sequence typing (cgMLST) was discriminatory and separated the outbreak strains of Salmonella Dublin from the non-outbreak strains that were concordant with the epidemiological data however cgMLST could neither discriminate between the outbreak and non-outbreak strains of Salmonella Typhimurium nor confirm that contaminated mayonnaise is the source of infection, On the other hand, other WGS-based subtyping methods including multilocus sequence typing (MLST), ribosomal MLST (rMLST), whole genome MLST (wgMLST), clustered regularly interspaced short palindromic repeats (CRISPRs), prophage sequence profiling, antibiotic resistance profile and plasmid typing methods were less discriminatory and could not confirm the source of the outbreak.Single nucleotide polymorphism (SNP)-based cluster analysis of Foodborne salmonellosis is an important concern for public health therefore, it is crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological surveillance and outbreak investigation. In this study, we showed that SNP-based analyses do not only have the ability to confirm the occurrence of the outbreak but also to provide definitive evidence of the source of the outbreak in real-time. Salmonella enterica, which includes more than 2600 serovars [Salmonella infections are classically divided into diseases caused by typhoidal or non-typhoidal salmonella (NTS). Typhoid fever is caused by the human restricted Salmonella enterica serovars Typhi and Paratyphi [Salmonella (NTS) serovars, predominantly cause a self-limiting diarrhoeal illness they have adapted to cause invasive extra-intestinal disease known as invasive NTS (iNTS) which can result in bacteraemia and focal systemic infections [Salmonella serovars responsible for typhoid fever kill over 250,000 humans per year [Salmonella (NTS) serovars responsible for diarrhoeal illness cause over 155,000 deaths annually [Salmonella Typhimurium and Salmonella Dublin have been associated with systemic illness [Salmonella Typhimurium and Salmonella Dublin were reported in developed countries [Foodborne salmonellosis is an important concern for public health. It is caused by the enteric pathogen serovars . Human Sfections , 4 . Thefections moreoverper year while noannually . Interesannually . Salmoneountries \u201311.Salmonella enterica and have their limitations in epidemiological surveillance, it is therefore crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological characterisation and outbreak investigation.Conventional laboratory methods such as pulsed field gel electrophoresis (PFGE) do not usually provide adequate discrimination among outbreak and non-outbreak strains of Salmonella Typhimurium and Salmonella Dublin that occurred in 2013 in UK and Ireland respectively [Here, we evaluate different whole genome sequence (WGS)-based subtyping methods (including single nucleotide polymorphism (SNP)-based cluster analysis, multilocus sequence typing (MLST), ribosomal MLST (rMLST), whole genome MLST (wgMLST), core genome MLST (cgMLST) as well as clustered regularly interspaced short palindromic repeats (CRISPRs), prophage sequence profiling, antibiotic resistance profile and plasmid typing) for retrospective investigation of two outbreaks of ectively , 12.Salmonella Dublin that occurred in 2013 in Ireland [Salmonella Typhimurium occurred in 2013 in UK [Salmonella Typhimurium and Salmonella Dublin respectively. Non-outbreak strains were also included for comparison. Details of all Salmonella Dublin and Salmonella Typhimurium isolates analysed in this study are provided in supplementary Tables We carried out retrospective investigation of a human outbreak of Ireland and anot13 in UK . We inclSalmonella Dublin [Salmonella Dublin were indistinguishable by PFGE. Although multiple loci VNTR analysis (MLVA) was of value in discriminating the outbreak strains from an epidemiologically unrelated isolate in 2013 it was not able to provide a conclusive link between the outbreak strain and a historical isolate from 2011 (11F310) since all outbreak strains had the same MLVA pattern (3-6-1-10-2-3-12) and the historical isolate had similar MLVA pattern (3\u20136\u20131-10-2-3-11/12).PFGE was of a limited value for the investigation of the outbreak of a Dublin since alSalmonella Typhimurium [Despite the technical limitation of phage typing, it was of value for investigating the outbreak of himurium and confdenovo assembly for the raw Fastq paired end (PE) reads for all Salmonella Dublin and Salmonella Typhimurium strains using two different assemblers including Velvet available at Centre for genomic epidemiology (CGE) (http://www.genomicepidemiology.org/) and SPAdes available at Enterobase (http://enterobase.warwick.ac.uk/). We then assessed the quality of the assembly for each strain was assessed using Quast assessment tool (http://quast.bioinf.spbau.ru/).We carried out https://cge.cbs.dtu.dk/services/CSIPhylogeny/) where raw reads were mapped to reference sequences using BWA software (http://bio-bwa.sourceforge.net). The depth at each mapped position was calculated using genomeCoverageBed, which is part of BEDTools (https://bedtools.readthedocs.io/en/latest/). High quality SNPs were called using mpileup which is part of SAMTools (http://samtools.sourceforge.net). Genome mappings were then compared and an alignment of the SNPs are then created by concatenating the SNPs. A maximum likelihood (ML) phylogenetic tree was then created based on the concatenated alignment of the high quality SNPs.SNP analysis was carried out using CSIPhylogeny (http://enterobase.warwick.ac.uk/) and CGE (http://www.genomicepidemiology.org/).The assembled sequences of each strain were analyzed to detect the MLST, rMLST, cgMLST and wgMLST available at Enetrobase .Prophages were determined with the draft genomes generated by Velevt and SPAdes for all http://www.genomicepidemiology.org/) to construct a phylogenetic tree based on the SNPs of detected prophages. Phylogenetic trees were constructed using assembled genomes generated by Velvet and SPAdes assemblers to check if the assembly could affect the tree.We then used CSI phylogeny available at CGE .Spacers sequence within the draft genomes of all Salmonella Dublin and Salmonella Typhimurium strains using the plasmid database; PLSDB (https://ccb-microbe.cs.uni-saarland.de/plsdb/).We determined the plasmids within the draft genomes of all Salmonella Dublin and Salmonella Typhimurium strains using ResFinder (https://cge.cbs.dtu.dk/services/ResFinder/).We determined acquired antibiotic resistance genes and mutations within the draft genomes of all Salmonella Typhimurium were grouped together in two clades and they are very closely related to strains isolated from mayonnaise . Interestingly, outbreak isolates of Salmonella Dublin displayed identical rMLST (type 1429) however, some of the non-outbreak strains showed the same rMLST. Moreover, the wgMLST was different among the outbreak strains however, the cgMLST was unique among outbreak strains and can easily separate the outbreak strain from the non-outbreak strains including the 2011 historical isolate (11F310).As illustrated in Table\u00a0Salmonella Typhimurium as illustrated in Table\u00a0On the other hand, MLST, rMLST, cgMLST and wgMLST could not discriminate between the outbreak and non-outbreak strains of Salmonella Dublin isolates including outbreak and non-outbreak strains harbour one CRISPR locus and we observed 3 to 5 unique spacers for CRISPR1 locus. Identical spacers were detected among the outbreak and non-outbreak strains as shown in Table All Interestingly, the number of spacers in three isolates changed from (4 spacers) based on Velvet to (5 spacers) based on SPAdes.Salmonella Typhimurium isolates harbour 3 CRISPR loci. Identical spacers were detected among the outbreak and non-outbreak strains as shown in Table All Salmonella Dublin strains including the outbreak strains are lysogenic for three prophages . However, phylogenetic analyses of Salmonella Dublin strains based on the SNPs of prophages showed that outbreak strains are intermixed with the non-outbreak strains based on velvet assembler and the Edwardsiella specific phage (GF-2).All Salmonella Typhimurium genomes assembled by Velvet were lysogenic for two Salmonella specific prophages (Gifsy 2 and RE-2010). All strains except one outbreak isolate (H132940750) harbour Salmonella 118970_sal3 phage.On the other hand, Interestingly, all strains harbour Edwardsiella GF-2 prophage except three outbreak isolates .Salmonella Typhimurium strains based on the SNPs of prophages showed that outbreak strains are intermixed with the non-outbreak strains using velvet assembler as shown in Table\u00a0All outbreak and non-outbreak strains of Same plasmids were determined using Velvet and SPAdes assemblers.Salmonella Typhimurium harbour 3 plasmids except the outbreak strain H133300609 which did not carry plasmid pATCC14028 but it harbours a different plasmid (pSLT_VNP20009) instead -Iaa gene. No mutations were detected against gyrA and parC genes in all isolates except one isolate (MF038630) that carried a non-synonyms mutation within the gyrase protein and it is associated with bacterial resistance to nalidixic acid -Iaa gene\u201d. No known mutations were detected against gyrA and parC -based cluster analysis of Salmonella Typhimurium strains. However, cgMLST defined the genetic relatedness among Salmonella Dublin isolates more precisely and confirmed there is no relation among the 2013 outbreak isolates and the 2011 historical isolate (11F310) of Salmonella Dublin.On the other the WGS-subtyping methods including MLST, rMLST, wgMLST, cgMLST showed limited discrimination for the outbreak and non-outbreak isolates of It was reported that MLST might not be the most suitable epidemiological tool but it iThe cgMLST bridges the classic MLST with the novel WGS-based approach since it combines the discriminatory power of MLST with large-scale data obtained from WGS enabling to exploit a considerable number of gene targets throughout the bacterial genome which would maximize the quality and resolution for surveillance and research works.Salmonella Enteritidis in Europe [A recent study showed that cgMLST has shown the robustness of cgMLST as a tool to investigate multi-country outbreak of n Europe .Escherichia coli (VTEC) O157:H7 in Canada showed that wgMLST provided higher discrimination than PFGE and MLVA [The difference between the cgMLST and wgMLST is that unlike cgMLST, wgMLST indexes the variation of pre-defined set of genes from both core and accessory genes . Anotherand MLVA .Salmonella Dublin isolates of outbreak group from the non-outbreak group. However, both cgMLST and wgMLST were unsuccessful in differentiating outbreak-related Salmonella Typhimurium isolates from outbreak-unrelated isolates.Research studies have shown that cgMLST and wgMLST are viable typing methods for outbreak surveillance. In our study, cgMLST proved to provide higher discriminatory resolution for differentiating Salmonella serovars [Salmonella subtyping is the sensitivity and accuracy of the assembly as some prophage regions might be lost during assembly. We used two different denovo assemblers (SPAdes and Velvet) and found that prophage sequence profiling could not differentiate between the outbreak and non-outbreak isolates.Bacterial genome comprises a considerable amount (10 to 20%) of prophages integrated in their core genome . Prophagserovars . HoweverSalmonella outbreaks [Salmonella enetrica outbreaks as we showed in our previous studies [Salmonella serovars.Recent studies have suggested that high throughput CRISPR typing has the potential to be used for epidemiological surveillance and investigation of utbreaks , 27. How studies , 29 howePlasmid profiles and antimicrobial- susceptibility profiling have been used as an epidemiological tool since many decades. However, it was reported that analysis of plasmid profiles provided higher discrimination in the outbreak investigations than analysis of antimicrobial-susceptibility pattern , 31. In In this study, we compared several retrospective WGS-based subtyping methods and we showed that SNP-based cluster analysis is superior to other subtying methods to define the source of outbreak in real-time.In conclusion, foodborne salmonellosis is an important concern for public health therefore, it is crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological surveillance and outbreak investigation. The rapid development of next-generation sequencing (NGS) technology and bioinformatics tools have enabled WGS of any bacterial strain feasible. Various typing tools have been proposed by using WGS data but currently, the adoption of WGS-based methods have proved to be difficult due to lack of standardization. There are many layers on obtaining WGS data and there is need of standardization from the type of sequencers used to the bioinformatics analysis. Therefore, the emerging genetic analysis techniques should be combined with conventional phenotypic and molecular methods for routine surveillance and outbreak investigation until the WGS-based methods can be fully exploited, improved and standardized.Additional file 1: Supplementary Table\u00a01. Details of Salmonella Dublin strains analysed in this study. Supplementary Table\u00a02. Details of Salmonella Typhimurium strains analysed in this study"} {"text": "Dual-task gait performance is a marker of motor-cognitive interactions modulated by the frontal lobes. After a stroke, gait disturbances are more evident, particularly when concurrently completing a mental task and walking, an effect called high dual-task cost (DTC). Following a stroke, the potential association of high-DTC, integrity of the frontal lobes and cognitive functioning is unclear. This study screened 161 participants with stroke history from the Ontario Neurodegenerative Disease Research Initiative (ONDRI)-cerebrovascular disease cohort . Individuals scoring zero in the National Institute of Health Stroke Scale were analyzed (n=102). DTC was the percentage change in gait speed from the single to dual-task condition. Standardized normal-appearing white matter (NAWM) and grey matter (NAGM) volumes from superior, middle and inferior frontal lobe were compared between DTC quartiles using a multivariate model (MANOVA), with total frontal lobe volume as a covariate. Another model compared group performance across 5 adjusted cognitive domains . Univariate tests revealed that NAWM volume in the superior frontal lobe was significantly different across DTC quartiles. Contrast tests suggested that the first quartile had larger NAWM than the second and fourth. DTC quartiles also showed differences in attention and contrast tests indicated that the first quartile performed significantly better than second and fourth. DTC poststroke may be a proxy for structural integrity of superior frontal lobe regions and attention."} {"text": "Microbacteriaceae from plants infested by plant-parasitic nematodes were obtained using Illumina technology. The sequence data will provide useful baseline information for the development of comparative genomics and systematics of Microbacteriaceae and facilitate understanding of molecular mechanisms involved in interactions between plants and nematode-associated bacterial complexes.Draft genome sequences of 28 strains of Microbacteriaceae from plants infested by plant-parasitic nematodes were obtained using Illumina technology. The sequence data will provide useful baseline information for the development of comparative genomics and systematics of Microbacteriaceae and facilitate understanding of molecular mechanisms involved in interactions between plants and nematode-associated bacterial complexes.Draft genome sequences of 28 strains of Microbacteriaceae (class Actinobacteria) inhabit various terrestrial and aquatic ecosystems and often occur in plants as endophytes and pathogens , 4. Alonragariae , 5\u20138.Microbacteriaceae were isolated from plant galls induced by different anguinids and from plant tissues affected by Aphelenchoides species (Corynebacterium agar (http://www.vkm.ru).Novel nematode-associated strains of species . The airium agar or Reasoium agar , 11 and For genome sequencing, DNA was extracted with a QIAamp DNA minikit from biomass grown in liquid peptone-yeast medium as described previously or usingDefault parameters were used for all software unless otherwise specified. The quality of the reads was checked with FastQC 0.11.8 . AdapterAdditional comparative phenotypic study of the sequenced strains, along with genome-wide analyses of phylogenetically closely related plant endophytes and pathogens, will facilitate understanding of their role in bacterial-nematode complexes, including mechanisms of molecular interactions between members of these complexes and plants.These whole-genome shotgun projects have been deposited in DDBJ/ENA/GenBank under the accession numbers listed in"} {"text": "Despite some insurance plans now paying for home-based palliative care, recent reports have suggested that coverage for palliative care may be insufficient to expanding patient access to home-based palliative care. Research has yet to explore palliative care barriers from the perspective of palliative care-eligible patients and their caregivers. To identify patients and caregivers\u2019 perceived barriers to home-based palliative care and their recommendations for overcoming these barriers, we conducted a qualitative study using semi-structured individual interviews. Participants who were eligible for a randomized controlled trial of home-based palliative care were interviewed via telephone. Our interview protocol elicited participants\u2019 perspectives on home-based palliative care services; positive and negative aspects of the program explanation; and suggestions for improving messaging around home-based palliative care. Researchers used grounded theory to identify the themes within the transcripts. Two researchers independently coded the transcripts and then met to compare coding and reconciled discrepancies until 100% consensus was reached. Identified themes related to home-based palliative care referral barriers included reluctance to have home visits, timing, lack of palliative care knowledge, misconceptions of palliative care, and patients\u2019 self-perceived health condition . Themes related to recommendations for overcoming these barriers included preferring a palliative care referral from healthcare providers or from insurance company and clearer presentation of palliative care service. Findings reinforce the need for additional palliative care education among patients with serious illness and the importance of delivering the information from a trusted source."} {"text": "Physical frailty is an age-related clinical syndrome that is related to adverse health outcomes, including cognitive impairment and dementia. Recent studies have shown structural neuroimaging correlates with frailty. However, most existing evidence relies on brain volumetric measures. Whether brain microstructure is associated with frailty and its spatial distribution have not been explored. In the Baltimore Longitudinal Study of Aging, we identified 776 cognitively normal participants aged 50 and older who had concurrent data on frailty and brain microstructure by diffusion tensor imaging (DTI), including mean diffusivity (MD) of gray matter and fractional anisotropy (FA) of white matter. We first identified neuroimaging markers that were associated with frailty score (0-5) and further examined their relationships with frailty status using multivariate linear regression. Models were adjusted for age, sex, race, years of education, and Apolipoprotein E e4 carrier status. DTI-based neuroimaging markers that were associated with frailty status were localized in the supplementary motor area of the frontal lobe, several subcortical regions , and body and splenium of corpus callosum. This study demonstrates for the first time that microstructure of both gray and white matter differs by frailty levels in cognitively normal older adults. Brain areas were not widespread, but mostly localized in gray matter subcortical motor areas and white matter corpus callosum. Whether changes in brain microstructure precede future frailty development warrants further investigation."} {"text": "Sambucus nigra lectin-reactive) fibronectin in prediction of gestational diabetes mellitus (GDM).To evaluate the performance of first trimester maternal serum glycosylated . There was no difference in assay formats for adiponectin.There was no difference in maternal serum glycosylated fibronectin concentrations between women with consequent GDM and control women . Maternal serum fibronectin levels were significantly lower in GDM group , compared to the control group fibronectin and GDM. Meanwhile, this study provides information on the screening performance of glycosylated fibronectin in women with GDM. This study also evaluated glycosylated fibronectin levels in different BMI subgroups.According to our results, neither first trimester maternal serum glycosylated fibronectin nor serum fibronectin are effective in screening for GDM. Further larger studies in prospective settings are needed to evaluate first trimester glycosylated fibronectin as a screening method for GDM alone and in combination with other markers."} {"text": "Central retinal artery occlusion (CRAO) represents one of the most devastating ophthalmic emergencies, since the inner two-thirds of the retina lose their blood supply. The acute obstruction of the central retinal artery is characterized by severe, sudden and unilateral painless visual loss and usually occurs secondary to an embolus of cardiovascular origin. A paradoxical thromboembolic event of the central retinal artery through patent foramen ovale is an exceptionally unusual clinical entity as well as a great diagnostic challenge since the source of initial thrombus formation requires extensive investigation. Herein, we aim to describe a patient with no significant comorbidities who experienced a paradoxical thromboembolic episode of central retinal artery associated with patent foramen ovale. Central retinal artery occlusion represents the ophthalmic analogue of ischemic stroke and is typically manifested with sudden, severe and painless loss of vision . HoweverCRAO is usually the result of an embolus, either of cardiac origin or dislodged from an unstable atherosclerotic plaque of carotid bifurcation. Subsequently, the most common risk factors for CRAO include carotid atherosclerosis, cardiac valvular disease and cardiac arrhythmias, mainly atrial fibrillation . CongeniThe most important and well-documented clinical manifestation of PFO is the cryptogenic ischemic stroke due to a paradoxical embolus. CRAO or branch retinal artery occlusion (BRAO) associated with PFO represents an unexpected site of systemic paradoxical embolism that requires high index of clinical suspicion and meticulous laboratory investigation in order to unravel the concealed initial source of thrombus generation .Herein, we aim to present a middle-aged male patient who experienced an episode of severe, painless and unilateral visual loss due to CRAO associated with PFO. We also discuss the clinical complexity of such a diagnosis as well as we briefly review the current literature regarding similar published case reports.A 62-year-old Caucasian male, with no previous ocular or neurological symptoms, experienced a sudden and painless loss of vision in the left eye while swimming. He had no significant past medical history apart from an episode of deep vein thrombosis of the left lower extremity four years ago, provoked by a non-displaced fracture of the tibia after a motor vehicle accident. He also reported a previous history of hospitalization due to an episode of acute left-sided loin pain associated with macroscopic haematuria at the age of\u00a060 years. Then the patient had been thoroughly investigated and no specific diagnosis of renal infarct of unknown origin had been made. Otherwise, he did not take any regular medication and he neither smoked tobacco nor drank alcohol.On initial examination, he was afebrile and his pulse rate was 82/min and regular. His blood pressure was 130/85 mmHg and there were no abnormalities to find in the cardiovascular or respiratory systems. No carotid or over the umbilicus bruits were audible and pedal pulses were palpable. Physical examination was otherwise normal apart from a clearly swollen left lower extremity accompanied with engorged superficial veins, hyperpigmentation and trophic skin changes. On palpation, there was no tenderness of his left calf muscles and no venous ulcerations were observed. As regards neurological examination it was also unremarkable including the muscle tone, reflexes, coordination and sensation as well as power, in all muscle groups.\u00a0Afterwards, the patient was immediately evaluated on the basis of fundoscopic examination that revealed left retinal whitening, macular edema and cotton-wool spots compatible with CRAO Figure . The aboOnce CRAO with sparing of cilioretinal artery diagnosis had been made, a meticulous investigation was performed in order to unwind the thread of this unanticipated thromboembolic event.Routine hematological and biochemical investigations were unremarkable barring the slightly elevated creatinine and urea levels, up to 1.6 mg/dL and 60 mg/dL respectively, but accordant with a prolonged history of chronic kidney disease stage III with GFR estimated at 46ml/min/1.73m2. Inflammatory markers (C- Reactive Protein and Erythrocyte Sedimentation Rate) and clotting parameters including d-dimers and fibrinogen levels were within normal values. Further investigation for autoimmune diseases, occult infectious conditions and thrombophilic disorders were also negative. More specifically, thrombophilia testing was performed including factor V Leiden, prothrombin gene mutation, antithrombin III, protein C and protein S, lupus anticoagulant screen as well as antinuclear antibodies, anti-dsDNA antibodies, anti-cardiolipin antibodies (ACA) and anti-beta 2 glycoprotein antibodies (anti-\u03b22GPI).Regarding radiological examination, a renal ultrasound confirmed the previously mentioned asymmetrical kidney size and showed a small as well as echogenic left kidney, consistent with the past history of renal infarction without apparent cause. Carotid Doppler ultrasound did not identify any extracranial vulnerable atherosclerotic plaque potentially at risk for disruption and thromboembolic ischemic retinal event. Similarly, abdominal aorta ultrasound imaging and ultrasonographic assessment of renal arteries did not depict any atherosclerotic lesions that could be possibly the source of the reported renal vaso-occlusive event.Venous ultrasound imaging unveiled no relapse of the previously recorded deep vein thrombosis although the diagnosis of post-thrombotic syndrome was made on the basis of post-thrombotic popliteal valve incompetence accompanied with significant reflex at the same level. Residual thrombi were also recognized mainly in the left popliteal vein and partially recanalization of both popliteal and gastrocnemius veins was described. Residual thrombi in left popliteal vein raised the question of whether a paradoxical embolus could explain not only the CRAO event but also the past embolic event in renal artery circulatory system.With the completion of these steps, a meticulous cardiologic examination was undertaken and included 48-hour Holter monitoring and transthoracic echocardiography followed by bubble contrast echocardiography testing. Holter monitoring results excluded the possibility that CRAO event could be correlated with an obscured supraventricular arrhythmia, predominantly an episode of paroxysmal and symptomless atrial fibrillation. Transthoracic echocardiography examination also eliminated the option that the embolic event originated from a cardiac valvular defect. Surprisingly, bubble contrast echocardiography testing revealed more than 25 saline microbubbles in the left atrium of the heart at the first three cardiac cycles while the patient was asked to perform a Valsava maneuver in a quarter of the population .The frequency and significance of PFO in association with ocular circulatory disturbances were evaluated in forty patients with acute arterial occlusions of the posterior bulb segment through transthoracic and transesophageal echocardiography by Steuber and colleagues . PFO wasCertainly, the emerging association between undiagnosed PFO and retinal artery occlusion has been predominantly reported in young patients. An example of this is the report of a 35-year-old man with branch retinal artery occlusion (BRAO) and concomitant PFO, which was firstly diagnosed during the evaluation of BRAO, by Chatziralli and colleagues . In a siHence, it could be conceivably argued that retinal artery occlusion in an otherwise healthy adult patient, should always consider the PFO as a differential that requires meticulous cardiologic examination. Despite the fact that transesophageal echocardiography (TEE) is a potentially useful and effective tool for detecting possible sources of retinal artery emboli , in our Patent foramen ovale (PFO) is a common congenital intracardiac defect that can cause right-to-left shunting under certain conditions and may predispose individuals to paradoxical embolic events from the venous to arterial district. Rarely, PFO has been correlated to central retinal artery occlusion and branch retinal artery occlusion with visual sequelae not only in young but also in advanced-aged patients at low atherosclerosis or cardioembolic risk, concomitant with a propensity for deep vein thrombosis."} {"text": "Pharmacoresistance and adverse drug events designate a considerable group of patients with focal epilepsies that require alternative treatments such as neurosurgical intervention and neurostimulation. Electrical or magnetic stimulations of cortical brain areas for the treatment of pharmacoresistant focal epilepsies emerged from preclinical studies and experience through intraoperative neurophysiological monitoring in patients. Direct neurostimulation of seizure onset zones in neocortical brain areas may specifically affect neuronal networks involved in epileptiform activity without remarkable adverse influence on physiological cortical processing in immediate vicinity. Noninvasive low-frequency transcranial magnetic stimulation and cathodal transcranial direct current stimulation are suggested to be anticonvulsant; however, potential effects are ephemeral and require effect maintenance by ongoing stimulation. Invasive responsive neurostimulation, chronic subthreshold cortical stimulation, and epicranial cortical stimulation cover a broad range of different emerging technologies with intracranial and epicranial approaches that still have limited market access partly due to ongoing clinical development. Despite significant differences, the present bioelectronic technologies share common mode of actions with acute seizure termination by high-frequency stimulation and long-term depression induced by low-frequency magnetic or electrical stimulation or transcranial direct current stimulation. Epilepsies are characterized by unpredictable seizures and affect more than 70 million people worldwide Beghi . Focal sPharmacoresistance and TEAEs designate a considerable group of patients with focal epilepsies that requires alternative treatments such as neurosurgical intervention and neurostimulation. Whereas neurosurgical resection can only be applied to non-eloquent brain areas in a minority of patients that compared repetitive TMS with sham or placebo controls in the period from 2014 to 2018 as compared to the meta-analysis done in 2014 by the same group on a localized epileptic focus was significantly larger than in the sham patients (17%) (Xia and Storm LFS induces LTD by N-Methyl-D-aspartate (NMDA) receptor activation and the subsequent slight increase in CaNoninvasive cathodal tDCS is suggested to provoke transient and long-term effects on cortical excitability (Antal et al. Electrical or magnetic stimulations of cortical brain areas for the treatment of pharmacoresistant focal epilepsies emerged from preclinical studies and experience from intraoperative neurophysiological monitoring in patients Table . Noninva"} {"text": "Oregon\u2019s Behavioral Health Initiative for Older Adults and People with Disabilities is entering its fifth year. This novel state-level Initiative seeks to better coordinate services and resources for older adults and people with disabilities who have behavioral health needs by assigning a Behavioral Health Specialist (BHS) for every 60,000 adults 65 + and embedding them within local service agencies around Oregon. BHS primary job functions include improving coordination and collaboration between local service agencies, providing complex case consultations (CCC), and delivering workforce development training and community education. Five years of data from Portland State University\u2019s Institute on Aging\u2019s ongoing evaluation of the Initiative suggests significant impact in terms of workforce development trainings, community education, and new community partnerships. Data are collected from BHS and Initiative stakeholders . Data collection tools include quarterly reports from the BHS, including a CCC reporting instrument; semi-structured interviews with stakeholders assessing Initiative involvement; and an electronic post-training survey (and two-month follow-up survey) for stakeholders attending BHS trainings. After five years, the evaluation appears to show the Initiative has delivered an abundance of innovative collaborations, workforce trainings, and educational opportunities aimed at better supporting the behavioral health of older Oregonians. It also highlights several persistent systemic barriers including a need for additional public funding of behavioral health, the challenges of accessing Medicare for behavioral health, and siloed agencies and organizations. Future evaluative efforts could explore adding outcomes-based assessments of the Initiative, including local-level quality improvement projects initiated by BHS within their communities."} {"text": "Cytokine storms, defined by the dysregulated and excessive production of multiple pro-inflammatory cytokines, are closely associated with the pathology and mortality of several infectious diseases, including coronavirus disease 2019 (COVID-19). Effective therapies are urgently needed to block the development of cytokine storms to improve patient outcomes, but approaches that target individual cytokines may have limited effect due to the number of cytokines involved in this process. Dysfunctional macrophages appear to play an essential role in cytokine storm development, and therapeutic interventions that target these cells may be a more feasible approach than targeting specific cytokines. Nanomedicine-based therapeutics that target macrophages have recently been shown to reduce cytokine production in animal models of diseases that are associated with excessive proinflammatory responses. In this mini-review, we summarize important studies and discuss how macrophage-targeted nanomedicines can be employed to attenuate cytokine storms and their associated pathological effects to improve outcomes in patients with severe infections or other conditions associated with excessive pro-inflammatory responses. We also discuss engineering approaches that can improve nanocarriers targeting efficiency to macrophages, and key issues should be considered before initiating such studies. Circulating levels of pro-inflammatory cytokines correlate with the severity of many infections. Severe infections can result in uncontrolled immune responses accompanied by excessive release of pro-inflammatory cytokines, frequently referred to as a \u201ccytokine storm\u201d, that can be responsible for a significant degree of the pathology and mortality associated with severe infections Effective therapeutic strategies to prevent or suppress cytokine storms and attenuate their effects, or other conditions prone to this response, during severe infection do not yet exist Macrophages and related monocyte-lineage immune cells, which reside in most body tissues and play essential roles in regulating cytokine-mediated inflammatory responses and innate and adaptive immune reactions, are good potential targets for such strategies In this mini-review, we focus on the pathology of cytokine storms in severe infections, highlight the role of macrophage dysfunction in this process, and discuss nanomedicine-based therapies that could be used to target macrophage dysfunction to improve clinical outcomes in patients with severe acute infections.via chemotaxis in response to concentration gradients Many cytokines released during pro-inflammatory immune responses can activate specific leukocyte populations and target their recruitment to sites of inflammation e.g., CCL2 and CCL3) that promote local accumulation of other pro-inflammatory immune cells, including neutrophils, monocytes, and dendritic cells that can release more cytokines and reactive oxygen species to increase the severity of lung injury The term cytokine storm, first used in 1993 in reference to runaway inflammatory responses in graft-versus-host disease Most individuals are vulnerable to SARS-CoV-2 infection, but can exhibit a broad range of symptom severity, and several risk factors are associated with cytokine storm development, including age (> 60 years old), smoking, poor nutrition and pre-existing conditions that can affect immune responses, including obesity, diabetes, hypertension, cardiovascular and chronic lung disease, and cancer No specific therapeutic strategies have yet been developed to attenuate cytokine storm mediated pathology, despite the established link between cytokine storms and disease pathology and mortality.COVID-19 offers a compelling example of the effect of cytokine storms on pathology and mortality. The precise mechanisms responsible for the pathological changes observed in severe COVID-19 cases are not well understood, but several studies have reported that most patients with severe pathology have markedly elevated circulating levels of multiple pro-inflammatory cytokines, including IL-1, IL-6, IL-8, IL-21, TNF-\u03b1, and MCP-1 Macrophages are multifunctional and heterogeneous innate immune cells that reside in most tissues and play essential roles in innate immunity, the regulation of adaptive immunity, and pro-inflammatory responses to control the virulence and pathology of infectious diseases in vitro characterization studies Macrophages act as an initial defense against infection Macrophages can also display pathogen-derived proteolytic peptides on their type I and type II major histocompatibility complexes (MHCI and MHCII) to activate T lymphocytes that recognize these peptides and initiate a pathogen-specific adaptive immune response A rapid and well-coordinated innate immune response is the first line of defense against infection, but excessive immune responses can cause local and systemic tissue dysfunction and damage Figure 1) + macrophages containing SARS-CoV-2 nucleoprotein, which exhibit IL-6 up-regulation, have also been detected in the spleen and lymph node marginal sinuses of patients who died from COVID-19 Macrophage dysfunction can initiate uncontrolled cytokine release leading to the development of cytokine storms observed in many severe infectious diseases, including SARS and COVID-19 family Macrophage dysfunction also plays important roles in the pathology of other infections caused by viral and microbial pathogens, particularly when these infections progress to sepsis, due to overlap of monocyte/macrophage responses to these pathogens. Macrophages are normally activated in response to recognition of danger-associated stimuli produced upon recognition of various components of viral and bacterial pathogens (PAMPs) via therapies that exhibit macrophage-specific or -selective toxicity; (ii) inhibiting macrophage invasion to limit inflammatory responses at disease sites by blocking chemotactic monocyte surface receptors Both clinical and experimental findings strongly suggest that dysfunctional macrophages are a major source of inflammatory cytokines in severe infections, and thus therapeutic interventions that target these macrophages may prove beneficial in attenuating cytokine storms that contribute to the increased pathology and mortality of severe infections. Therapeutic approaches designed to manipulate macrophage responses using conventional drug delivery mechanisms have been studied in preclinical models of inflammatory diseases and cancer Table 1).Nanomedicine, the medical application of nanotechnology, has emerged as a powerful platform to resolve issues associated with conventional therapeutics, including bioavailability, tissue specificity, and toxicity in vitro studies indicate that some nanoparticles are also preferentially engulfed via clathrin- or caveolin-mediated endocytosis mechanisms via different approaches that add macrophage-specific molecules to their surfaces Nanoparticles employed for macrophage targeting approaches can vary markedly in their origin and composition, but macrophage uptake generally occurs through one of two distinct pathways: non-specific phagocytosis (passive targeting) regulated by nanoparticle physical properties, or receptor-mediated endocytosis (active targeting). Passive targeting is usually responsible for macrophage uptake of unmodified nanoparticles of medium size (10~300 nm diameter), which include most extracellular vehicles (EVs) and liposomes. These nanoparticles primarily accumulate at infection or inflammation sites as a result of phagocytosis and/or macropinocytosis by monocyte/macrophage-lineage cells that are abundantly present at these sites Figure 1). These studies used synthetic liposomes, FDA-approved nanocarriers composed of one or more lipid bilayers surrounding a hollow core that can contain therapeutic cargoes via disruption of the mitochondrial electron transport chain and cytosolic release of cytochrome C At least two studies have now examined the efficacy of nanoparticle-mediated drug delivery to transiently deplete macrophages to attenuate dysfunctional macrophage responses . EVs are natural nanoparticles (~50-500 nm) that facilitate cell-to-cell communication, and are readily engulfed by circulating monocytes and tissue resident macrophages following their infusion into mouse models of human disease ex vivo model in which perfused human lungs rejected for transplant were injured by E. coli exposure to induce severe bacterial pneumonia e.g., miR-21, miR-124) and proteins shuttled by MSC-EVs Other studies examined the potential of unmodified EVs with anti-inflammatory properties to suppress macrophage dysfunction e.g., solid-lipid, polymeric, or metallic nanoparticles) using this strategy have been developed for macrophage-targeted drug delivery in models of inflammatory and infectious diseases Functionalizing nanoparticle therapeutics with ligands or peptides that have high affinity for extracellular macrophage membrane factors can enhance their specific uptake to attenuate dysfunctional macrophage responses , which contain viral coat proteins but lack viral genetic material, have recently been considered as nanoparticle platforms for drug delivery, imaging, and vaccine approaches A growing body of evidence indicates the potential of macrophage-targeted nanomedicines to reduce excessive cytokine production during severe infection. We therefore believe that nanomedicine approaches designed to regulate macrophage-mediated inflammatory responses should receive greater consideration as alternative therapies for conditions where macrophage dysfunction has the potential to induce a cytokine storm and its associated pathological effects. To the best of our knowledge, studies have yet to examine the therapeutic potential of macrophage-targeted nanomedicines in animal models of COVID-19, the most recent disease where cytokine storms have been shown to play a central role in disease pathology and mortality. At minimum, we propose that EV and liposome studies should be performed using commercially available human ACE2 (hACE2) transgenic mice, which can serve as a model of human COVID-19 disease, to clarify whether nanomedicine-mediated macrophage depletion or attenuation of macrophage activation is beneficial in severe COVID-19 disease. Nanomedicine delivery approaches may also be useful to increase the targeted bioavailability or reduce potential side effects of anti-inflammatory small molecule drugs and antibody therapeutics currently under investigation for treatment of COVID-19 in clinical trials. It will be important to comprehensively evaluate the therapeutic effects of these and other potential nanomedicines using clinically relevant indicators, including, but not limited to, effects on survival, lung lesions, and cytokine profiles.e.g., at or immediately prior to the hyperinflammatory phase), to have a beneficial effect, since suppression of the innate immune response in the early phase virus infection is likely to be harmful. Since cytokine storm development can be highly dynamic during severe infections, serial evaluation using a well-designed cytokine panel is necessary to determine the most effective therapeutic period and the specific effects of an intervention. Combination therapies that employ both nanomedicines and conventional antiviral drug delivery may also provide synergistic beneficial effects. Finally, it is also necessary to address the potential for increased risk of immune disorders and bacterial infections that may be associated with any strategy to deplete macrophages or attenuate their activity. Even if data from animal models proven to be promising, additional preclinical studies are required to address biosafety, mechanisms of action, and optimal administration routes and doses. Clinical translation will also require the development of nanomedicine manufacturing approaches with standard processes and quality control early in these studies. The massive degree of collaboration now ongoing across diverse disciplines and industries, offers hope for an unprecedent rate of development for new therapies and therapeutics to combat severe infectious diseases such as COVID-19. We believe that novel nanomedicine approaches are a worthy target of such efforts.Some key issues should be considered before initiating such studies, however. Macrophage-targeted nanomedicines may need to be given at the correct stage of infection ("} {"text": "Despite recommendations to include a distinct intervention phase in Adult Protective Services (APS), most APS programs close cases following investigation/substantiation phases without engaging in a defined intervention phase. This study implements and evaluates a novel APS service planning/intervention model in the state of Maine. Using an experimental efficacy trial design with stratified random sampling at the level of Maine APS offices, this study compares standard APS care with an enhanced/integrated APS intervention model involving \u201celder advocates\u201d. Advocates were trained in motivational interviewing, supported decision-making, teaming, restorative justice, and goal attainment scaling to develop capacity to work with both the older adult victim and perpetrator and to strengthen the family and social systems surrounding the victim-perpetrator dyad. This presentation will present results on the efficacy of this integrated APS/elder advocate model and discuss the challenges and successes in conducting elder abuse intervention research in collaboration with APS and APS clients. Part of a symposium sponsored by Abuse, Neglect and Exploitation of Elderly People Interest Group."} {"text": "Unconventional oil and gas exploration generates an enormous quantity of wastewater, commonly referred to as flowback and produced water (FPW). Limited freshwater resources and stringent disposal regulations have provided impetus for FPW reuse. Organic and inorganic compounds released from the shale/brine formation, microbial activity, and residual chemicals added during hydraulic fracturing bestow a unique as well as temporally varying chemical composition to this wastewater. Studies indicate that many of the compounds found in FPW are amenable to biological degradation, indicating biological treatment may be a viable option for FPW processing and reuse. This review discusses commonly characterized contaminants and current knowledge on their biodegradability, including the enzymes and organisms involved. Further, a perspective on recent novel hybrid biological treatments and application of knowledge gained from omics studies in improving these treatments is explored. Technological advances have led to unprecedented growth in unconventional oil and gas extraction in the US over the last few decades . This enCurrent disposal methods mainly rely on reinjecting FPW into newly drilled wells or disposal into deep Underground Injection wells. Disposal into underground injection wells irreversibly removes water from the hydrological cycle and has raised concerns due to induced seismicity . AlternaAmong the 1,198 chemical compounds identified in FPW, only 14% have existing toxicity data and 24% can be detected through standard analytical methods . PresencThis review aims to summarize recent trends in biological treatment of FPW with an emphasis on organic contaminants and microbial groups involved in their degradation . We brie1, are fairly well-documented and generally involve gas chromatography paired with mass spectrometry (GC-MS), the methods developed for surface and groundwater have to be modified to account for the complex matrix in FPW using non-targeted Liquid Chromatography-Electrospray Ionization-Mass spectrometry (LC-ESI-MS) approaches, many of which provide semi-quantitative estimation of identified compounds , especially Benzene/Toluene/Ethyl Benzene/Xylenes (BTEX), are the most commonly analyzed hydrocarbons in FPW with concentrations varying from a few ormation . BTEX arormation . Microbiormation . However+) as the dominant cation, with calcium (Ca2+), magnesium (Mg2+), and potassium (K+) as minor cations, and chloride (Cl\u2013) as the major anion, along with small amounts of bicarbonate . Trace m (SO42-) . Though A meta-analysis of published data on biological treatment of oilfield wastewater found average COD removal in actual wastewaters to be about 74% when TDS was low . IncreasTreatment of a complex matrix like FPW should not only meet the requirements of the intended application but also be cost-effective. TDS greater than 40,000 mg/L leads to elevated desalination costs, thus, low TDS western brines are more likely to be treated and reused .Experiments simulating a PW spill on soil concluded that the high salt content of PW can disrupt soil structure and mobilize metal ions like copper, lead, aluminum and manganese during subsequent rainfall events . StudiesHF involves addition of several chemicals to water that regulate viscosity to perform various functions ranging from generating fissures to ensuring smooth flowback from the formation . Among aBiocides are added to prevent biofouling by sulfate-reducing bacteria during HF and to prevent growth of microbes that clog the pipelines during gas production . BiocideGA, a non-oxidizing, electrophilic biocide, inactivates bacteria by crosslinking amines present on bacterial membrane proteins . HypersaDBNPA is the second most commonly used biocide , howeverPseudomonas are frequently used amphiphilic biocides that have been found to persist in FPW . Benzalkudomonas , Thalassiabensis isolatedpduCDE) from dominant Firmicutes was predicted to be responsible for surfactant degradation under anaerobic conditions. In another study on PEG and PPG degradation under aerobic conditions in sediment-groundwater microcosms amended with PW mapped to Halanaerobium in PW samples and in laboratory experiments with an isolate, Halanaerobium congolense WG10.Non-ionic surfactants, including both unsubstituted polyglycols [Polyethylene glycol (PEG) and Polypropylene Glycol (PPG)] and substituted ethoxylates [Alkyl ethoxylates (AEOs) and Nonylphenol ethoxylates (NPEOs)], are employed as emulsifiers, corrosion inhibitors and crosslinkers in HF. These surfactants are generally present as a mixture of homologs and are identified by calculation of Kendrick mass defect from LC-MS data . A few r with PW , authorsin situ. Reaction with persulfate (added as a breaker in the fracturing fluid) and other abiotic processes were implicated in the production of these halogenated organic compounds, along with biotic transformation by iodide-oxidizing bacteria, specifically Roseovarius spp. HF operations, those based on oilfield PW with comparable TDS have also been included. The reactor configurations and dominant microbial groups identified are summarized in Activated sludge (AS) systems are the most popular form of biological reactor for wastewater treatment around the globe. A typical AS system consists of an aerated tank for mixing microbial biomass with wastewater, followed by a settling/sedimentation unit to separate biomass (sludge) from treated water. Such systems are operated in continuous flow conditions and a portion of the settled sludge is often recycled back into the aeration tank. A sequencing batch reactor (SBR) consists of a single tank to perform all the steps of an activated sludge and hence is operated in a batch mode. Both these approaches have been used to treat FPW, and a few studies have investigated the microbes found in these systems.Pseudomonas, Ochrobactrum, Corynebacterium and Burkholderia were major bacterial groups identified from the reactor sludge using a Biolog MicrologTM System.Cellvibrionaceae, Rhodocyclaceae, Rhodobacteraceae, and Phyllobacteriaceae were some dominant groups that were found to be enriched at a TDS of 50,000 mg/L.A typical membrane bioreactor (MBR) consists of an aerated tank containing sludge fed with wastewater and a submerged membrane module to filter out the treated effluent. In high salinity wastewater like PW where bacterial floc formation is disrupted, MBRs can overcome the floc settling requirement and retain the biomass in the reactor.A lab-scale MBR was acclimated to high salinity in phases using PW from different wells to investigate impact of salinity on the microbial community . Upon inIdiomarina genus and Rhodospirillaceae family in Sample A1/2 and B, respectively.Emulating the naturally occurring stratified microbial consortia (or mats) often found in hypersaline environments, engineered microbial mats have been grown and evaluated for PW treatment in the laboratory. Biological treatability of PW samples from Utica and Bakken shale was also studied using microbial mats . These sBiologically active filters (BAF) employ microbial biofilms attached to a filter media (most commonly activated carbon) to adsorb and degrade organic compounds in wastewater along with removal of suspended solids. BAF successfully removed organic matter from three different wastewaters with varying salinity and organic composition (DOC: 35.6\u2013732 mg/L) as a pretreatment to ultrafiltration and nanofiltration . This BAFlavobacteria (predominantly genus Fluviicola) and Gammaproteobacteria) over non-aerated filters .The scalability of BAF was tested using bench-scale and lab-scale columns fed with different wastewaters under different operating conditions like aeration, pretreatment, operating temperature and empty bed contact time . AeratioBioelectrochemical systems (BES) can simultaneously achieve reduction in organic carbon and salinity, making them a promising technology, and an advancement over other biological systems to treat PW. BES harness the microbial capacity to degrade organic compounds anaerobically to generate electrons. These electrons can then be transported, via a pair of electrodes (anode to cathode), to terminal electron acceptors like oxygen or the system can be maintained anaerobic to produce hydrogen.Several configurations of BES have been tested to treat PW. Microbial Fuel Cell (MFC) is the simplest design consisting of two electrodes separated by an ion-exchange membrane in which the wastewater to be treated is added to the anode. Microbial Desalination Cell (MDC) is a modification of MFC with a pair of ion exchange membranes between anode and cathode resulting in three chambers. Microbial Capacitive Desalination Cell (MCDC), like MDC, has three chambers but the middle chamber contains electrodes for Capacitive Deionization. These electrodes have a large surface area that adsorbs organic and inorganic ions under applied electrical potential . On the MCDC desalinated 18 times faster than MDC and 5 times faster in COD removal during treatment of Piceance basin PW . A literHalanaerobium prevalens and Marinobacter hydrocarbonoclasticus, both originating from the PW (Cyanobacterium aponinum and Parachlorella kessleri) with halophilic bacteria could grow in PW over a wide range of salinities and the harvested algal biomass was suitable for biodiesel production. Researchers are now looking beyond traditional methods to treat FPW. l value) . HopkinsThough biological treatment of FPW is promising and can be initiated with a readily available inoculum , most reactors need lengthy acclimation periods which may not be practical for a field-operating full-scale reactor. Reactor parameters such as temperature, mixing/oxygenation and retention time will affect both reactor performance and community composition. Faster, more effective strategies are needed to achieve a consortium that can both tolerate the varying inorganic and organic composition of FPW and efficiently remove chemically diverse contaminants. Biological processes also have the potential to create new potentially harmful contaminants, e.g., iodinated organic compounds detected in the effluent of a BAF attributed to the activity of iodide-oxidizing bacteria . Thus, iRoseovarius was shown to be capable of leaching gold from its ore in the presence of iodide, in a process more ecofriendly than traditional cyanide leaching , particularly the dominant phosphate-accumulating organism is (CAP) . In factis (CAP) . That stis (CAP) .Another application of metagenomics and metatranscriptomics to wastewater treatment involved studies of reactors degrading terephthalate, a plastics byproduct, where a preliminary multi-organism pathway postulated based on early metagenome sequencing efforts was later expanded upon with a complex network of cross-feeding relationships that highlights the multilayered nature of these systems . FinallyHalanaerobium and methanogenic archaea during later PW, when anoxic conditions develop and TDS rises , were described based on their genomes, which in turn explained the changes in key metabolites observed in the samples collected. Viral predation of these major groups was also implicated in community dynamics and nutrient cycling. Further research revealed the viral (phage) diversity in shales and phage-induced lysis of dominant Halanaerobium was shown to release intracellular metabolites that support microbes in such ecosystems have further shed light on microbes that reside in shale with the help of metagenomics and metabolite profiling combined with supporting laboratory experiments. osystems . As a byaerobium , Frackibkibacter , Marinobnobacter , Methanolophilus , and Arccobacter \u2013 have bin silico tests. Thorough molecular characterization of bioreactor communities with varying performance combined with machine learning could identify biomarkers of successful treatment and potentially enable current monitoring strategies to be augmented or even replaced by molecular methods, allowing early warning of adverse events affecting reactor performance. Eventually, molecular methods will become a key part of a wastewater engineer\u2019s toolkit.On the other hand, there are few metagenomic studies on bioreactors optimized to treat FPW or even petroleum refinery wastewater. Molecular-level understanding of FPW treatment, however, is critical to successfully targeting multiple high-priority contaminants under a wide range of environmental conditions. Accurate, predictive models of FPW treatment bioreactors would dramatically accelerate optimization by replacing empirical manual parameter adjustments with rapid Treatment of FPW is challenging due to its complex chemical composition coupled with geographical and temporal variability. The low cost and effective treatment options offered by biological treatment systems in treating municipal wastewater have made them ubiquitous. Only in the past decade have we been able to understand core microbes and microbial processes behind treatment efficacy and resilience of these systems to shocks and overloads. Many studies have shown that FPW is amenable to biological treatment and different treatment modules to treat FPW have been discussed. Several studies indicate halophiles are effective for FPW treatment, but a systematic study to identify these halophiles during operation of a reactor and understand the key degradation pathways is not available. Omics guided study of core microbes should aid in constructing a core microbial community with broad metabolic potential to handle diverse contaminants and salinities as are common in FPW. Aided with optimized reactor design and robust microbial communities, a hybrid decentralized treatment module capable of handling fluctuations in composition as well as quantity of FPW could be a reality. Such a system could reduce the impacts of accidental release, promote a sustainable hydrological cycle and safeguard the environment.SA wrote the manuscript with inputs and edits from ST and RC. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "A 59-year-old man fell onto his outstretched hands. He was diagnosed with a left-sided transscaphoid transcapitate perilunate fracture-dislocation in the setting of previous scaphoid open reduction internal fixation (ORIF), resulting in a nonunion and scaphoid nonunion advanced collapse (SNAC). Wrist salvage in the form of primary partial wrist fusion was performed and resulted in excellent clinical and functional outcomes.What are perilunate dislocations and/or perilunate fracture-dislocations?What physical and radiologic examination findings are typically encountered with perilunate dislocations and fracture-dislocations?How are perilunate dislocations and fracture-dislocations managed?When a perilunate fracture-dislocation presents in the setting of previous scaphoid nonunion and SNAC wrist, what is the best surgical option to give the best functional outcome?Perilunate dislocations and fracture-dislocations are debilitating wrist injuries resulting from high-energy trauma. Dislocations can be purely ligamentous or involve a combination of bony and ligamentous structures. When involving only ligaments surrounding the lunate, these dislocations are referred to as lesser arc injuries. When the dislocation is associated with a radial styloid or carpal bone fractures, they are referred to as greater arc injuries.Physical examination often reveals a grossly swollen wrist with limited range of motion with or without signs of acute median neuropathy. The presence of acute carpal tunnel syndrome is an indication for urgent operative intervention if closed reduction has failed. Posteroanterior radiographic evaluation may demonstrate alteration of Gilula's lines with loss of carpal height . There m,Surgical correction involves acute carpal tunnel decompression, relocation of the carpus, repair of the capsular rent, and stabilization of the carpus with percutaneous pin fixation. Controversy exists whether acute scapholunate ligament reconstruction should be performed.4We present a case of a patient who suffered a transscaphoid transcapitate perilunate fracture-dislocation in the setting of a prior scaphoid nonunion and SNAC wrist. Radiographs revealed a greater arc injury with transmission of force through the previous scaphoid nonunion site, resulting in displacement of the cannulated screw from the proximal pole of the scaphoid and 2. S"} {"text": "Understanding food web responses to global warming, and their consequences for conservation and management, requires knowledge on how responses vary both among and within species. Warming can reduce both species richness and biomass production. However, warming responses observed at different levels of biological organization may seem contradictory. For example, higher temperatures commonly lead to faster individual body growth but can decrease biomass production of fishes. Here we show that the key to resolve this contradiction is intraspecific variation, because (i) community dynamics emerge from interactions among individuals, and (ii) ecological interactions, physiological processes and warming effects often vary over life history. By combining insights from temperature-dependent dynamic models of simple food webs, observations over large temperature gradients and findings from short-term mesocosm and multi-decadal whole-ecosystem warming experiments, we resolve mechanisms by which warming waters can affect food webs via individual-level responses and review their empirical support. We identify a need for warming experiments on food webs manipulating population size structures to test these mechanisms. We stress that within-species variation in both body size, temperature responses and ecological interactions are key for accurate predictions and appropriate conservation efforts for fish production and food web function under a warming climate.This article is part of the theme issue \u2018Integrative research perspectives on marine conservation'. A key link in these feedbacks underlying observed warming responses is population size structure, because of how it arises from, as well as influences, individual body growth and survival figures\u00a0a and 2."} {"text": "Complication in acute kidney injury (AKI) is significantly associated with developing acute respiratory failure (ARF), while ARF is one of the most important risks for AKI. These data suggest AKI and ARF may synergistically worsen the outcomes of critically ill patients and these organ injuries may not occur independently. Organ crosstalk between the kidney and the lung has been investigated by using animal models so far. This review will focus on innate immune response and neutrophil activation among the mechanisms that contribute to this organ crosstalk. AKI increased the blood level of an inflammatory mediator in high-mobility group box 1, which induces an innate immune reaction via toll-like receptor 4. The remarkable infiltration of neutrophils to the lung was observed in animal AKI models. IL-6 and IL-8 have been demonstrated to contribute to pulmonary neutrophil activation in AKI. In addition, the formation of a neutrophil extracellular trap was also observed in the lung after the exposure of renal ischemia reperfusion in the animal model. Further investigation is necessary to determine whether targeting innate immune response and neutrophil activation will be useful for developing new therapeutics that could improve multiple organ failure in critically ill patients. Acute kidney injury (AKI) is a common complication in critically ill patients treated in the intensive care unit (ICU). Reportedly, AKI occurs in ~30\u201360% of patients admitted to the ICU and is associated with significantly poor outcomes including morbidity and mortality . ICU patThough the primary roles are different, lung and kidney functions are intimately related regarding the maintenance of homeostasis. The blood acid-base balance is regulated by carboxy dioxide excretion by the lung and bicarbonate reabsorption by the kidney. A compensative mechanism will activate when one organ fails to keep these levels within a normal range by the other organ. Thus, respiratory complication in AKI patients is particularly important. Clinical studies revealed AKI patients were twice as likely to require invasive mechanical ventilation . On the In this review, we provide a brief overview regarding (1) the clinical data on AKI and ARF/ARDS and (2) the potential mechanisms by which AKI leads to lung injury. Recently identified mechanisms of the innate immune system including toll-like receptors (TLRs) and damage-associated molecular patterns (DAMPs) were evaluated in the kidney-lung crosstalk using animal models. Neutrophil extracellular traps (NETs) was identified as another player in the innate immune response. NETs were also demonstrated to contribute to AKI-induced lung injury.Many clinical studies suggested associations between AKI and ARF/ARDS in critically ill patients. AKI often occurs in ARF/ARDS patients, while ARF/ARDS is often observed in AKI patients. First, clinical data about AKI complication in ARF/ARDS are described below. The secondary analysis of a randomized control trial conducted by the ARDS network reported AKI occurred in ~25% of ARDS patients. The mortality rate of AKI patients was significantly higher than the non-AKI patients . AnotherSecond, ARF/ARDS complication in AKI is described below. Severe ARF requiring MV was observed in more than 70% of AKI patients in a multinational, multicenter prospective observational study. MV requirement was significantly associated with higher mortality . TherefoThird, AKI and ARF/ARDS are organ failures that can be simultaneously complicated in a critically ill patient. An observational study conducted in 18 French ICUs reported ARDS occurrence as 23%, while AKI occurrence was at 31%. Hospital mortality was 14% in this population and it increased to 42% in patients with both AKI and ARDS . In a laThe pathophysiological mechanisms of respiratory failure in patients with AKI can be categorized into inflammatory and non-inflammatory mechanisms . Non-infRabb and colleagues first demonstrated increased inflammatory gene expressions in the lung after exposure of renal ischemia reperfusion injury by using microarray analysis . Faubel Although these studies suggested that the induction of an inflammatory reaction by AKI is involved in lung injury, other studies demonstrated AKI suppressed inflammatory reactions and subsequently worsened pulmonary infection. Neutrophil function against pneumonia was evaluated in the model of bacterial pneumonia in mice complicated with AKI by folic acid administration or glycerol injection (rhabdomyolysis) . NeutropTaken together, increased humoral mediators by reduced clearance and increased expression in AKI seem to contribute to lung injury. On the other hand, few studies revealed the mechanisms of the opposite direction of crosstalk, i.e., ARF/ARDS-induced kidney injury. Slutsky et al. reportedNeutrophil infiltration is a major finding in lung injury induced by AKI. A remarkable neutrophil infiltration in the lung together with increased neutrophil elastase (NE) activity in blood and lung tissues were observed in a mouse AKI model and specific NE inhibitor reduced lung injury . Toll-liin vitro caused by hypoxia stimulated neutrophils to form NETs by extracellularly released histones. In a mouse intestinal ischemia-reperfusion model, extracellular histone accumulation and NETs formation were observed in the liver rather than the intestine , that comprise DNA studded with histones and proteases, including neutrophil elastases . Extracentestine . Extracentestine . Human r animals .These findings above suggest that extracellular histones and NETs formation might be responsible for AKI-induced lung injury, although other pathways of inflammatory mediators such as IL-6 also contribute to AKI-induced lung injury. For the development of new therapeutics against organ crosstalk between the kidney and lung, targeting multiple pathways will be necessary. In addition, extracellular histones and NETs formation have not been sufficiently evaluated in human ARDS and no cThe novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan in December 2019, which has spread around the world. SARS-CoV-2 dominantly affects the respiratory system and recent clinical studies reported AKI as a significant comorbidity in COVID-19 . The celMultiple organ failure frequently observed in critically ill patients was previously considered as the \u201csum\u201d of each organ failure. The sequential organ failure assessment (SOFA) score, which is widely used for evaluating the severity of ICU patients, is calculated by summing up each organ injury score. No consideration for organ crosstalk can be found in these scoring systems. Several clinical studies demonstrated possible organ crosstalk in ICU patients by applying network analysis , 35. As This review covers kidney-lung crosstalk mostly regarding lung injury caused by AKI. The opposite pathological mechanism in which ARF/ARDS causes AKI should also be considered. As described above, only a limited number of basic studies reported possible mechanisms in animal experiments. In clinical studies, ARF/ARDS caused a systemic release of pro-inflammatory mediators , which could induce or worsen AKI .Mechanical ventilation-induced lung injury has been investigated so far. Low tidal ventilation strategy against ARDS is recommended based on evidence obtained by both basic and clinical studies . Does MVAM, NH, and KD contributed to the writing of the manuscript and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Endometriosis, an estrogen-dependent inflammatory disease, is commonly observed in gynecologic practice. Spontaneous hemoperitoneum is a rare but serious complication of endometriosis. Most cases of endometriosis-induced hemoperitoneum are attributable to a ruptured endometrioma or utero-ovarian vessel hemorrhage. We report a case of massive hemoperitoneum secondary to intra-abdominal bleeding from the peritoneal endometriotic deposits with spontaneous abortion that was misdiagnosed as a ruptured ectopic pregnancy.A 36-year-old Korean woman was admitted to our hospital for acute abdominal pain and vaginal bleeding. She was suspected of ruptured ectopic pregnancy on the basis of a positive serum human chorionic gonadotropin test result and ultrasonographic evidence of pelvic fluid collection. During hospitalization, her symptoms deteriorated with peritoneal irritation sign on physical examination, hypotension, and tachycardia. Emergency exploratory laparoscopy was performed and revealed active bleeding from the peritoneal endometriotic deposit, which was treated with laparoscopic electrocoagulation. The patient\u2019s postoperative course was uneventful. Spontaneous abortion was diagnosed on the basis of decreased serial serum human chorionic gonadotropin level estimation.Although rare, gynecologists should consider endometriosis-induced hemoperitoneum with spontaneous abortion in the differential diagnosis in women of reproductive age presenting with a positive serum human chorionic gonadotropin test result and acute abdomen with intra-abdominal bleeding. Endometriosis is an estrogen-dependent inflammatory disease characterized by the deposition of endometrial tissue at extrauterine (ectopic) sites. It is a relatively common condition that mainly affects women of reproductive age . CurrentA 36-year-old gravida 1, para 1 Korean woman presented to our emergency department with a 1-day history of acute abdominal pain and vaginal bleeding. Her physical examination showed lower abdominal tenderness, and her speculum examination revealed a small amount of vaginal bleeding. Her menstrual cycle was regular at 30-day intervals, and her last menstrual period had been approximately 5\u2009weeks prior to presentation.Upon admission, her vital signs were stable . Her laboratory test results showed mild anemia with a serum hemoglobin level of 10.1\u2009g/dl and hematocrit of 29.0%. Her urine pregnancy and serum human chorionic gonadotropin (hCG) (1149 mIU/ml) tests showed positive results.Transvaginal ultrasonography revealed a large amount of complex fluid and material of mixed echogenicity compatible with blood and blood clots in the pelvic cavity. The bilateral ovaries were not well visualized by ultrasonography, and a normal gestational sac was not identified in the endometrial cavity.During her hospitalization, the patient developed pallor with dizziness, and physical examination showed positive peritoneal irritation signs along with hemodynamic instability , necessitating emergency exploratory laparoscopy.Laparoscopy revealed approximately 1800\u2009ml of fresh liquid and clotted blood in the abdominal cavity. After suctioning the blood, we explored the entire abdominal cavity to identify the source of bleeding. Continuous active bleeding was observed from the peritoneal wall of the pouch of Douglas. Excisional biopsy was performed at the site of bleeding, and bleeding was controlled using electrocoagulation . The gold standard for definitive diagnosis remains visual inspection via laparoscopy and histopathological examination of biopsy specimens .Our patient presented with vaginal bleeding and acute abdominal pain and had a positive serum hCG test result. Transvaginal ultrasonography revealed hemoperitoneum without a normal gestational sac in the endometrial cavity. Considering that she presented with a positive serum hCG test result and that her serum hCG level was less than the discriminatory level (3510 mIU/ml), we could not exclude the possibility of a normal intrauterine pregnancy despite the absence of an intrauterine gestational sac on transvaginal ultrasonography . TherefoSeveral complications related to endometriosis that most gynecologists can overlook have been reported. Endometriosis-related spontaneous hemoperitoneum in pregnancy causes increased maternal and fetal morbidity and mortality, and endometriosis-related ascites often cause a diagnostic dilemma due to symptoms similar to an ovarian malignancy \u20135. In adet al. reported a case of hemoperitoneum caused by active bleeding from a peritoneal endometriotic deposit on the pouch of Douglas. The patient presented with sudden onset of lower abdominal pain from day 5 of her menstrual cycle and showed a negative serum hCG test result [Acute abdomen and hemoperitoneum are rarely attributable to intra-abdominal bleeding from endometriotic deposits, and only a few cases have been reported previously in the literature. Togami t result . Mutihirt result .Our patient\u2019s case is similar to the two aforementioned cases in that endometriosis-induced hemorrhage occurred during progesterone withdrawal , 10. TheSeveral studies have reported differences in the incidence of abortion between women with and without endometriosis or the possibility of reducing the incidence of abortion in women treated for endometriosis; however, convincing clinical evidence is unavailable . EndometGynecologists should consider hemoperitoneum secondary to intra-abdominal bleeding from endometriotic deposits with spontaneous abortion, as well as ruptured ectopic pregnancy or intrauterine pregnancy with corpus luteal hemorrhage in women of reproductive age presenting with acute abdomen and hemoperitoneum and a positive serum hCG test result."} {"text": "Widespread transmission of a novel coronavirus, COVID-19, has caused major public health and economic problems around the world. Significant mitigation efforts have been implemented to reduce the spread of COVID-19 but the role of ambient noise and elevated vocal effort on airborne transmission have not been widely reported. Elevated vocal effort has been shown to increase emission of potentially infectious respiratory droplets, which can remain airborne for up to several hours. Multiple confirmed clusters of COVID-19 transmission were associated with settings where elevated vocal effort is generally required for communication, often due to high ambient noise levels, including crowded bars and restaurants, meat packing facilities, and long-stay nursing homes. Clusters of COVID-19 transmission have been frequently reported in each of these settings. Therefore, analysis of COVID-19 transmission clusters in different settings should consider whether higher ambient noise levels, which are associated with increased vocal effort, may be a contributing factor in those settings. Mitigation strategies that include reduction of ambient noise, softer speech practices, and the use of technology such as microphones and speakers to decrease vocal effort will likely reduce the risk of transmitting COVID-19 or other airborne pathogens. They calculated a 0.37% probability that a 10-\u03bcm droplet contains at least one virion, which suggests that the risk of transmission is significantly increased during loud speech when large numbers of respiratory droplets are emitted. Several recent studies have characterized respiratory droplets emitted during different types of speech, which are potential vectors of viral particles. et al., of social distancing impacts on COVID-19 transmission found that closing restaurant dining rooms and bars and/or entertainment centers/gyms led to statistically significant reductions in COVID-19 cases (These findings have important implications for settings with increased ambient noise where elevated levels of vocal effort are required for communication . A recen19 cases . In theiOther settings have also been associated with increased transmission of COVID-19, and there appears to be a significant association between centers of outbreaks and areas of increased ambient noise and/or elevated vocal effort in most cases. Significant outbreaks of COVID-19 have been reported in senior living centers and nursing homes . These lSignificant levels of COVID-19 transmission have also been reported in meat packing plants (These studies reveal that high levels of vocal effort due to increased ambient noise could be an important factor in the airborne transmission of COVID-19 in settings where physical distancing is limited. Broad implementation of countermeasures to promote softer speech and reduce vocal effort could have a significant impact on decreasing emission of potentially infectious respiratory droplets. This has important implications for businesses, schools, and other venues that are implementing policies to reduce the risk of COVID-19 transmission in their facilities.There is substantial evidence that softer speech and decreased vocal effort may have an impact on reducing COVID-19 transmission. This suggests that settings with lower levels of ambient noise may have reduced risks of COVID-19 transmission. Strategies to reduce the risk of COVID-19 transmission may include community-based emphasis on approaches to decrease ambient noise exposures when feasible, combined with steps to promote softer speech practices and reduce vocal effort. Masks and face coverings can provide some protection by filtering infectious respiratory droplets in situations where vocal effort is required , but oth"} {"text": "Medicare home health providers are required to offer family caregiver training; however, there is little information regarding the impact of family caregiver training on home health care intensity. A better understanding of this relationship is necessary to inform development and prioritization of caregiver training interventions in this setting. This research assesses whether and how family caregiver need for training affects care intensity during Medicare home health. We examine 1,217 fee-for-service Medicare beneficiaries who participated in the National Health and Aging Trends Study (NHATS) between 2011-2015 and received Medicare-funded home health care within one year of survey. Using propensity score adjusted, multivariable logistic and negative binomial regression, we model the relationship between family caregiver need for activity-specific training and the number/type of visits received during Medicare home health. We found that older adults whose family caregiver required training on self-care tasks had greater odds of receiving any therapy visits , aide visits , or training visits . Older adults whose family caregiver required training on medication management had greater odds of receiving any nursing visits and incurred 1.06 additional nursing visits. Findings support the importance of connecting family caregivers to training resources. Additionally, findings suggest that home health providers should consider prioritizing training interventions which focus on caregiving activities most closely tied to resource utilization: self-care and medication management."} {"text": "Nonalcoholic fatty liver disease is a major global health concern with increasing prevalence, associated with obesity and metabolic syndrome. Recently, quantitative ultrasound-based imaging techniques have dramatically improved the ability of ultrasound to detect and quantify hepatic steatosis. These newer ultrasound techniques possess many inherent advantages similar to conventional ultrasound such as universal availability, real-time capability, and relatively low cost along with quantitative rather than a qualitative assessment of liver fat. In addition, quantitative ultrasound-based imaging techniques are less operator dependent than traditional ultrasound. Here we review several different emerging quantitative ultrasound-based approaches used for detection and quantification of hepatic steatosis in patients at risk for nonalcoholic fatty liver disease. We also briefly summarize other clinically available imaging modalities for evaluating hepatic steatosis such as MRI, CT, and serum analysis. Nonalcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of metabolic syndrome and is dramatically increasing in prevalence, paralleling the global obesity epidemic Early detection of NAFLD, continuous monitoring, and early therapeutic intervention, such as lifestyle modifications as well as treatment with pharmaceutical agents can improve overall patient outcomes and potentially decrease the economic burden on healthcare costs. Other patient subgroups such as those undergoing chemotherapy or bariatric surgery are at risk of development of fatty liver and may also benefit from monitoring of hepatic fat fraction. Non-targeted liver biopsy remains the gold standard for diagnosis and grading of hepatic steatosis, fibrosis, and inflammation Here, we summarize methods in grading of NAFLD, including non-imaging biomarkers and corresponding scoring systems currently in use for managing hepatic steatosis. We then provide a comprehensive review of imaging in liver fat quantification, focusing on innovative QUS approaches studied in human subjects Table . FinallySeveral non-imaging biomarkers such as electrical impedance tomography Conventional ultrasound is the most common imaging modality for subjective evaluation of hepatic steatosis, with good sensitivity and specificity in detecting moderate to severe levels of steatosis Several QUS techniques have been studied to improve the diagnosis and classification of hepatic steatosis in NAFLD. These include controlled attenuation parameter (CAP) measured by transient elastography (TE) device; attenuation (AC) and backscatter coefficients (BSC); computerized calculation of hepatorenal index (HRI); and ultrasound envelope statistic parametric imaging . Speckle statistics include acoustic structure quantification (ASQ) and Nakagami imaging; QUS spectroscopy; speed of sound (SoS); and shear wave elastography (SWE) metrics such as dispersion and viscosity. Emerging QUS techniques, integrating statistical methods most notably attenuation-based Nakagami imaging and backscatter-derived quantitative ultrasound spectroscopy show promise and could potentially become the noninvasive imaging method of choice in screening, grading, and monitoring NAFLD patients on therapy. These techniques compared to liver biopsy, could be implemented for screening purposes, compared to an ordinal scale, or provide an accurate continuous measurement of liver fat; the latter two would be most useful for the longitudinal follow-up of NAFLD patients to assess treatment response. Limitations of QUS techniques include confounding effects of body habitus and ascites. Further, QUS cannot simultaneously quantify fat in other organs as can be done with MRI based techniques. Finally, multiple simultaneously emerging QUS techniques from different vendors may prohibit widespread-buy in and may limit inter-vendor comparisons.Controlled attenuation parameter (CAP) is the best-studied and clinically available technique for liver fat quantification, with the first clinical studies dating back to 2010 volume, which is significantly larger than the region analyzed through a liver biopsy, decreasing the potential risk for sampling bias. Limitations of CAP include poorly standardized cut-off values in classifying hepatic steatosis and the potential for CAP estimation of hepatic steatosis to be affected by differences in skin-to-capsule ratio, which may also confound other fat quantification methods. Furthermore, although CAP is an ultrasound technique, measurements are obtained without visualization of the liver. Thus, blind estimation of liver fat may result in inadvertent inclusion of masses, vessels, ducts, or uneven steatosis, any of which may limit accurate assessment. As such, there is a need for QUS parameters to be associated with radiological ultrasound machines to overcome these challenges.Measuring CAP has multiple advantages, including simultaneous assessment of hepatic steatosis and fibrosis, which is valuable in predicting progression and treatment strategies in NAFLD. Measurement of CAP is typically performed by a hepatologist in an office setting in less than five minutes. Values are obtained from a 3 Acoustic waves are attenuated differently by steatotic versus normal liver parenchyma, and this difference is quantified in AC measurements. Unlike CAP, AC values are obtained from ultrasound systems Figure . AttenuaBackscatter coefficient (BSC) is another widely studied QUS parameter first described in 1973 In conventional ultrasound, the diagnosis of hepatic steatosis is typically made by comparing the echogenicity of the liver and right kidney in the same image. Multiple factors affect this comparison, including variations in machine parameters such as gain/depth/power, time-gain- compensation settings and patient anatomy such as attenuation caused by rib shadow or subcutaneous fat, etc. These variations can result in variability of results Prior studies have shown an excellent correlation between HRI and fat fraction obtained through MRS Ultrasound-based envelope statistical imaging, also known as speckle statistics, is based on the passive parametrization of ultrasonic speckle patterns using established statistical distributions/models, which in turn relate to the structural and acoustic properties of tissues (scatterer density and size) Nakagami imaging is one of the most popular model-based speckle statistic methods, first introduced in 2000 . Only a few animal studies have explored the utility of spectroscopy techniques in evaluating fatty liver and demonstrated the potential of spectroscopy parameters to detect and characterize steatosis Quantitative ultrasound spectroscopy uses frequency-dependent parameters extracted from raw RF ultrasound data related to characterize tissue microstructures 82Speed of sound (SoS) measurement is a QUS parameter used for evaluating hepatic steatosis, and can be used to characterize tissue properties based on alterations in ultrasound echo wave speeds in various media Transient elastography and SWE are ultrasound-based elastography methods that measure liver stiffness, which have been successfully adopted clinically to detect and classify hepatic fibrosis Hepatic fat fraction estimated by MRS has proven to be an accurate substitute for liver biopsy and noninvasive imaging standard reference for liver fat quantification The MRI-PDFF is a newer method to estimate liver fat utilizing chemical-shift imaging (CSI) in a single breath-hold. Water protons precess faster than fat protons by about 3.5 parts per million (ppm) Hepatic steatosis can be detected with unenhanced and contrast-enhanced computed tomography (CT) when absolute attenuation of the liver is \u2264 40 Hounsfield units (HU), especially when hepatic fat is > 30% In conclusion, nonalcoholic fatty liver disease is a major health issue with a worldwide increase in prevalence, paralleling the global obesity epidemic. Accurate noninvasive alternatives to liver biopsy in evaluating and monitoring levels of hepatic steatosis are have evolved significantly in the past decade. Emerging quantitative ultrasound-based approaches, integrating innovative statistical methods are promising new technologies to non-invasively assess hepatic steatosis."} {"text": "An 85-year-old man with cardiac history notable for atrial fibrillation diagnosed 10 years ago which was being treated with atenolol and warfarin presented to our institution with persistent atrial fibrillation. His echocardiogram showed ejection fraction (EF) of 56%, no regional wall motion abnormalities, mild mitral and pulmonary regurgitation, and trivial tricuspid regurgitation. Despite this treatment, he had recurrent episodes of paroxysmal symptomatic atrial fibrillation with a rapid rate requiring multiple emergency department visits and hospital admissions. Given difficulty to control the rate, he underwent atrioventricular (AV) nodal ablation and leadless pacemaker insertion. Fifteen days after the procedure, he was found to have a severe mitral regurgitation murmur. Leadless pacemakers have been shown to have lesser risk of complications such as pocket infections, endocarditis, pacemaker-induced tricuspid regurgitation, and tamponade. However, this newer technology can lead to significant mitral regurgitation due to iatrogenic LBBB and left ventricular (LV) dyssynchrony.An 85-year-old man presented to our institution complaining of recurrent fever and a mitral regurgitation murmur. He has a past history significant for atrial fibrillation being treated with apixaban status post leadless pacemaker implantation and AV nodal ablation 15 days ago, hypertension, hyperlipidemia, obstructive sleep apnea on continuous positive airway pressure, diverticulosis and diverticulitis, dental caries, melanoma in situ, and persistent pulmonary coccidioidomycosis on fluconazole.He underwent a transthoracic echocardiogram which showed normal left ventricular size and no wall motion abnormalities, LVEF of 56%, severe mitral regurgitation due to incomplete coaptation of the mitral valve leaflets Figures , mild riHis cardiac history is notable for atrial fibrillation diagnosed 10 years ago which was treated with atenolol and warfarin. Despite this treatment, he had recurrent episodes of paroxysmal symptomatic atrial fibrillation with a rapid rate requiring multiple emergency department visits and hospital admissions . Given dGiven the absence of degenerative mitral valve abnormality and no evidence of cardiomyopathy, his diagnosis of new-onset severe mitral regurgitation is the direct result of abnormal electrical conduction related to iatrogenic LBBB due to AV nodal ablation and single-chamber paced rhythm.Mitral regurgitation in majority of cases is related to primary mitral valve diseases such as mitral valve prolapse, endocarditis, or rheumatic heart disease which was not the case in our patient . Mitral In conclusion, given the prior absence of mitral valve abnormality and cardiomyopathy, this diagnosis of new-onset severe mitral regurgitation is the direct result of abnormal electrical conduction related to iatrogenic LBBB due to A"} {"text": "Arterial stiffness assessed by arterial tonometry \u2013 in particular pulse wave velocity and augmentation index \u2013 is associated with increased cardiovascular risk. It is now possible to use cardiovascular magnetic resonance imaging (CMR) for direct imaging of aortic function. This provides a precise assessment of the elastic properties of the aorta within distinct regions of the aorta. We therefore studied what parameters of aortic function are related to arterial tonometry-derived indices of arterial stiffness.We compared aortic stiffness assessed by cardiovascular magnetic resonance (CMR) pulse wave velocity (PWV) based on flow, velocity or acceleration, and aortic distensibility (AD)) to widely used arterial stiffness estimates provided by arterial tonometry (pulse wave velocity (PWVS) and pulse wave analysis (AI)).Thirty young healthy volunteers (aged 23\u201333) underwent tonometry (Sphygmacor) for determination of carotid to femoral PWVS and radial pulse wave analysis for AI estimation. They then underwent CMR to assess aortic elastic properties.Aortic distensibility was assessed from breath-hold ECG-gated, steady state free precession (SSFP) images acquired at the level of the right pulmonary artery through the ascending and proximal descending aorta and through the distal aorta below the diaphragm to determine aortic distensability. Distensibility was calculated as the relative change in area divided by the central pulse pressure.Pulse wave velocity was measured by an ECG-gated, free breathing, spoiled gradient echo phase-encoded acquisition at the same locations as the aortic cine images. Three variations of the transit time method were used for calculation of pulse wave velocity (PWV). Arrival of the pulse wave was defined as a) the foot of the curve of mean blood velocity of the blood during the cardiac cycle b) the foot of the curve of total blood flow during the cardiac cycle c) maximum blood acceleration rate during the cardiac cycle Figure but withAortic pulse wave velocity calculated by all three MR methods yielded an inverse correlation with descending aortic distensibility Figure but PWVSPWVS and AI most closely reflect acceleration-based CMR PWV measurements of overall aortic stiffness. Arterial tonometry has been validated in large scale clinical studies suggesting this CMR method may be most useful for interpretation of clinical risk. Regional and overall aortic measures of elasticity were not strongly related. However, CMR PWV measures inversely correlated with aortic distensibility, suggesting that MR PWV values may provide a closer estimate of local aortic elastic properties."} {"text": "Internal jugular vein (IJV) thrombosis is an unusual condition, especially when it develops bilaterally. This is a case of bilateral IJV thrombosis in a 77-year old female who presented to the emergency department with neck and arm swelling after discontinuing apixaban and undergoing an oropharyngeal procedure. The diagnosis of bilateral IJV thrombosis was made with the use of point-of-care ultrasound to evaluate bilateral jugular vein distention and bilateral upper extremity pitting edema found on her physical examination. A 77-year-old female with a history of atrial fibrillation currently taking apixaban presented to the emergency department (ED) with swelling of her neck and arms for the past seven days. Two weeks prior, she underwent an embolization of a greater palatine pseudoaneurysm, for which she stopped taking apixaban. After being discharged from the hospital, she continued to experience neck swelling, and had an upper extremity ultrasound evaluation which was negative for thrombus. She returned to the ED for worsening neck swelling. She denied shortness of breath, chest pain, fever, or a history of thromboembolic disease. Her physical exam showed pitting edema on bilateral upper extremities and bilateral jugular vein distention. Point-of-care ultrasound was performed on patient\u2019s neck and upper extremities, revealing thrombosis in bilateral internal jugular veins (IJV) as seen in the IJV thrombosis is an uncommon condition and very rare when it occurs bilaterally. Previous studies indicate that it usually occurs in patients with a history of malignancy, oropharyngeal infections, or deep vein thrombosis.What do we already know about this clinical entity?Internal jugular vein (IJV) thrombosis may develop in patients with malignancy or oropharyngeal infections.What is the major impact of the image(s)?IJV thrombosis may develop bilaterally in patients presenting with jugular vein distention without exhibiting the common causes of bilateral thrombosis of the internal jugular veins.How might this improve emergency medicine practice?Point-of-care ultrasound is effective at providing a prompt diagnosis of bilateral IJV thrombosis and should be monitored after anticoagulation is provided.Video.A) Thrombus in the right internal jugular vein (arrow) seen on transverse view. B) Sagittal view of right internal jugular vein thrombus (arrow) with color doppler showing obstruction of venous outflow and turbulence proximal to the thrombus. C) Thrombus in the distal left internal jugular vein (arrow) seen on transverse view. D) Color doppler of the left internal jugular vein thrombus (arrow) showing partial occlusion of the lumen seen on transverse view."} {"text": "Subjective cognitive decline (SCD) is a construct of high interest in aging and dementia because individuals endorsing it are at higher risk of developing cognitive problems. It is unclear how individuals arrive at the judgement that they have SCD. Here we aimed to understand which SCD symptoms give rise to the perception of decline as older adults age. Community-dwelling adults , completed the Subjective Cognitive Decline Questionnaire (SCD-Q) online, using an online crowdsourcing site. The SCD-Q consists of one global question regarding self-perceived decline (yes/no) and 24 questions about everyday functioning which we utilized to form a memory, language, and executive functioning domain score, higher for greater perceived decline. Logistic regression revealed that memory and language domains predicted the likelihood of endorsing SCD for adults aged >64 . Only the memory domain predicted the likelihood of endorsing SCD for adults <63 . Executive functioning domain scores did not play a role in the relationship between SCD likelihood in either age group. The higher the self-perceived memory or language decline, the more likely older adults are to conclude they have SCD. Our results suggest there is an age-related trajectory in how people evaluate their cognition, with younger people only considering memory and older people considering both memory and language. Clinicians should be aware of this trajectory when examining patients with SCD. Executive functions should be specifically queried because they may not emerge from older adults\u2019 self-reported cognitive problems."} {"text": "Engaging in physical activity (PA) in adulthood has multiple protective health effects in later ages. However, unknown are the extent to which PA habits are laid down earlier in life and persist into adulthood, and the extent to which greater opportunities for PA during adolescence stem from differences in socioeconomic status (SES) which then affect opportunities for PA. We investigated potential mechanisms underlying these relationships using the longitudinal Project Talent Twin and Sibling Study (assessments in 1960 and 2014). With this design, we are able to hold genetics constant by modeling relationships between monozygotic twins (who share 100% of their genes) and therefore isolate effects of contextual factors on later-life PA (mean age ~70). We found that higher family SES and sports participation in adolescence predicted PA 55 years later, adjusted for gender and physical limitations. This held true when partialling out genetic variation that could otherwise explain these relationships. More education also predicted later-life PA separately from family SES and partially mediated the effect of family SES on PA. While school-level resources did not predict later life PA, they did associate with adolescent sports participation . Overall, later-life physical activity was influenced by earlier life sports participation and education, with family rearing resources being more important than high school resources. As twin pair correlations suggest gender differences, future research will examine whether family or school resources differentially benefit males or females for later-life physical activity."} {"text": "HighlightsAt the acute phase of epidermal necrolysis, patients requiring mechanical ventilation had more alveolar macrophages and higher alveolar concentrations of IL-13 than age- and sex-matched patients with the acute respiratory distress syndromePatients with epidermal necrolysis also showed longer duration of mechanical ventilation and more frequent ventilator-acquired pneumonia episodesTo the Editor,+ T lymphocytes, monocytes/macrophages, and natural killer cells. Yet, the pathophysiology of respiratory system involvement during the acute phase of EN is not well understood. The current study aimed at exploring the clinical and biological characteristics of acute lung injury during the acute phase of EN in mechanically ventilated patients.During the acute phase of epidermal necrolysis , mucosal lesions involving the tracheo-bronchial tract have been reported , 2 and aThis is a retrospective monocentric cohort study including patients with EN admitted in the intensive care unit (ICU) of the French National Reference Center for EN during 2011 and 2015 who required endotracheal intubation for acute respiratory failure. This observational cohort study was approved by the institutional ethics committee . Patients received information during hospital stay that data abstracted from their medical charts could be used for research purposes.i.e. percent of neutrophils, macrophages and lymphocytes) cell counts were measured as recommended [2 or Fisher tests for qualitative variables and the Mann\u2013Whitney test for continuous variables. Ventilator-associated pneumonia was defined according to the presence of clinical findings suggesting infection along with a radiographic infiltrate that is new or progressive and a positive distal quantitative sample [EN patients were age- and sex-matched with a historical control cohort of patients with pneumonia-associated acute respiratory distress syndrome (ARDS) . As stanommended . Cytokine sample .2/FiO2 ratios both at ICU admission and during ICU stay and lower SOFA scores at admission. Yet, EN patients had longer durations of mechanical ventilation than ARDS patients and underwent more frequent ventilator-acquired pneumonia. Total BAL cell counts were not significantly different between EN and ARDS patients . Patients received information during hospital stay that data abstracted from their medical charts could be used for research purposes.Not applicable.The dataset used during the current study is available from the corresponding author upon reasonable request.All authors declare no competing interest for this work."} {"text": "Previous studies show that physical activity is beneficial for emotional well-being. This study extends prior research by examining whether engagement in physical activity moderates the association between daily stressor severity and daily emotional well-being. We used data from the second wave of the National Study of Daily Experiences, a sub-project of the Midlife in the United States (MIDUS) study. Respondents reported their daily experiences across eight consecutive days. Multilevel models explored concurrent and lagged interaction effects between daily stressor severity and physical activity on negative and positive affect and whether these associations differed by age. Physical activity was measured by engagement in vigorous physical activity for at least 30 minutes. Results showed significant interactions between stressor severity and physical activity on same-day negative and positive affect. Specifically, stressor severity was associated with smaller elevation in daily negative affect on physically active days compared to non-active days . Reductions in daily positive affect were greater on physically inactive days compared to active days . These associations did not differ by age, but additional findings revealed that stressor severity was associated with greater elevation in negative affect among younger respondents than older adults . These results highlight the importance of engagement in physical activity for emotional well-being under stressful situations in daily context."} {"text": "This paper investigated whether experiencing a major asset shock changed the cognitive health trajectories of older adults (aged 65+ at baseline)? There is a robust literature supporting a relationship between potentially modifiable environmental and individual risk factors and cognitive health and emerging literature supporting a relationship between physical health shocks and later-life financial stability in both the US and internationally. This analysis employed six waves of Health and Retirement Study Core Data (2006-2014) to estimate the causal effect of major asset losses in the period of the 2008 financial crisis. We matched respondents using a rich variety of covariates including education, race/ethnicity, income, total assets, chronic health conditions, depressive symptoms, frequency of physical activity engagement, and engagement with religious activities. Using both propensity score-matched growth curve and difference-in-differences models, we found a small, but significant, negative relationship between major asset shocks and total cognition scores. We also identified a significant overall negative effect on total cognition on all older adults in this sample regardless of exposure to asset shocks. Additionally, both the frequency of asset shock exposure and magnitude of effect on total cognition scores was larger for low-income African-American and Hispanic older adults. These findings suggest in part that recovery from large economic crises may be especially difficult for older adults occupying vulnerable socioeconomic positions and that such events may accelerate the cognitive decline of those who are at or near retirement when asset shocks occur."} {"text": "Bos mutus f. grunniens) and cattle (B. primigenius f. taurus)), which resulted in the higher loss. Further, compensation and insurance schemes were dysfunctional, with few households insuring their livestock and receiving compensation for depredated livestock over the past two years. We recommend improving herding practices and the implementation of compensation and insurance schemes to lower the economic loss faced by herders due to predation and creating positive avenues for the co-existence of snow leopards and humans.Conflict between snow leopards and humans across the trans-Himalaya is a pressing conservation concern. Conflict severely impacts the socio-economy of the local pastoralist community and threatens snow leopard survival. We investigated the socio-economic factors influencing such conflict and pastoralist attitudes towards snow leopard conservation using semi-structured interviews for a better understanding of what factors influence the variability in losses among the households in the Narphu valley, Nepal. While snow leopards caused significant losses to impoverished pastoralist households, respondents were generally accepting of their presence due to religious reasons and strict law enforcement. We observed poor herding and guarding practices with households owning larger numbers of total livestock using semi-structured questionnaires targeting herders in the Narphu valley of the Annapurna Conservation Area, Nepal. During the two years (2017/18 and 2018/19), 73.9% of the households interviewed (n = 65) lost livestock to snow leopards, with an annual average loss of two livestock per household. Of the total depredation attributed to snow leopards, 55.4% were yak , 31.7% goat, 6.8% sheep, 3.2% horse and 2.8% cattle. Results from applying Generalized Linear Mixed Models (GLMMs) revealed the total number of livestock owned and the number of larger bodied livestock species as the main explanatory covariates explaining livestock depredation. Forty-one (41%) of all herders considered snow leopard\u2019s preference for domestic livestock as the main factor in livestock predation, whereas only 5% perceived poor herding practice as the main reason for the loss. Our study found poor and changing herding practices in the valley, whereby 71% herders reported careful herding as a solution to snow leopard depredation, and 15% of herders considered the complete extermination of snow leopards as the best solution to the problem. Tolerance levels and awareness among herders towards snow leopard conservation is increasing, mainly due to the Buddhist religion and strict law enforcement within this protected area. We recommend the effective implementation of a community-based livestock insurance scheme to compensate the economic loss of herders due to predation and improved herding practices as the recommended mitigation measures for ensuring livestock security and snow leopards\u2019 conservation in the valley.Livestock depredation across the trans-Himalaya causes significant economic losses to pastoralist communities. Quantification of livestock predation and the assessment of variables associated with depredation are crucial for designing effective long-term mitigation measures. We investigated the patterns and factors of livestock depredation by snow leopards ( Panthera uncia) and Himalayan wolf (Canis lupus chanco) are key mountain species across Himalayan range countries with their presence indicative of a healthy ecosystem . Th. Th17]. The total mean attitude scores of respondents close to zero suggests that local people were very weakly accepting the presence of snow leopards, probably due to the high level of livestock losses by snow leopard . On the We found a decrease in livestock holdings with higher predation from snow leopards over the study period. Herders owning larger livestock size and larger bodied livestock incurred more economic loss due to livestock depredation. The livestock herding trend is decreasing mainly due to livestock predation by snow leopards and outmigration of village youths to urban centers. In order to reduce economic losses, we recommend encouraging small bodied livestock while encouraging other appropriate changes in livestock composition (number and livestock species). Moreover, the effective implementation of a community-managed insurance program, with education toward improvement of herding practices and equitable compensation for depredation losses would help in building positive attitudes among herders for supporting snow leopard conservation and minimize these conflicts in the Narphu valley. Similarly, conservation programs focused on empowering herders through educational programs to improve herding techniques and herder motivations would likely reduce overall losses, especially when livestock are grazed on open pastures or housed in poorly constructed corrals at night. Programs that reduce out-migration of the younger generation and encourage them towards herding could help preserve traditional herding practices in the Narphu valley. For reasons stated above, this paper highlights conflict between snow leopard and humans as a complex phenomenon requiring holistic, multi-pronged approaches for minimizing negative impacts and ensuring positive species coexistence with pastoral-dependent communities."} {"text": "Bats play important roles as pollen disseminators and pest predators. However, recent interest has focused on their role as natural reservoirs of pathogens associated with emerging infectious diseases. Prior to the outbreak of severe acute respiratory syndrome (SARS), about 60 bat virus species had been reported. The number of identified bat viruses has dramatically increased since the initial SARS outbreak, and most are putative novel virus species or genotypes. Serious infectious diseases caused by previously identified bat viruses continue to emerge throughout in Asia, Australia, Africa and America. Intriguingly, bats infected by these different viruses seldom display clinical symptoms of illness. The pathogenesis and potential threat of bat-borne viruses to public health remains largely unknown. This review provides a brief overview of bat viruses associated with emerging human infectious diseases."} {"text": "Coronary angiography (CAG) sometimes shows nonobstructive coronary arteries in patients with suspected angina or acute coronary syndrome (ACS). The high prevalence of nonobstructive coronary artery disease (CAD) in those patients has recently been reported not only in Japan but also in Western countries, and is clinically attracting attention. Coronary spasm is considered to be one of the leading causes of both suspected stable angina and ACS with nonobstructive coronary arteries. Coronary spasm could also be associated with left ventricular dysfunction leading to heart failure, which could be improved following the administration of calcium channel blockers. Because we rarely capture spontaneous attacks of coronary spasm with electrocardiograms or Holter recordings, an invasive diagnostic modality, acetylcholine (ACh) provocation test, can be useful in detecting coronary spasm during CAG. Furthermore, we can use the ACh-provocation test to identify high-risk patients with coronary spasm complicated with organic coronary stenosis, and then treat with intensive care. Nonobstructive CAD includes not only epicardial coronary spasm but also microvascular spasm or dysfunction that can be associated with recurrent anginal attacks and poor quality of life. ACh-provocation test could also be helpful for the assessment of microvascular spasm or dysfunction. We hope that cardiologists will increasingly perform ACh-provocation test to assess the pathophysiology of nonobstructive CAD. We often perform percutaneous coronary intervention (PCI) with coronary stent implantation for significant organic coronary artery stenosis with induced myocardial ischemia. PCI has become a useful treatment for relief of chest symptom in patients with significant coronary organic stenosis. However, coronary angiography (CAG) sometimes shows nonobstructive coronary arteries that do not need revascularization in patients with suspected angina \u201311. IndeYasue and coworkers previously reported that the intracoronary injection of acetylcholine (ACh) is a useful test for the provocation of coronary spasm \u201323. SincAlthough the etiologic mechanisms of stable angina and acute coronary syndrome (ACS) in patients with nonobstructive CAD remain obscure, coronary spasm can play an important role in the pathogenesis of these diseases , 36, 37.In this review article, we discuss the significance of ACh-provocation test as a tool for pathophysiological evaluation in nonobstructive CAD including coronary spasm.Coronary spasm usually occurs at rest, particularly from midnight to early morning \u201327. CoroACh usually causes vasodilation by releasing nitric oxide from the endothelium, and intracoronary injection of ACh in humans provokes coronary vasodilation in young healthy subjects, whereas it causes vasoconstriction in patients with coronary endothelial dysfunction such as coronary atherosclerosis \u201351. The Nonobstructive CAD includes not only angina with epicardial coronary spasm but also microvascular spasm \u20137, 62. H\u00ae (ACh chloride) was approved as an inducer of coronary spasm during CAG in 2017 in Japan. This approval will lead to more testing for provocation of coronary spasm in Japan, adaptation of the treatment based on the patient's progress, and detailed pathophysiological evaluation of nonobstructive CAD including coronary spasm.OvisotIn addition to ACh, ergonovine (ER) is also useful for pharmacological provocation of coronary spasm. According to the Japanese Circulation Society (JCS) Guidelines , the intStudies in Japan have made many contributions to the pathophysiology, diagnosis, and treatment of coronary spasm, leading to the development of the Guidelines for Diagnosis and Treatment of Patients with Vasospastic Angina by the JCS , 75\u201378. According to the JCS Guidelines for Vasospastic Angina (Coronary Spastic Angina) Fig.\u00a02)2), we caWe and others previously reported different patterns of angiographic changes including focal and diffuse spasm (severe diffuse vasoconstriction) during the spasm provocation test , 81, 82.According to the JCS Guidelines, ACh-provocation test is not recommended during emergent CAG in patients with ACS . The AmeT/C single nucleotide polymorphism in endothelial nitric oxide synthase gene were associated with ACh-provoked myocardial lactate production in patients with coronary spasm [Epicardial coronary spasm can be seen angiographically during the ACh-provocation test; however, it is unclear whether the coronary spasm causes myocardial ischemia. For this reason, we usually measure myocardial lactate production in the coronary circulation during ACh-provocation tests in the left coronary artery as a supporting diagnostic marker for the evaluation of coronary spasm-induced myocardial ischemia , 86. OurCoronary spasm can occur at sites of varying arteriosclerosis severity. We and others previously reported that coronary spasm could be associated with the progression of atherosclerosis \u201391. PatiWe previously reported that ACh-provoked coronary spasm occurring at the site of significant coronary artery stenosis was a more significant prognostic factor for MACE than ACh-provoked coronary spasm occurring at the site other than the site of organic stenosis, suggesting that coronary spasm can be associated with the cause of MACE when the coronary spasm occurs at the site of organic stenosis , 101. ThAt present, we often perform PCI with coronary stent implantation for significant organic coronary artery stenosis. Coronary spasm occurring after coronary stent implantation has become a clinical problem , 102\u2013107Recent studies reported that epicardial coronary spasm could be associated with left ventricular (LV) dysfunction \u201341. We pA previous study reported that the ACh-provocation test induced coronary spasm in 20/42 patients (48%) who had idiopathic DCM-like LV dysfunction without significant organic coronary arteries stenosis . PatientOn the other hand, ACh-provoked coronary vasomotor abnormality in our previous study was shown to be closely associated with myocardial fibrosis (expressed as late gadolinium enhancement in cardiac MRI) in patients with heart failure and without organic coronary artery stenosis , 112. CoThe coronary arterial tree consists of not only the epicardial coronary arteries, but also smaller arteries and arterioles (<\u2009500\u00a0\u03bcm). The latter feed the capillaries and play an important role in the coronary microcirculation, being the main site of regulation of myocardial blood flow , 119. EpModalities for diagnosing obstructive CAD such as CAG or CTA have improved remarkably. However, in patients with suspected angina, we can sometimes see both nonobstructive epicardial coronary arteries and non-ACh-provoked epicardial coronary spasm. Nonobstructive CAD has included not only angina with epicardial coronary spasm but also microvascular spasm or dysfunction , 124 5). We de2, respectively. These clinical features of the microvascular spasm, such as female sex, middle age, and low body mass index, are reminiscent of postmenopausal phenomena, which invites speculation of an association between the pathogenesis of microvascular spasm and age-dependent estrogen deficiency in those patients.Our report mentioned above of the 1The ACh-provocation test has several limitations. The ACh-provocation test cannot provoke coronary spasm in all patients with coronary spasm, although our previous study showed high sensitivity and specificity of the test in patients with variant angina , 21. In ACh-provocation test has several potential complications. In our institution, the number of life-threatening arrhythmias during ACh-provocation test was 9 (0.5%) of 1637 patients who underwent this test . A previAs summarized in this review, ACh-provocation test can be a safe and reliable method not only to diagnose epicardial coronary spasm but also to assess the pathophysiology of nonobstructive CAD. The ACh-provocation test is not often performed in routine clinical cardiovascular practice because multiple procedures of this test are required. However, the pathophysiology showed by ACh-provocation test can be associated with prognosis in patient with nonobstructive CAD. We can identify the high-risk patient with coronary spasm or microvascular spasm diagnosed by ACh-provocation test and treat with intensive care for the patients.We hope that cardiologists will routinely perform the ACh-provocation test to assess the pathophysiology of nonobstructive CAD."} {"text": "Prior research has established transitions into and out of nursing homes as periods of suicide risk for older adults. Deaths by suicide were found to be 2.4 times as likely among Veterans within six months of discharge from US Veterans Health Administration (VA) nursing homes when compared with gender and age-matched Veterans from the general VA patient population . Despite these trends, suicide prevention interventions implemented during nursing home and post-acute care transitions, including those taking place from Centers for Medicare and Medicaid Services regulated nursing homes, are lacking. Suicide Awareness for Veterans Exiting the Community Living Center (SAVE-CLC) was piloted as a quality improvement intervention to reduce suicide risk for older Veterans discharging from VA nursing homes. VA clinicians from three sites provided a friendly contact by phone after discharge (n = 66) to screen for depression, facilitate a strengths-based discussion about service needs, and provide service referrals. Compared to a group of patients discharged prior to the start of the intervention , SAVE-CLC patients received more depression screening within 30 days after discharge and were seen more quickly for mental health care when indicated. Implications for suicide prevention with older Veterans and for the general population of older adults receiving short stay services in US nursing homes will be addressed."} {"text": "Microplastics in the biosphere are currently of great environmental concern because of their potential toxicity for aquatic biota and human health and association with pathogenic microbiota. Microplastics can occur in high abundance in all aquatic environments, including oceans, rivers and lakes. Recent findings have highlighted the role of microplastics as important vectors for microorganisms, which can form fully developed biofilms on this artificial substrate. Microplastics therefore provide new microbial niches in the aquatic environment, and the developing biofilms may significantly differ in microbial composition compared to natural free-living or particle-associated microbial populations in the surrounding water. In this article, we discuss the composition and ecological function of the microbial communities found in microplastic biofilms. The potential factors that influence the richness and diversity of such microbial microplastic communities are also evaluated. Microbe-microbe and microbe-substrate interactions in microplastic biofilms have been little studied and are not well understood. Multiomics tools together with morphological, physiological and biochemical analyses should be combined to provide a more comprehensive overview on the ecological role of microplastic biofilms. These new microbial niches have so far unknown consequences for microbial ecology and environmental processes in aquatic ecosystems. More knowledge is required on the microbial community composition of microplastic biofilms and their ecological functions in order to better evaluate consequences for the environment and animal health, including humans, especially since the worldwide abundance of microplastics is predicted to dramatically increase. Plastics have been produced since the 1940s, and world production reached 360 million metric tons in 2018, which has resulted in severe plastic pollution of the environment worldwide were also enriched in microplastic biofilms and one plant pathogen (Pseudomonas syringae) were exclusively found in microplastic biofilms biofilms represent the major groups of bacteria capable of degrading PHBH represented important microbial associations within microbial communities of the plastisphere microplastic characteristics (\u201csubstrate-specific\u201d), (ii) period/succession (\u201ctime-specific\u201d), (iii) microbial community and (iv) environmental conditions Fig.\u00a0. The lasAlphaproteobacteria and Gammaproteobacteria, while Burkholderiales (formerly Betaproteobacteria) dominated on polyethylene microplastic biofilms in the North Atlantic garbage patch for microbial growth, pollutants , physicochemical parameters and aquatic biota are critical factors controlling microbial biofilm formation and succession on microplastics. In lake water, temperature, nutrient levels and suspended particle concentrations determined microbial assemblages on various plastics (Chen et al. Mytilus edulis developed a similar bacterial community composition as the mussel\u2019s gut microbiome (Kesy et al. Aquatic plants and animals play an important role in the transfer of microplastics across complex food webs (Au et al. The formation and development of the microbial community structure of microplastic biofilms to a large extend depend on \u201clocation-specific\u201d, \u201ctime-specific\u201d and \u201csubstrate-specific\u201d characteristics. However, most studies reveal that location-specific characteristics play a more important role than substrate-specific\u201d factors in shaping the bacterial community composition of microplastic biofilms (Amaral-Zettler et al. Factors influencing microbial community composition and function require further studies to better understand underlying processes and mechanisms. Most prior studies have been restricted to traditional non-degradable plastics, but the worldwide increasing use of degradable plastics means that these less refractory polymeric compounds also need to be carefully considered. A total of 127 countries have adopted some form of legislation to regulate the use of plastic bags UNEP , but mosThe advantages and limitations of current research methods for microplastic biofilms have been summarized (see Arias-Andres et al. The focus of future studies on microbial biofilms on microplastics should concentrate on functional and ecological aspects affecting aquatic food web dynamics and biogeochemical processes. Meta-transcriptomics, metaproteomics and metabolomics are now well established and important tools to assess functions and ecological roles of microbial communities Fig. . These m"} {"text": "Frail community-dwelling older adults increasingly receive home care and continue to face barriers to participating in physical activity (PA) that could help maintain their function. Home care aides (HCAs) are well-positioned to promoting PA among older home care recipients because of their established relationship and regular interpersonal exchanges; yet, the role of HCAs in promoting and supporting PA in home care settings is seldomly studied. Using the quantitative and qualitative data from a 4-month home-based gentle PA intervention delivered by HCAs to their clients in a Medicaid-funded home care setting, the current study examined whether outcome expectations for exercise (OEE) held by HCAs led to client PA outcomes through social support for exercise (SSE) provided by HCAs. Longitudinal mediation analysis of 46 HCA-client dyads showed that higher baseline OEE held by HCAs were related to greater SSE reported by clients after the intervention , controlling for client-level covariates, including baseline OEE, age, gender, comorbidity, and whether HCA was client\u2019s family member. Unexpectedly, SSE did not have significant association with client PA outcomes nor mediated the relationship between OEE held by HCAs and client PA outcomes. Qualitative data suggested alternative factors may explain the results, such as clients\u2019 family beliefs in the intervention and clients\u2019 participation experiences (such as expectation fulfillment). Future research should consider older home care clients\u2019 family contexts to enhance our understanding of HCAs\u2019 roles in preserving the function of growing numbers of older home care recipients."} {"text": "This knowledge is critical to understand how crust-forming processes are related to metal accumulations at specific time and conditions of Earth evolution. To this end, high-precision absolute geochronology utilising the rhenium-osmium (Re-Os) radiometric system in specific sulphide minerals is becoming a method of choice. Here, we present a procedure to obtain mineral separates of individual sulphide species that may coexist within specific mineralized horizons in ore deposits. This protocol is based on preliminary petrographic and paragenetic investigations of sulphide and gangue minerals using reflected and transmitted light microscopy. Our approach emphasizes the key role of a stepwise use of a Frantz isodynamic separator to produce mineral separates of individual sulphide species that are subsequently processed for Re-Os and sulphur isotope geochemistry. Specifications TablePolished thin sections of the arsenopyrite-pyrite-mineralised samples were studied using transmitted and reflected light microscopy in order to establish the paragenetic relationships and constrain the workflow for optiAll sulphide samples were cut into slabs that were thoroughly cleaned using silicon carbide grit, milli-Q water and ethanol to remove any metal traces potentially introduced through hammering or sawing . These clean sulphide-bearing samples were then crushed using a zirconia ceramic dish and puck and sieved through disposable home-made nylon sieves to produce 70\u2012200 mesh size fractions . Each 70An aliquot of each arsenopyrite and pyrite mineral separate was embedded in epoxy to operate a quality control of these mineral separates . The mounts were studied by reflected light microscopy. We recommend the use of a scanning electron microscope (SEM) operated in backscattered electron mode (SEM-BSE) if doubts persist regarding the quality of mineral separates. Qualitative observations may then be complemented by point wavelength-dispersive spectroscopy (WDS) quality control analyses of arsenopyrite and pyrite in the mounts using the following suite of elements: S, Fe, Ni, Cu, As.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} {"text": "The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies. Identification of a general and suitable target that is unambiguously oncogenic or tumor suppressive is a foundation on which cancer therapeutic strategies could be designed and developed. Fibronectin (FN) A has lonAccomplishment of cancer development, a rather slow and chronic process, temporally and spatially requires various cellular activities across different tissues. Tumor cells originate from healthy, often epithelial, cells that acquire hereditary mutations or somatIn contrast to such intratumor heterogeneity, immune and stromal cells in the tumor microenvironments (TMEs) initially arise to eliminate pre-tumor abnormal cells and early transformed cells that encounter environmental stresses. Consequently, these stresses impose early transformed cells enormous selective pressures to force evolution, rendering tumor cells staying in the equilibrium stage for a long while before being able to escape immunosurveillance and make a malignant progression ,26,27. HOxygen delivery within the TMEs is inefficient mainly due to various abnormalities in the tumor vasculature . Indeed,The liberation and survival of circulating tumor cells (CTCs) is a requirement for the colonization of disseminated tumor cells (DTCs) in secondary organs and finally outgrowth and macrometastasis development ,34. Like+ bone marrow-derived cells (BMDCs) that have been driven by cytokines or exosomes secreted by the metastatic competent tumor cells in primary tissues long before extravasation of DTCs in distant tissues formed ted data] [unpubli435 DTCs . Uncouplt organs . Such pht organs ,350, likhigh CTCs colonize more and form more metastatic tumor nodules in distant organs, unless there are strategies to reverse FNhigh CTCs back to pro-epithelial phenotypes that tend to render CTCs suffer more from anoikis and mechanical stresses and injuries.Since how cancerous FN and ECM FN participate in tumor progression remains obscure and paradoxical, FN-based cancer therapies have so far only been focused on the functions of drug delivery. For example, EDA- and EDB-containing oncofetal variants have often been utilized for that purpose ,351,352.At the same stage of tumor patients, FN deposition in ECM of TMEs exacerbates tumor growth and subsequent progression. Therefore, approaches targeting such matrix-depositing FN may be ideal for effectively slowing down the tumor progression. FN secretion and deposition may due in part to tumor-infiltrating pro-tumor stromal cells including CAFs and TAMs . Ablatiohigh CTCs prior to extravasation in distant organs as DTCs. Blockade of the attachment of FNhigh CTCs to DPP IV-expressing endothelia can be an ideal strategy to prevent tumor metastasis and improve patients\u2019 prognosis. Indeed, in experimental metastasis assays, polypeptides derived either from FN harboring DPP IV-binding sites [In later stages of tumor progression, tumor cells with the metastatic potential begin to intravasate into the circulation and become FNng sites or from ng sites ,2 have bng sites . More imng sites . Intrigung sites .high CTCs become highly metastatic and capable of colonizing distant organs. The prevailing therapeutic strategies are to switch to a second line of tumor-killing drugs or combinatory therapies including immune checkpoint blockade, which may cause further genetic or epigenetic evolutions and eventually lead to another drug resistance. These problems may be avoided by finding a drug that by itself has no cytotoxic effect on tumor cells but is able to sensitize the resistant tumor cells to the original drugs. Efforts can be exerted to screening such drug from either small molecule library or a series of less harmful natural phytochemicals. By combining such drug with periFN/DPP IV binding blockade treatments, the drug-resistant tumor cells can be re-sensitized and controlled in the primary sites and FNhigh CTCs can simultaneously prevented from entering distant sites.In most cases, tumor patients receive either tradition chemo/radiotherapies or targeted anti-tumor therapies. As aforementioned, tumor patients often develop resistance to these anti-cancer drugs, driving tumor evolution, malignant progression, intravasation of tumor cells to become CTCs, and metastatic recurrence simultaneously with the upregulation of endogenous FN. Although therapy-elevated FN expression in resistant tumor cells slow down the tumor growth, the blood-borne FNIn summary, after extensively reviewing the bulk literature regarding the roles of FN in cancer progression, we provided intriguing possibilities that reasonably reconcile the seemingly paradoxical roles FN plays. We hypothesized that cancerous FN and FN mactrices in TMEs can coordinately regulate tumor transformation and malignant progression in temporal and spatial manners. Upon accomplished experimental proof of concept, FN can be carefully targeted at the right location and in the right time. We finally provided a few FN-based therapeutic strategies as future perspectives. Hopefully, this review article can attract more cancer researchers to be delved into concerted efforts in unveiling and validating what had been proposed here."} {"text": "Despite the well-understood benefits of vaccination in older adults, national rates still fall below public health targets, especially among certain racial and ethnic groups. Recent scholarship examining healthcare use patterns in adults revealed that health care providers miss several opportunities to provide vaccination during regular healthcare encounters, including Medicare annual wellness visits. Several barriers to older adult vaccination have been identified, including lack of patient and provider understanding of the importance of vaccination, financial barriers to vaccines covered under Medicare Part D, and patient hesitancy about the safety and effectiveness of vaccines. Strategies to address these barriers will be discussed, including the use of national quality measures to strengthen incentives for adult vaccination. Part of a symposium sponsored by the Health Behavior Change Interest Group."} {"text": "Individual sensory deficits have been associated with adverse outcomes, including dementia, in older adults. Using data from the Baltimore Longitudinal Study of Aging (BLSA) (N=259) and Atherosclerosis Risk in Communities Study (ARIC) (N=962), we examined the prevalence of one, two, or three sensory deficits among older adults \u226570 years. Any hearing loss was the most prevalent sensory deficit , followed by vision loss and olfactory loss. Hearing and vision impairments were more prevalent than hearing and olfactory losses as well as vision and olfactory losses in both age groups and studies There were few people with deficits in all three senses . Further research should investigate the potential impact of multisensory impairments on older adults."} {"text": "PLOS Genetics publications that exemplify recent progress in human genetic admixture studies, and we discuss potential areas for future work.Throughout human history, large-scale migrations have facilitated the formation of populations with ancestry from multiple previously separated populations. This process leads to subsequent shuffling of genetic ancestry through recombination, producing variation in ancestry between populations, among individuals in a population, and along the genome within an individual. Recent methodological and empirical developments have elucidated the genomic signatures of this admixture process, bringing previously understudied admixed populations to the forefront of population and medical genetics. Under this theme, we present a collection of recent One of the major insights from the modern genomic era is the ubiquity of migration and admixture throughout human history \u20137. Admix\u2014the population origins of material within a genome. This is related to, but distinct, from genetic similarity and from genealogical ancestry, with the relationship further discussed by Mathieson and Scally [Human population movement frequently lacks historical records. Many migration events have occurred through colonization or forced displacement, and ancient admixture often predates historical records. Therefore, genetic studies provide an opportunity to understand population history and the forces generating variation. Recent empirical work has shown that studying the genetics of a wider set of human populations can yield historical insights as well as medically relevant information about health and phenotypes. The mosaic ancestry patterns of admixed populations can also be used to elucidate the mechanisms and timescales of evolution in humans more generally. For example, ancestry patterns in admixed populations have been used to infer recombination rates \u201315 and td Scally .PLOS Genetics publications. This compilation is a limited selection of work that exemplifies recent key advances and stimulates discussion about priorities for the future.Here, we highlight recent progress and discuss future directions for the study of admixed human populations . The terBroader genetic sampling of populations worldwide is increasingly being combined with advances in theory and computational methods to elucidate human history.Genetic ancestry often varies along a chromosome within an individual and between individuals within an admixed population . SummariClassic statistical methods in population genetics typically rely on allele frequencies, patterns of linkage disequilibrium (LD), and interpopulation sequence differences. However, the admixture process may distort patterns of LD, break up runs of homozygosity, and combine allele frequency distributions from distinct parental populations \u201329. Yet,PLOS Genetics that improve our understanding of the demographic processes shaping genetic variation in admixed populations and human evolutionary history. Ragsdale and colleagues (2019) generalize 1- and 2-locus genetic summary statistics in a computationally efficient algorithm able to explore complex demographic models [A number of major theoretical and methodological advances have recently been published in c models . Other rc models . Methodoc models . Identifc models \u201338. Browc models \u201341. A rec models .Intricate sociocultural practices such as marriage customs, colonization events, and phenotypic preferences direct how parental populations interact to form admixed human populations. Whereas computational methods are increasingly considering these intricacies, empirical studies of admixed populations have already made substantial progress on fine-scale demography providing insight into how sociocultural practices shape the admixture process and within-region variation.Using these new methods, empirical studies have brought to the forefront within-continent variation, particularly for historically excluded and under-sampled populations. Analyses of genomic ancestry within the context of geography have revealed between and within continent population structure . For exaEmpirical studies such as these highlight the role social processes play in shaping genetic variation; for example, male and female demographic histories can differ. Considering population structure, sex-biased admixture, and effective population size changes, Font-Porterias and colleagues (2019) clarified the dynamic demographic history of European Roma groups, including showing that they share a common South Asian origin but have complex contributions from West Eurasian groups . AnotherSelective pressures, such as those from environments and pathogens, play an important role in genetic variation and disease risk. Admixture both obscures genetic signatures of selection in source populations and provides new genetic material upon which selection can rapidly act.Despite major progress on theory and methods to study demography in admixed human populations, methodological advances to study other processes such as adaptation and phenotypic variation remains an open area with substantial room for growth. Recent admixture may obscure genetic signatures of selection in the source populations by distorting linkage, rapidly changing allele frequencies, and breaking up homozygosity ,56. TherDARC locus is protective against malaria-causing Plasmodium vivax infection, which is estimated to be one of the strongest selective pressures in recent human history. The Duffy-null allele is nearly fixed in sub-Saharan African populations and mostly absent in non-African populations, producing a classic signal in which the DARC locus is an outlier in its proportion of local African ancestry in multiple admixed populations [DARC locus is not typical of human adaptation. These local ancestry outlier approaches likely miss many loci under weaker or polygenic selection or those not highly differentiated in the sources. Additionally, outlier approaches generate false positives due to drift or long-range LD and discard other genetic information along the genome. For example, in Western African rainforest hunter\u2013gatherer populations, Jarvis and colleagues (2012) found reduced levels of switching between ancestry types in a genomic region that may contribute to adaptive phenotypes such as short stature [A common approach to identify candidate regions under selection post-admixture looks for outliers in local ancestry \u201321,59,60ulations . However stature . DespiteDespite the challenges of identifying phenotypically important loci and regions under selection in admixed populations, recent empirical studies have highlighted the importance of using admixed populations to understand how selective pressures shape genetic variation and disease risk. Discovering phenotypically important loci in admixed populations requires careful consideration of the data, including strategies to integrate genotypes, local ancestry, and information from source populations. Once phenotypically important loci are identified, admixed populations can provide insight into how these loci interact with different ancestral backgrounds and how characteristics of the source populations shape post-admixture selection.ApoE is the strongest known risk gene for late-onset Alzheimer disease; Rajabli and colleagues (2018) showed that variation in risk for Alzheimer disease across populations may be at least partially explained by the ancestral background interacting with the risk allele [In addition to looking for correlations between genotype and phenotype, phenotypically important loci in admixed populations can be identified by looking for correlation between local ancestry and phenotype when the phenotype differs in the source populations . A combik allele . The relk allele . In Latik allele . Going fNotably, these types of studies of quantitative variation and disease risk in admixed populations rely on careful consideration of the genotype and local ancestry calls, including reference-bias and characteristics of the source populations. Identifying phenotypically important loci in admixed populations is challenging in the absence of appropriate reference panels and knowledge of the source populations. The growing availability of genetic data from diverse groups shows that the unique LD structure of admixed groups and limited availability of suitable reference panels can particularly impair variant mapping and detection for novel or rare alleles. For example, Kowalski and colleagues (2019) recently analyzed a large cohort of phased genomes from African and Hispanic/Latino individuals (NHLBI TOPMed), revealing significant phenotypic associations for rare variants that were not detected with imputation using 1000 Genomes reference data .Contributing source populations also have their own distinct selective and demographic histories. Although recent admixture obscures genetic signatures of selection in the source populations, consideration of past selective pressures can help identify important loci and clarify the genetic basis of disease risk. For example, Yao and colleagues (2018) found that in African ancestral backgrounds, past selection for the Duffy-null allele may also contribute to population differences in plasma levels of chemokines involved in a variety immune processes and diseases . In IndiThe set of papers highlighted here exemplifies recent advances and important areas for future work in the study of genetic admixture and its roles in human evolution. Recent theoretical and methodological advances have improved our understanding of the dynamic and complex demographic histories of modern human populations. New empirical insights will continue to emerge with the development of approaches that consider complex sociocultural variables, account for within-population heterogeneity, and avoid reference bias. With increasing genomic and phenotypic data available from populations around the world, we are only beginning to characterize genetic underpinnings of traits, the importance of their genetic background, and mechanisms of adaptation. Importantly, as we move forward, the field must emphasize the inclusion of local communities, ensure that people maintain agency over their genomic information, prioritize infrastructure for science, and improve scientific theories by collaborating across disciplinary knowledge \u201375."} {"text": "According to the World Health Organization, the global population is aging, but ageism may now be the most socially \u201cnormalized\u201d of any prejudice, more pervasive than sexism or racism. Ageism produces avoidant and disrespectful treatment of older adults and contributes to a shortage of college students seeking careers with older adults. To foster positive intergenerational contact and combat ageism, we organized life-story sharing by older adult community members in four undergraduate psychology courses with lifespan themes . A panel visited each class; instructors and graduate students facilitated discussion between students and panelists. Students completed pre- and post-surveys of ageism and attitudes toward aging. A majority of students recommended integrating the activity into future semesters. In free-responses, students also frequently expressed surprise that panelists reported not feeling different than they had at age 20, and that this information challenged previously held stereotypes."} {"text": "Nineteen percent (13 million) older adults have incomes below 150% of the Federal Poverty Level, leaving them with limited means to afford basic living expenses. Public benefits can help bridge the gap allowing older adults to afford food, home energy, and health expenses. There are studies demonstrating the positive health outcomes associated with public benefits in older adults. It remains unclear how benefits may also improve subjective measures of well-being in older adults. To examine this question, baseline measures of well-being including the CFPB Financial Well-Being Scale were administered to older adults before they enrolled in benefits and again six months after receiving benefits to examine changes in well-being as a result of accessing benefits to help ease some of their financial burdens. Results revealed that older adults experience subjective, psychological improvements from benefits. These findings have implications for the social and behavioral determinants of health in older adults."} {"text": "Older adults in the deep south are living with high food insecurity rates; this is exacerbated by challenges with rural-living, like transportation limitations and no grocery stores. To address this, we must increase emergency food assistance offerings and adopt best practices for food pantries including choice food pantry approaches, which empowers clients with some autonomy in choosing the foods they receive as part of their pantry distribution. Coalitions in eight income-limited, aging, rural Mississippi Delta counties received support from a Centers for Disease Control and Prevention Grant to enhance the food-related infrastructure in their communities through technical assistance and economic investments. A detailed process evaluation was conducted on this effort. Each coalition adopted food pantry-related policies like adding new food pantries and adapting their existing food pantries with the choice model. Both aging volunteers and clients indicated positive outcomes from the process of adding pantries and adapting existing ones."} {"text": "Military service during early life can result in exposure to traumatic events that can reverberate throughout life. Although much attention is focused on the negative effects of military service, many veterans report positive effects. These papers explore life course effects of military service on veterans\u2019 health and well-being. Three used national US longitudinal cohorts ; two sampled veterans from Oregon or from Korea. Three compared veterans to non-veterans; two examined veterans only. Cheng and colleagues found that veterans in HRS are more likely to be risk-averse than non-veterans. Risk aversion matters because it determines how people make decisions and predicts a wide array of health and economic outcomes. Kurth and colleagues examined Oregon veterans from several wars, finding PTSD symptoms were highest among Vietnam combat veterans, the oldest cohort; there were no differences among non-combat veterans. Piazza and colleagues examined in MIDUS the impact of veteran status on cortisol, a stress biomarker, finding older veterans more likely had non-normative patterns than did younger or non-veterans. Lee and colleagues studied patterns of mental health among Korean Vietnam veterans, identifying two patterns as \u2018normal\u2019 and \u2018resilient\u2019 encompassing half the sample; these veterans demonstrated positive outcomes of military service. Frochen and colleagues compared depression trajectories between veterans and non-veterans in HRS, finding veterans had less depression than non-veterans, but among veterans, trajectories varied based on extent of service. in sum, these papers demonstrate that military service can have positive as well as negative effects on veterans\u2019 health and well-being in later life. Aging Veterans: Effects of Military Service across the Life Course Interest Group Sponsored Symposium."} {"text": "Person-centered caregiving approaches emphasize efforts to protect and maintain the personhood of people living with dementia (PLWD). The influence on person-centered caregiving approaches on PLWD have predominantly focused on deficit-oriented outcomes, such as absence or reduction of behavioral symptoms. While important to quality of life, the absence of measurable \u201cpositive\u201d responses to person-centered caregiving approaches limit opportunities to specify sensitive and meaningful outcome measures that more holistically represent PLWD\u2019s care experiences as more than the absence of a negative outcome. To address these gaps, we conducted a secondary analysis of video-observations of PLWD (N=9) surrounding mealtime cares using a descriptive ethnographic approach. Our objectives were to descriptively summarize specific responsive behaviors demonstrated by PLWD surrounding person-centered caregiving interactions, specifying observable features of these responses and consider their utility in future video-observational research. Findings indicate PLWD contribute both verbal and non-verbal communication surrounding person-centered approaches which can be characterized as conversational , expressing preferences , emotional responses , and reflexive (mirroring of caregiver\u2019s actions), with overlap between categories. Findings suggest that PLWD not only contribute and respond in meaningful ways to person-centered interactions, but also initiate a significant number of these interactions. This study contributes to a growing body of research and advocacy that examines the personhood and abilities of PLWD and establishes the utility of observational data in studying PLWD contributions."} {"text": "Almost a hundred and thirty years ago, Emil Kraepelin described important weight changes in patients diagnosed with dementia praecox during the acute state of psychosis outbreaks . KraepelTwenty years later Eugenie Bleuler in his seminal book \u201cDementia praecox oder Gruppe der Schizophrenien\u201d described that body weight of patients underwent irregular and severe variations from which no cause had been identified (being sometimes as much as 25 Kg), suggesting that it could not be considered as a compensation mechanism after the stressful circumstances of a psychotic outbreak . He alsoNevertheless the link faded with the introduction of chlorpromazine in 1952 like other medical conditions . HoweveWith the reintroduction of clozapine in the market, new studies regarding this association in patients diagnosed with schizophrenia or schizoaffective disorder appeared in the literature. Lamberti, without aiming at it, showed an inverse correlation between clinical symptom severity change and weight gain in 36 inpatients evaluated for 6 months with the brief psychiatric rating scale (BPRS) . LeadbetThe same approach was taken with olanzapine in patients diagnosed with schizophrenia spectrum disorders. Czobor showed a significant correlation between weight gain and improvement in 38 patients . GaryfalThe placebo effect found in some studies is remarkable regarding previous considerations. Ascher-Svanum described that patients under placebo treatment presented a significant association between greater weight gain and greater therapeutic improvement suggesting that weight gain may serve as an important indicator of improved clinical status among acutely ill patients with schizophrenia who do not receive antipsychotic medication , 24. AlsDespite the paradox that a secondary side effect of antipsychotics such as weight increase might underlie clinical improvement, these mechanisms are worth being discussed. Initially authors underlined this issue suggesting hospital diet, physical inactivity, and the psychological and physical shelter provided by hospitalization as the cause . Later sNevertheless, recent research suggests that the gut-brain axis (GBA), specifically its neurohormones, might behave as a potential pathway underlying both conditions and a key player in promoting weight gain and clinical improvement. The biological effect on the central nervous system of leptin, adiponectin, ghrelin, cholescytokinin (CCK), neuropeptide Y (NPY), glucagon like protein I (GLP-I), and insulin has accumulated further evidence . InitialGBA has been described as a pathophysiological mechanism implicated in antipsychotic-induced weight gain , 34, howConsidering specifically clozapine or olanzapine, the two pharmacological agents more related with weight gain, they seem to display a direct effect on the hormonal pathways of energy homeostasis (adiponectin and ghrelin) rather than on weight gain . Indeed Overall, previous literature suggests that GBA might be a necessary element in both conditions and so underlie the undeciphered association between weight gain and clinical improvement. However, this association lacks specific studies evaluating the issue and so further studies are required to prove its implication .The author confirms being the sole contributor of this work and has approved it for publication.CC-R has received honoraria/speaker fees/research and travel support/from Adamed, Alter, Angelini, Janssen-Cilag and Lundbeck."} {"text": "The world\u2019s population is aging at an alarming rate, and the incidence of osteoporosis is skyrocketing. One major consequence of the decline in skeletal health is increased fracture risk in patients 65 years and older. Osteoporosis-related fractures are predicted to result in more than $25 billion in annual health care costs by 2025. For elderly patients, who demonstrate poor capacity for regeneration and a limited physiologic reserve, surgery has increased complication rates and higher risk of failed healing outcome which is potentially devastating and can result in morbidity and mortality . CurrentStem cell therapy has emerged as a potent new strategy to repair and replace injured tissue. Readily available bone marrow aspirates and adipose tissue have been used as a source for the isolation, study, and transplantation of bone forming cell populations. Despite often being called \u2018stem cells\u2019 the isolation of these cells has been largely retrospective in nature and relying on inexact separation criteria such as plastic adherence which produces highly variable and heterogeneous cellular mixtures of multiple tissue types including bone, blood vessels, blood, fat, and fibroblast cells which makes treatment outcomes difficult to evaluate or predict . In contIn our recent study, we applied this methodology to isolate human fracture derived SSCs (hSSC) from a broad cohort of patients to test if changes in SSC function were associated with patient age . We prosWe analyzed genetic regulation of aged SSC traits such as fibrogenicity by performing gene expression analysis on purified hSSCs. We utilized microarray analysis to compare global gene expression in purified hSSCs from young versus aged patients along with corresponding functional evaluation in vitro. Consistent with age-related functional changes, we found downregulation of genes related to bone formation in aged hSSCs. Moreover, aged hSSCs upregulated genes that are related to fibroblast-like extracellular matrix secretion and cellular senescence. Curiously, we also observed that the histone deacetylase Sirtuin1 was significantly downregulated in geriatric hSSCs, which hints at epigenetic mechanisms underlying hSSC aging. We showed that specific blockade of Sirt1 in young hSSCs impairs osteogenic potential in vitro. Excitingly, Resveratrol and a Sirtuin1-specific small molecule restored mineralization capacity in impaired hSSCs thus providing a rationale for future translational strategies.In summary, our report of an association between patient age and hSSC function opens new possibilities to identify diagnostic, prognostic, and therapeutic strategies for poor fracture healing and potentially even the preservation of youthful bone health and prevention of skeletal injuries. Targeted molecular therapies that inhibit cellular senescence pathways may reverse age-related fracture phenotypes without broad off-target systemic side effects of current regimens. Continued investigation of larger groups of patients will reveal if simple in vitro assays of hSSCs, or antigens associated with aged hSSCs might serve as a prognostic tool to predict healing outcome of fractures. Furthermore, analyzing hSSCs isolated from nonunions will yield insights into the involvement of hSSCs in the etiology of failed fracture healing. A more comprehensive approach including the analysis of all cells present at the fracture site might also help to elucidate the role of the stem cell microenvironment or \u201cniche\u201d in facilitating proper bone regeneration ."} {"text": "Research shows regular physical activity (PA) is associated with better health and longevity; however, few studies consider contextual factors related to PA among African American (AA) older adults living in socioeconomically disadvantaged neighborhoods. The Physical and Cognitive Health Pilot Study (n=50) was used to examine associations between PA and level of neighborhood socioeconomic disadvantage among sedentary, AA older adults from four public housing communities in Durham, NC and Annapolis, MD . Participants were administered the Community Healthy Activities Model Program for Seniors (CHAMPS), a self-report questionnaire measuring weekly frequency and duration of PAs. Neighborhood socioeconomic disadvantage was defined by the Neighborhood Atlas Area Deprivation Index (ADI), which ranks neighborhoods according to Census block group/neighborhoods within each state and nationally. For the present sample, two of the Durham housing facilities were located in communities in the most disadvantaged block groups. Meanwhile, one Durham location and the Annapolis community were located in the least disadvantaged block groups. Bivariate correlations showed greater neighborhood socioeconomic disadvantage was associated with less participation in various PAs (p<.05). Next, ANOVA revealed the Annapolis group participated in statistically significantly more PAs, including visiting the senior center, church attendance, and light gardening (p<.05) compared to the most disadvantaged groups. The present findings suggest there are benefits to living in advantaged contexts despite lower-income status. These findings also suggest barriers within disadvantaged neighborhoods that limit access to recreational activities favorable to health status. Future research should address ways to overcome such barriers."} {"text": "Exposure to harmful substances and chemicals such as tobacco smoke, chemicals and metal dust has been associated with increased risk of developing cancer, cardiovascular disease, and other diseases that contribute to shorter life expectancy. Associations with brain health in relation to these exposures are less well studied. We examined the relationship between brain health and prolonged exposure to different harmful substances in 498 male participants average age 68 (range 61 to 73) from the Vietnam Era Twin Study of Aging (VETSA). For self-reported tobacco smoke, herbicides/pesticides, and metal dust we created three groups reflecting recency of exposure (current/former/never). For Agent Orange we examined two exposure groups (ever/never). Brain health, defined as predicted brain age (PBAD), was evaluated by applying Brain-Age Regression Analysis and Computation Utility software (BARACUS) to magnetic resonance images collected at age 68. Tobacco smoking was significantly correlated with PBAD and remained significant in multivariate analyses adjusted for age, socioeconomic status (SES), age 20 general cognitive ability, and non-independence of twins within pairs. Never smokers had significantly younger brains than current or former smokers. PBAD did not differ for current versus former smokers. In other analyses, more advanced PBAD was associated with non-amnestic MCI. In this sample, tobacco smoking had the strongest relationship with overall brain health in late midlife compared with other types of environmental exposures, reinforcing its role in pathological aging and its importance as a public health priority."} {"text": "Recent findings suggest that childhood exposures can lead to chronic inflammation decades later, but the mechanisms underlying this relationship are relatively unknown. We investigate how childhood exposures influence adult chronic inflammation (measured by C-reactive protein) and examine five potential mediators comprising two midlife domains: socioeconomic status (SES) and health lifestyles. Using a sample of 8,891 adults aged 51 and older from the Health and Retirement Study (HRS), the analysis tests whether these life course mediators operate differently for Black, White, and Hispanic Americans. Among the six childhood domains examined, low SES and risky parental behaviors predict adult chronic inflammation, but adult health lifestyles mediate the effects of childhood SES and parental behavior. Adult SES also mediates the effect of childhood SES. Smoking and wealth exert stronger direct and indirect effects on adult inflammation for White Americans compared to Black Americans whereas BMI and exercise exert stronger direct and indirect effects for White Americans compared to Hispanic Americans. Although education mediated the effect of childhood SES on adult chronic inflammation, its effects did not vary by race. These results demonstrate that the physiological consequences of childhood exposures are carried into late-life via adult lifestyle factors and SES. In addition, the life course antecedents of chronic inflammation are distinct for Black, White, and Hispanic Americans. Future research investigating the early origins of adult health should consider not only multiple midlife mechanisms but also how resource mediation varies by race and ethnicity."} {"text": "The nonunion of distal phalangeal communized fracture is relatively rare in hand fractures. However, if it occurred, the surgical treatment is quite difficult because of small piece of fragmentations. We developed a new fixation method that involves the insertion of two wires and external wire compression fixation using a metal clamp. The aim of this technique was to increase the compression force between fragments and rigidity of conventional percutaneous Kirschner wire fixation. Here, we present a patient with the nonunion of distal phalangeal communized fracture who was satisfactorily treated with open reduction and percutaneous interfragmentary compression fixation with a linking external wire fixator (the Ichi-Fixator system). Such a treatment that enables compression fixation for communized distal phalangeal fracture of nonunion will clearly boost bone healing. Linked external wire-type compression fixator (the Ichi-Fixator system) enables enhanced security of fixation and facilitates the bone healing. Distal phalangeal fractures can be managed conservatively with good outcomes if diagnosed early. However, if the initial reduction is imperfect with total displacement between fragments such as communized fracture, then it may be necessary to use headless screw or Kirschner wire (K-wire) for fixation after closed or open reduction. Moreover, if conservative treatment failed, fracture site was occupied by soft tissue and fibrous connective tissues and finally become nonunion. Treatment of nonunion will need to firmly fix at fracture site after sufficient refreshment for increasing the bone union rate. The treatment options for nonunion of distal phalangeal fracture include conservative management with use of ultrasound , bone grrd distal phalangeal fracture was made based on radiographs and computed tomography scans. Anteroposterior, lateral, of the right middle finger showed dorsal displacement of the distal phalangeal fracture, with communized fracture treatment of distal phalangeal nonunion. This system enables to increase the compression force at the nonunion site compared with conventional percutaneous K-wire fixation."} {"text": "Cardiac regenerative therapy is expected to be a promising therapeutic option for the treatment of severe cardiovascular diseases. Artificial tissues or organoids made from cardiovascular cell lineages differentiated from human induced pluripotent stem cells (iPSCs) are expected to regenerate the damaged heart. Even though immune rejection rarely occurs when iPSC-derived graft and the recipient have the same HLA type, in some cases, such as tissue transplantation onto hearts, the HLA matching would not be sufficient to fully control immune rejection. The present review introduces recent immunomodulatory strategies in iPSC-based transplantation therapies other than MHC matching including the induction of immune tolerance through iPSC-derived antigen-presenting cells, simultaneous transplantation of syngeneic mesenchymal stem cells, and using the universal donor cells such as gene editing-based HLA modulation in iPSCs to regulate T cell compatibility. In addition, we present future perspectives for proper adjustment of immunosuppression therapy after iPSC-derived tissue/organoid-based cardiac regenerative therapies by identifying biomarkers monitoring immune rejection. Cardiovascular diseases are leading causes of death and medical expenditure worldwide even recent progresses in medical treatments . TherapeAn immunological privilege of iPSCs in regenerative medicine is that autologous iPSCs which are considered to be immunologically identical with the host can be established from the host somatic cells and used for transplantation therapies . HoweverMacaca fascicularis). iPSCs from MHC-homozygous animals were differentiated into cardiomyocytes (iPSC-CMs) and subsequently transplanted to MHC-matched monkeys by direct intramyocardial injection. The grafted cardiomyocytes showed electrically coupling to the host heart and survived without immune rejection in monkeys treated with clinically relevant doses of immunosuppressants, whereas the transplantation of iPSC-CMs to MHC-mismatched monkeys even treated with immunosuppressants exhibited immune rejection of grafted cardiomyocytes with severe infiltration of T lymphocytes [Several allogeneic transplant models have been tested to validate whether the use of HLA-homozygous iPSCs can mitigate immune rejection. The experiments using cynomolgus monkeys demonstrated that immune rejection is rarely detected in allograft transplantation differentiated from major histocompatibility complex (MHC) type-matched iPSC. In transplantation experiments of retinal pigment epithelial (RPE) cells derived from monkey MHC-homozygous iPSCs, fair engraftment of RPE cells transplanted to MHC-matched animal models was confirmed without the use of immunosuppressants . Anotherphocytes .On the other hand, the benefits of MHC-matching seem to be alleviated in transplantation of iPSC-derived bioengineered heart tissues which is a promising strategy in cardiac regenerative medicine to promote therapeutic efficiency \u201323. KawaIn this context, several attempts have been made to overcome immune rejection through strategies other than HLA-matching so far. One of the promising strategies is the induction of immune tolerance in iPSC-based transplantation. There are two pathways in immune tolerance: central pathway by selective elimination of self-antigenic immune cells in the thymus and bone marrow and peripheral pathway. An important mechanism for this peripheral pathway of immune tolerance is the immunosuppression mediated by regulatory T cells (Tregs) Fig. a. Tregs Therapeutic approaches for the establishment of immune tolerance are reported so far Table . Otsuka + cytotoxic T cells against the transplants which accordingly achieved the induction of immune torelance [In addition to the induction of immune tolerance by antigen-presenting cells of identical MHC type, tolerance induction using syngeneic mesenchymal stem cells (MSCs) has also been reported Fig. b. Yoshidorelance .+ cytotoxic T cells. The modulated iPSCs were also protected from immune responses from natural killer cells because HLA-C, HLA-E, HLA-F, and HLA-G were preserved. Differentiated cells from the modulated iPSCs would be considered as an immunologically ideal cell source for transplantation therapies with enhanced immunocompatibility suppressing immune rejection after transplantation. It is also estimated that only 12 strains of iPSCs with HLA modulation theoretically cover more than 90% of the population worldwide which encourages the establishment of clinical-grade human iPSC bank covering almost all mankind [Another intriguing approach is HLA modulation in iPSCs to regulate T cell compatibility which depends on HLA types Fig. c. Xu et mankind . Even thCRISPR-Cas9 and other gene-editing systems have recently been used to create donor cells that escape interference from the immune system . As previously described, it is not only possible to genetically modify the expression patterns of HLA class I and class II, but also to apply the immune escape mechanisms that occur in nature, such as cancer cells and placentas, to prevent the expansion of T cells and NK cells and promote Treg cell responses. Recently, some groups reported the creation of universal donor cells expressing immunomodulatory transgenes that have improved viability in allogeneic transplants . On the Although aforementioned approaches may possibly solve the problems in iPSC-based transplantation immunity, it remains to be further investigated whether these approaches will sufficiently work in iPSC-based cardiac regenerative therapies considering possible severe immunological circumstances of the heart. Another immunological consideration in iPSC-based cardiac regenerative therapies is the possible transition of transplantation subjects from \u201ccells\u201d to \u201ctissue/organoids\u201d . This paIt also means that immune regulation strategies which would even work in organ transplantation would be required in future iPSC-based cardiac regenerative therapies based on iPSC-derived tissue/organoid transplantation. Given the long history of research on immune rejection in organ transplants , it woulA strategy for the alleviation of immunosuppressant-related complications is to establish a system that can detect immune rejection in daily clinical practices to precisely control the immunosuppression level Fig. . To consIn the present review, we introduced present status and possible immunological problems in iPSC-based transplantation therapies including ongoing research attempts for immune regulation such as production of \u201ccells that control the immune system\u201d and \u201ccells that get past the immune system.\u201d Further investigations on immune regulation are required for standardization of iPSC-derived cardiac regenerative therapy based on distinctive features of iPSC-based tissue/organoid transplantation of the heart."} {"text": "With the emergence of affordable, clinical-orientated gait analysis techniques, clinicians may benefit from a general understanding of quantitative gait analysis procedures and their clinical applications. This article provides an overview of the potential of a quantitative gait analysis for decision support in three clinically relevant scenarios of early stage gait disorders: scenario I: gait ataxia and unsteadiness; scenario II: hypokinesia and slow gait; scenario III: apparently normal gait with a specific fall tendency in complex mobility situations. In a first part, we justify the advantages of standardized data collection and analysis procedures including data normalization and dimensionality reduction techniques that facilitate clinical interpretability of instrument-based gait profiles. We then outline typical patterns of pathological gait and their modulation during different walking conditions and highlight key aspects that are particularly helpful to support and guide clinical decision-making. Gait instability is prevalent in patients with balance problems, vertigo, and dizziness, and is associated with adverse health outcomes. Depending on the underlying disease entity, the risk of falling and consequent injuries is markedly increased . Falls aIn this context, quantitative, instrument-based gait analysis is a promising tool to capture and accurately assess gait function. Clinical approaches with a justifiable trade-off between the clinical benefit and infrastructural resources have been recently established. Central for clinical implementation of these techniques is application of standardized protocols for the recording, the analysis, and the interpretation of clinical gait profiles. Clinical experience and evidence from several studies emphasize that clinical gait examination should in particular assess patients\u2019 gait function during different walking conditions , 8, 15. This article provides an overview of typical alterations of spatial and temporal gait features related to three basic syndromic scenarios: (1) gait ataxia and unsteadiness of gait with fall risk; (2) hypokinesia and slow gait; (3) fall tendency in complex situations . A special emphasis is placed on the relevance of gait findings for supporting clinical differential diagnosis.\u00ae, CIR System, Franklin, NJ, USA). A multi-condition assessment protocol with walking at self-chosen walking speed (PWS), at slow speed (SS), at maximally fast speed (MS), with reclination of the head (HR), with eyes closed (EC), with performance of a serial seven dual task (DTC), with performance of a verbal fluency dual task (DTS), and while carrying an empty tray (DTM) was performed as described elsewhere [The clinical gait profiles, which are discussed in the subsequent paragraphs were recorded on a pressure-sensitive gait carpet . The healthy control group was collected by direct recruitment and covers the age spectrum from 18 to 99\u00a0years. The resulting data are arranged in a color-coded data matrix that at first glance provides a rapid overview on the individual patient\u2019s gait performance under various challenging conditions in comparison to age- and gender-matched healthy reference performance , gait paThe hallmarks of the gait impairments in patients with sensory deficits, cerebellar disorders, or functional ataxia comprise\u00a0distinct alterations in variability and support domains of walking. Accordingly, the spatial and temporal variability of stepping is typically increased in these cohorts \u2014a gait aWalking pace in patients with cerebellar and sensory ataxia is typically preserved or only slightly decreased. This observation can be explained by the fact that sensory integration for gait stabilization is speed dependent and less essential during fast locomotion . AccordiThe characteristic modulation of ataxic gait impairments during multi-condition gait assessment can further support the differential diagnosis in the context of gait ataxia. Slow walking modes accentuate gait instability in patients with vestibular and cerebellar disorders, in particular in terms of a considerably increased gait variability . As mentHypokinetic gait patterns can be observed in patients with Parkinsonism, patients with subcortical vascular encephalopathy (SAE), and patients with normal pressure hydrocephalus (NPH). The general identification of hypokinetic gait is not challenging for experienced neurologists. Typical features of gait impairments related to this syndromic category include a reduction of stepping pace, a reduced stride length, and reduced foot clearance during swing phases. Variability measures can be increased, especially in the late course of disease or when freezing-of-gait episodes are present . PatientIn hypokinetic gait disorders, alterations of gait parameters typically persist during all examination conditions. Patients with SAE or NPH show a further decline of walking performance during cognitive dual task , 26, 30\u2014Besides the interaction of sensory feedback with supraspinal and spinal locomotor regions, human postural control also relies on cognitive and attentional capacities. Patients with mild cognitive dysfunctions frequently consult clinical centers for balance problems due to apparent locomotion impairments. They typically report a slowing of gait during real-world mobility and the occurrence of falls in complex mobility situations. The clinical examination of sensory functions and simple motor tasks does not show any significant findings in these patients. Instrument-based gait analysis shows normal gait performance during single-task walking, but typically yields strikingly abnormal findings during cognitive dual-task conditions. Accordingly, walking pace and stride length become considerably decreased and walkDisturbances of mobility and gait are major symptoms of patients with balance disorders, dizziness, or vertigo. They are related to deteriorations of the functional status and to severe health outcomes, such as falls and fall-related morbidity . The cli"} {"text": "Mild traumatic brain injury (mTBI) represents more than 80% of total TBI cases and is a robust environmental risk factor for neurodegenerative diseases including Alzheimer\u2019s disease (AD). Besides direct neuronal injury and neuroinflammation, blood\u2013brain barrier (BBB) dysfunction is also a hallmark event of the pathological cascades after mTBI. However, the vascular link between BBB impairment caused by mTBI and subsequent neurodegeneration remains undefined. In this review, we focus on the preclinical evidence from murine models of BBB dysfunction in mTBI and provide potential mechanistic links between BBB disruption and the development of neurodegenerative diseases. Traumatic brain injury (TBI) is a leading cause of death and long-term disability around the world . Based oThe BBB is a highly selective membrane that mainly encompasses endothelial cells, sealed by tight junctions, and fortified by pericytes and astrocytic endfeet . This coMore importantly, clinical data indicated that BBB impairment can persist for many years and is highly associated with long-term neurological deficits in mTBI patients . TherefoMurine models have helped us tremendously to understand the pathogenic events after mTBI, including cerebral microvascular injury and BBB dysfunction. We searched over 6,000 publications related to mTBI on PubMed and found 232 studies potentially covering cerebrovascular impairment and BBB dysfunction . Among tin vivo imaging techniques including magnetic resonance imaging (MRI) and multi-photon imaging; and (iii) additional methods such as brain water content calculation for cerebral edema (wet/dry weight ratio). Analysis of the protein and mRNA expression of tight junction protein was also reported.We surveyed the BBB dysfunction and relevant pathologic changes found in mouse or rat models, covering the acute and subacute stages that evolve within the first 2 weeks after mTBI and the chronic stage that usually takes place 2 weeks after mTBI. The methods commonly used for BBB functional analysis in murine models are (i) histological assessment using plasma proteins such as immunoglobulin G (IgG) and/or exogenous tracers such as Evans blue dye, horseradish peroxidase (HRP), or fluoresce labeled albumin; (ii) via the in vivo two-photon imaging of intravenously injected rhodamine B. They showed that BBB disruption in wild-type C57BL/6 mice occurred at a very early stage of mTBI (between 5 and 60 min), which was even exacerbated in Slit2-Tg mice when compared with controls. Similar situations were also reported from patients diagnosed with concussion in adolescent sports and military service, which can be exacerbated by repetitive mild trauma injury . There aMechanistically, impairment of BBB can initiate a series of adverse events, including the leakage of serum-derived circulating agents into the brain parenchyma and improper activation of signaling pathways . As someMild traumatic brain injury is considered a long-term risk for neurobehavioral changes, cognitive decline, and neurodegenerative disease including AD . CognitiIn this review, we focused on BBB dysfunction after mTBI in murine models and found that BBB breakdown and microvascular impairment are important pathological mechanisms for cognitive impairment after mTBI. Restoring vascular functions might be beneficial for patients with mTBI and reduce the risk of developing cognitive impairments post-insult.ZZ and YW designed the review outline, wrote and reviewed the review, did the literature search, and data extraction and interpretation. HW, XG, and BP provided critical reviews, revised the manuscript, and provided relevant insights and edits. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "During recent years, Graduate Medical Education (GME) leaders in the United States of America have witnessed many substantive changes, including movement to a single accreditation system under the Accreditation Council for Graduate Medical Education. Both MD- and DO-trained residents and faculty must now meet an increasingly stringent set of accreditation standards outlined in Next Accreditation System standards. Specifically, updated scholarly activity standards emphasize a consistent volume and quantity of quality improvement/research projects and dissemination products. The GME literature to date has frequently provided general commentaries regarding individual project strategies or oriented to settings with greater project-related resources. There have also been few articles offering scholarly activity planning strategies for community-based GME officials striving to increase scholarly activity levels.The authors propose a customizable assessment-planning framework, largely derived from their combined decades of consultation experiences with hundreds of community-based resident and faculty projects. The authors will first describe the primary elements of their proposed scholarly activity planning approach for GME leaders so often subject to worsening resource constraints. They will describe six ongoing developmental strategies with several exemplars described. Such a framework will likely require ongoing reassessments and modification.The authors hope that this proposed planning framework will offer GME administrators, faculty and residents with a pragmatic set of strategies to develop scholarly activity projects and supports. Ideally, GME leaders can use this approach to inform their design of a sustainable system-customized infrastructure of scholarly activity supports. Next Accreditation System (NAS) standards.During recent years, the nation\u2019s graduate medical education (GME) leaders in the United States have witnessed substantive changes, including movement to a single accreditation system under the Accreditation Council for Graduate Medical Education (ACGME). Both MD and DO-trained resident and faculty physicians must now meet an increasingly stringent set of accreditation standards outlined in scholarly activity (SA) projects.SA to refer to both research and systems-oriented QIPS designs. Although both academic and community-based GME physicians contend with increasing resource constraints, a growing number of authors have contended that these types of challenges may be greater (or certainly different) in community-based GME settings.One particular standard that many GME authors have struggled to address relates to the enhanced requirements for Unfortunately, GME officials still lack a uniform definition of what comprises a minimal level of SA.More GME experts have concluded that community-based physicians may typically experience greater difficulty planning and conducting SA projects due to fewer available resources .Some GME authors have implemented SA resident teams, generally comprised of residents from multiple programs with complementary SA project interests.GME administrators have appointed later-year residents to chief research/QIPS resident positions to coordinate SA projects in some settings.Many authors have argued that any such mechanisms need to be modified due to system or program-specific influences, and that a standardized rollout approach is unlikely to work across diverse GME settings.Numerous experts have already shown that customized SA planning tools can help facilitate SA project development.non-sequential and ongoing strategies to enable community-based GME leaders to facilitate increased SA levels. The authors will also describe several exemplary settings with ongoing SA infrastructure developments.The SCS authors have developed this comprehensive planning approach from their 2016-2017 experiences consulting on over 210 community-based SA projects. Resident and faculty project leaders have requested SA consultations from many of the 190+ SCS-affiliated residency programs based at 37 healthcare systems. This paper will: a) describe the key elements of the authors\u2019 suggested SA developmental planning approach, and b) discuss six The first goal of this proposed SA planning framework is to provide community-based GME leaders with a specific set of criteria to assess their current in-house project resources and complexities. The authors propose that this approach will prove especially important for GME officials striving to first develop or improve their SA project supports. The authors have repeatedly seen that many community-based leaders\u2019 success in increasing their SA levels have required a broader perspective than simply completing a series of individual projects and dissemination products. In this paper, they assert that the longer-term development of a sustainable SA infrastructure of project supports will prove integral for maintaining SA productivity in lesser-resourced GME settings.lessons learned from earlier SA projects in their healthcare system. GME experts have increasingly supported this broader type of ongoing self-learning model of SA development that entails ongoing reassessments and modification efforts.stop and start approach to SA will impede the development of a sustainable SA project support infrastructure so later project leaders may feel as if they are starting from scratch.The key elements of this planning framework are largely derived from the authors\u2019 successful workshop, online module and individual consultation experiences with community-based GME leaders. They have concluded that many faculty and residents develop idealized projects without capitalizing on on-site resources, and/or conduct projects without the cultural realities: Faculty and resident SA attitudes and beliefs, varied specialty perspectives, perceived availability of project supports and mentoring.Referring to the upper-left of Figure 1, an effective SA support infrastructure should be oriented toward first developing projects that specifically capitalize on available specific resources, such as institutional review board (IRB) guidance, health library and data-capable personnel,Referring to the middle of Figure 1, certainly each SA project will need to be developed within the context of each project team\u2019s competing role demands .Referring to the right of Figure 1, over time, both the volume and quality of SA projects and dissemination products can be expected to increase and GME leaders may be able to realistically expect that improved SA levels will eventually impact patient care processes and outcomes.The following ongoing developmental strategies are encouraged for community-based GME leaders striving to attain an organized SA project support infrastructure:Periodically assess your project planners\u2019 SA learning needs and preferences by promoting available resources in an ongoing manner.It is also been shown to be necessary to periodically gauge the key learning needs of faculty and residents concerning SA projects.The SCS authors have generally concluded that many primary care physicians tend to prefer GME or QIPS project designs than surgical/procedure-oriented clinicians more oriented to complex research designs .Plan-Do-Check-Act planning sheets, pertinent articles, project conduction checklists, etc.) can prove key for first meeting the needs and preferences of lesser experienced project learners.GME leaders can certainly improve perceptions of available SA project resources by purposefully disseminating information concerning library, electronic health record and QIPS department materials and resources.non-human subjects, exempt, expedited, full review).GME officials should also periodically consider how their respective IRB have been distinguishing different types of SA projects by perceived level of research risks or types of suggested IRB applications program.One exemplar Te4Q learner was an emergency medicine physician who completed the program in 2016 after testing a QIPS curriculum with his senior chief resident.He had subsequently delivered this curriculum to two cohorts of residents with little SCS support. His curriculum-related projects have subsequently contributed at least a dozen regional/national resident poster presentations and two SA publications to date.Systematically embed SA planning activities into your pre-existing GME processes/groups.The GME literature contains a growing number of examples of how SA experts have incorporated project planning/evaluation activities into their current GME program/staff meetings.regular part of doing business in the minds of more residents and faculty.This approach may help SA activities become perceived as a Conduct a postmortem evaluation of every SA project and attempt to derive pragmatic system-specific knowledge for future projects.football coach analogy to GME officials striving to strengthen their SA team over several years by evaluating SA project successes and lessons. This routine practice of informing project novices about earlier project successes/failures may be integral for them to develop system-compatible projects. It is also unrealistic to expect a subset of residency programs or personnel to conduct most ongoing SA projects.writing mentor mechanisms since the responsibility of project leaders to report their community-based results in the GME literature remains increasingly important.GME officials may underestimate the impetus for future projects potentially derived from completed SA projects.The growing complexities of publishing one\u2019s final project results in many GME journals due to increased article processing fees and greater publication competition certainly needs to be acknowledged.Consider how to attain maximal SA efficiencies in your GME environment.Desire To Learn online course management software. QIPS in Healthcare: Origins and Principles, b) Research and QIPS: Differences and Similarities, c) Feasible Project Design Strategies, d) Preparing your IRB Application, and e) Building a Program of Scholarly Activity as a GME Leader. Between January 2016 and March 2018, 87 users have been enrolled and made over 280 group/individual module hits.Since many community-based GME leaders continue to experience worsening resource constraints, it may only be realistic to offer workshop/training content through coordinated asynchronous and online mechanisms.A growing number of GME experts have also indicated that it may become increasingly impractical for individual settings or programs to achieve sustainable SA progress without some type of intuitional/consortium coordination.There will never likely be any standardized solutions for development of sustainable project support SA infrastructures across our nation\u2019s diverse GME settings.This paper presents a non-sequential developmental planning approach comprised of strategies for community-based GME officials striving to address emerging accreditation standards. As GME setting conditions change, leaders\u2019 implemented SA project supports may require ongoing trial and error adjustments.The authors declare no conflict of interest."} {"text": "Studies using data from longitudinal health survey of older adults usually assumed the data were missing completely at random (MCAR) or missing at random (MAR). Thus subsequent analyses used multiple imputation or likelihood-based method to handle missing data. However, little existing research actually examines whether the data met the MCAR/MAR assumptions before performing data analyses. This study first summarized the commonly used statistical methods to test missing mechanism and discussed their application conditions. Then using two-wave longitudinal data from the Health and Retirement Study , this study applied different approaches to test the missing mechanism of several demographic and health variables. These approaches included Little\u2019s test, logistic regression method, nonparametric tests, false discovery rate, and others. Results indicated the data did not meet the MCAR assumption even though they had a very low rate of missing values. Demographic variables provided good auxiliary information for health variables. Health measures met the MAR assumptions. Older respondents could drop out and die in the longitudinal survey, but attrition did not significantly affect the MAR assumption. Our findings supported the MAR assumptions for the demographic and health variables in HRS, and therefore provided statistical justification to HRS researchers about using imputation or likelihood-based methods to deal with missing data. However, researchers are strongly encouraged to test the missing mechanism of the specific variables/data they choose when using a new dataset."} {"text": "Infections induce dramatic rearrangements in host macro- and micronutrient processes and like\u201cAntagonistic\u201d interactions between a host and a microbe involve host defense mechanisms that maintain the host\u2019s fitness status while having a negative impact on microbial fitness. By contrast, \u201ccooperation\u201d between a host and a microbe involves host mechanisms that promote host fitness while having a neutral to positive influence on microbial fitness . These mThe role of iron regulatory pathways in immunity against pathogens has been well studied (reviewed in ). HoweveSiderophores are molecules that chelate external iron with high affinity and transport iron into microorganisms through dedicated transport systems . Thus, sCaenorhabditis elegans physiological development [Fig 1A). Microbe-derived Ent was found to bind to the alpha subunit of the host mitochondrial ATP synthase, thereby increasing mitochondrial iron levels and host development under both low and high iron conditions. We propose that this work exemplifies iron-mediating cooperative host\u2013microbe interactions because development of the host facilitates replication, nutrient acquisition, and transmission of enterobacteria. Given that other canonical virulence factors for acquiring host iron are present in commensal or beneficial microbes, future work should reassess the role of these systems with the perspective of cooperative host\u2013microbe interactions.In addition to the role of siderophores in antagonistic host\u2013microbe coevolution, siderophores are also critical for interspecies competition between members of the microbiota . These ielopment Escherichia coli and Vibrio vulnificus, suggesting that transient hypoferremia is an effective metabolic defense to restrict certain extracellular pathogens [Salmonella enterica, Burkholderia pseudomallei, Chlamydia spp., and Legionella pneumophila [During acute infections, individuals experience inflammation-dependent hypoferremia . Hepcidiathogens , 21. Intumophila \u201324.Fig 1B). Regulation of iron levels was necessary for proper microbiome composition and mucosal repair because cDC-specific hepcidin-deficient mice were slower to recover following intestinal damage [In addition to hepatocytes, myeloid cell types are also a source of hepcidin production . In respl damage . TherefoDuring infections, microbial and host-derived toxic compounds can be generated that cause tissue damage. Detoxification mechanisms serve as antivirulence mechanisms to promote cooperative defenses by preventing damage to the host without affecting pathogen burdens . During Plasmodium or subjected to intestinal perforation leading to systemic bacterial infection [Plasmodium infection [Research into heme recycling and detoxification demonstrates the importance of these pathways for cooperative defenses . Heme denfection , 30. Thinfection , therebynfection . The HO-nfection . Given tFig 1C). Weis and colleagues established that the ferritin, the intracellular iron storage protein, regulates hepatic gluconeogenesis and is critical for host survival during polymicrobial sepsis [Recent dietary and metabolic studies in animals and humans link iron metabolism to glucose homeostasis at many levels (l sepsis . Knockoul sepsis . These sCitrobacter rodentium [C. rodentium infection caused increased tissue iron levels in the WAT and insulin resistance. The insulin resistance caused a reduction in the amount of glucose absorbed from the intestine into the bloodstream, increasing the amount of glucose available to the pathogen to metabolize, which suppressed the virulence program of C. rodentium [Sanchez and colleagues found that administration of dietary iron and transient insulin resistance promotes survival of mice given oral doses of the diarrheal pathogen odentium . Dietaryodentium . Consistodentium . The worodentium . TogetheAn entire field, called nutritional immunity, has focused on iron and other micronutrients in antagonism between host and invading microorganisms . Some in"} {"text": "Background: An estimated 25% of older adults with diabetes (DM) may have co-occurring Alzheimer\u2019s Disease and Related Dementias (ADRD), complicated by multiple treatment plans and providers. Assessing treatment burden has been limited to patients\u2019 perspectives; little is known about caregiver perceptions of treatment burden despite their important role in personal care and treatment adherence. The purpose of this qualitative study was to describe caregiver perceptions of treatment burden for older adults with DM-ADRD. Methods: This qualitative study was conducted in the formative phase of \u201cEnhanced Quality in Primary care for Elders with DM-ADRD (EQUIPED-ADRD) a pragmatic randomized controlled trial in a large, diverse healthcare system. A diverse sample of caregivers (n=15) of patients enrolled in the RCT participated in interviews about their caregiver role and perceptions of treatment burden of DM-ADRD clinical management. Qualitative data were analyzed using content analysis and themes about treatment burden were compared to domains on the Treatment Burden Questionnaire (TBQ). Results: Caregivers reported high levels of burden related to treatment plans for patients with DM-ADRD. Themes related to complexity and burden of medication management, monitoring , dietary and physical activity regimens, navigating healthcare providers and financial burden were reported. Caregivers also described high levels of emotional burden that was associated with patient\u2019s cognitive decline and family functioning stress. Conclusions: Interventions to reduce treatment burden for patients and caregiver should include activating social/nursing services, respite care and care coordination that may support caregivers especially as patient treatment increases in complexity over time."} {"text": "Chronic condition discordance has adverse mental health implications but little is known about mechanisms accounting for these links. We considered how chronic condition discordance at the individual level and the couple level was associated with perceived control among 2,676 couples from three waves of the Health and Retirement Study. Dyadic growth curve models revealed that when wives had greater individual-level discordance, they reported lower initial health-related control and personal mastery and steeper reductions in personal mastery. When husbands had greater individual-level discordance, they reported lower initial health-related control and faster declines in health-related control and personal mastery, and wives had faster declines in personal mastery. When there was greater couple-level discordance, wives reported lower initial health-related control. Targeting increases in perceived control among older couples managing complex conditions may be beneficial. Part of a symposium sponsored by Dyadic Research on Health and Illness Across the Adult Lifespan Interest Group."} {"text": "A standardized approach to annotating computational biomedical models and their associated files can facilitate model reuse and reproducibility among research groups, enhance search and retrieval of models and data, and enable semantic comparisons between models. Motivated by these potential benefits and guided by consensus across the COmputational Modeling in BIology NEtwork (COMBINE) community, we have developed a specification for encoding annotations in Open Modeling and EXchange (OMEX)-formatted archives. Distributing modeling projects within these archives is a best practice established by COMBINE, and the OMEX metadata specification presented here provides a harmonized, community-driven approach for annotating a variety of standardized model and data representation formats within an archive. The specification primarily includes technical guidelines for encoding archive metadata, so that software tools can more easily utilize and exchange it, thereby spurring broad advancements in model reuse, discovery, and semantic analyses."} {"text": "Over one in four older adults (65 years and older) in the US reports falling annually with estimated medical costs of $50 billion. Evidence-based strategies exist that can reduce falls with one of the most promising being multifactorial, clinically-based initiatives such as the Centers for Disease Control and Prevention\u2019s STEADI Initiative. STEADI includes three core components for health care providers: screen for risk factors, assess modifiable factors, and intervene to reduce falls with evidence-based strategies. Barriers to implementation include competing patient demands and limited time during patient visits. Efficient, effective implementation of clinical fall prevention is important to increase the use of multifactorial interventions. In addition, understanding older adult attitudes about the preventability of falls is needed to increase patient adherence to prescribed interventions. This symposium will cover:1. Background data on older adult falls over time,2. Description of an initial implementation of STEADI in an outpatient, Southeastern clinical practice including lessons learned,3. Attitudes of older adults toward fall prevention with implications for health promotion,4. Process evaluation of an ongoing implementation of STEADI in New York State with lessons learned. Understanding practical methods of implementing the three core components of fall prevention into practice supports wider dissemination of evidence-based fall prevention, while understanding patient attitudes toward falls informs the design of health promotion approaches to increase patient uptake of prescribed interventions. Wider dissemination and increased patient adherence in combination can reduce older adult falls and their associated medical costs."} {"text": "Late-life suicide is a complex public health issue, and older adults have a higher risk threshold than the national average . Most late-life suicide research focuses on elevated risk of older white males, and less is known about risk factors among Black older adults . Although fewer Black older adults die by suicide than White older adults, forms of suicidality do not differ between Black and White older adults . Suicide risk factors, such as psychological distress and chronic pain , are prevalent among Black older adults. According to the Interpersonal Theory of Suicide , thwarted belongingness and perceived burdensomeness inform the development of suicidal desire. These findings have been corroborated among older adult samples, though lacking racial diversity. To better understand how the IPTS functions for older adults, and probe whether suicide risk pathways operate differently depending on race, we used data from over 400 homebound older adults residing in a U.S. metropolitan area to clarify if this suicide risk pathway is similar for Black and White older adults. Race moderated the relationship between physical and psychological pain and thwarted belongingness and perceived burdensomeness, with pain among Black older adults having a greater impact on their sense of belonging and burdensomeness. Findings illuminate the need for culturally nuanced understandings of suicidality in older adulthood. The presenters will demonstrate these results and discuss implications for cross-cultural suicide prevention frameworks."} {"text": "Assisted living (AL) communities are increasingly home to frail, chronically ill older adults who remain until death. State laws mandate that AL facilities request copies of any advance care planning documents residents have and make forms available upon request. Using secondary data from a larger study funded by the National Institute on Aging (R01AG047408) that focuses on end-of-life (EOL) care in AL, this project investigated barriers and facilitators to conducting advance care planning in AL. Data included in-depth interviews (of 86 minute average length) with 20 administrators from 7 facilities around the Atlanta metropolitan area and aggregate data collected from each facility regarding facility, staff, and resident characteristics. Findings from thematic analysis of qualitative data showed that key barriers to planning in AL included lack of staff training and reluctance among administrators and families to discuss advance care planning and EOL care. Important facilitators included periodic follow-up discussions of residents\u2019 wishes, often during care plan meetings, educating families about the importance of planning, and external support for staff training and family education from agencies such as hospice and home health. Three study facilities exceeded state requirements to request and store documents by systematically encouraging residents to complete documentation. These facilities, whose administrators discuss advance care planning and residents\u2019 EOL wishes with residents and families during regular care plan meetings, were more likely to have planning documents on file, demonstrating the potential of long-term care communities, such as AL, to successfully promote advance care planning among residents and their family members."} {"text": "Adenosarcoma is an extremely rare malignancy of the female genital tract composed of stromal sarcoma with a benign epithelial component. Current treatment recommendations include total hysterectomy with bilateral salpingo-oophorectomy, precluding future fertility. Although most frequently diagnosed in postmenopausal women, it is occasionally present in younger women of reproductive age with desire for future fertility. In 2015, we reported the case of a 23-year-old patient diagnosed with uterine adenosarcoma, who having strong desire of future fertility, opted for fertility sparing surgery. At a follow-up five years later, we can now report her case of spontaneous pregnancy and livebirth. A review of the literature concerning fertility outcomes in patients with uterine adenosarcoma undergoing fertility sparing therapeutic options is presented. Uterine adenosarcoma (UA) is a rare gynaecological malignancy composed of sarcomatous stroma and a benign epithelial component . While tLee et al. describeA proposed fertility sparing treatment protocol includes fertility sparing surgery (FSS) consisting of a complete resection of the lesion followed by medical treatment with megestrol acetate 160 mg/day for at least 6 months. Once the desire for fertility is fulfilled, hysterectomy with bilateral salpingo-oophorectomy is recommended. A fertility sparing treatment protocol must be performed only in low-risk cases and close longterm follow-up is needed . PatientIn 2015, a nulliparous 23-year-old woman referred to our institution was diagnosed with UA stage IA according to FIGO 2009 criteria. Due to her strong desire of future fertility, after extensive counselling she opted for FSS. Hysteroscopic complete resection of the tumour was performed, followed by oral megestrol acetate 160 mg/d as adjuvant therapy . This waMullerian adenosarcoma is a rare gynaecological cancer composed of a benign epithelial component with sarcomatous stroma . Total hAdenosarcoma is an extremely rare gynaecological malignancy with only a few cases reported in patients of reproductive age. The current recommended treatment is hysterectomy with bilateral salpingo- oophorectomy, however, fertility sparing treatment options are feasible in selected patients.In cases of focal tumours without sarcomatous overgrowth and without sign of infiltration or metastasis, a fertility sparing approach may be proposed to young women diagnosed with UA and who strongly wish to preserve their fertility. There is currently insufficient evidence regarding the ideal follow up protocol for patients diagnosed with UA who are managed with FSS."} {"text": "Diversity and inclusion are essential perspectives on university campuses. In recent years, there has been a nationwide decline in admissions resulting in changes to traditionally FTIAC driven college campuses. An environmental scan was completed at a mid-sized midwestern university to explore age-inclusive barriers and opportunities for change. In-depth interviews were held with 28 EMU stakeholders representing a wide variety of ages in leadership positions across campus. Students aged 40 and above (N=248) were also surveyed about their experiences on campus. Qualitative analysis revealed ageist attitudes about older adults and older students from at all levels of the university. Results demonstrate that initial responses to \u2018age-friendly\u2019 focused on stereotypes of older adults, but attitudes adjusted when reframed as older learners and further refined when older learners were defined as 40 and above. Additionally, there was a distinct disconnect between ageist perceptions towards older adults and older students which highlights the importance of intergenerational opportunities as an approach to combat ageist attitudes on campus. While these barriers require long-term and complicated solutions, participants described the many benefits that older learners bring to enrich the campus. Results of this research revealed opportunities to reframe aging in the context of diversity and inclusion efforts on campus. Adopting diversity efforts to include age can benefit universities in not only admissions, classroom experiences, and connections to surrounding communities."} {"text": "Tachycineta bicolor). We address two questions: (1) do the cloacal bacterial communities differ between female and male tree swallows within a population? and (2) do pair-bonded social partners exhibit more similar cloacal bacterial communities than expected by chance? To answer these questions, we sampled the cloacal microbiome of adults during the breeding season and then used culture-independent, 16S rRNA gene amplicon sequencing to assess bacterial communities. Overall, we found that the cloacal bacterial communities of females and males were similar, and that the communities of pair-bonded social partners were not more similar than expected by chance. Our results suggest that social monogamy does not correlate with an increased similarity in cloacal bacterial community diversity or structure. As social partners were not assessed at the same time, it is possible that breeding stage differences masked social effects on bacterial community diversity and structure. Further, given that tree swallows exhibit high variation in rates of extra-pair activity, considering extra-pair activity when assessing cloacal microbial communities may be important for understanding how these bacterial communities are shaped. Further insight into how bacterial communities are shaped will ultimately shed light on potential tradeoffs associated with alternative behavioral strategies and socially-transmitted microbes.Host-associated microbial communities can influence the overall health of their animal hosts, and many factors, including behavior and physiology, can impact the formation of these complex communities. Bacteria within these communities can be transmitted socially between individuals via indirect or direct pathways. Limited research has been done to investigate how social interactions that occur in the context of mating shape host-associated microbial communities. To gain a better understanding of these interactions and, more specifically, to assess how mating behavior shapes an animal\u2019s microbiome, we studied the cloacal bacterial communities of a socially monogamous yet genetically polygynous songbird, the North American tree swallow ( Host-associated microbial communities can contribute to the overall health of their animal hosts \u20134, and mTachycineta bicolor) and house sparrows (Passer domesticus). More recent work using culture-independent methods has revealed that pair-bonded social partners experimentally blocked from making cloacal contact have significantly less similar cloacal bacterial communities compared to control pairs in black-legged kittiwakes (Rissa tridactyla) )munities . Given tStaphylococcus spp., Campylobacter spp., Salmonella spp., and Shigella spp. In our study, we used culture-independent, next-generation sequencing. We did not find that any of the cloacal bacteria they cultured were members of the core bacterial communities of birds within our study population. While Staphylococcus spp. and Lactobacilli were detected, their relative abundances were <0.001%. This suggests that culturing of cloacal bacteria may not consistently result in isolation of the most dominant bacteria in the system. It is also possible that the bacteria cultured by Lombardo et al. [Previous work examining the similarity of the cloacal bacteria of social partners in tree swallows used culture-dependent methods . The isoo et al. are rareIn conclusion, our results suggest that the cloacal bacterial communities of female and male tree swallows are similar within our study population and that pair-bonded social partners do not share more similar cloacal bacterial communities than expected by chance. Given that tree swallows exhibit high variation in rates of extra-pair activity, we argue that considering rates of extra-pair activity or the number of sexual partners per bird when assessing cloacal bacterial communities may be important for understanding how cloacal bacterial communities are structured. Also, since cloacal bacterial communities comprise bacteria derived from both the reproductive and digestive tract, diet should also be considered when assessing cloacal bacterial communities. Lastly, we suggest that pair-bonded social partners should be sampled simultaneously to control for any temporal shifts in individual behavior and physiology that may influence shifts in cloacal bacterial community structure across breeding stages."} {"text": "The Tailored Activity Program (TAP) is a proven program delivered primarily by occupational therapists addressing dementia-related clinical symptoms including caregiver well-being. Although used in 9 countries including the United States, scaling and widespread dissemination is challenging. We discuss key revisions to TAP to facilitate dissemination including matching assessments to those used in different practice settings, translation of materials into different languages, providing worksheets to help trainees adapt TAP to local contexts and a training/certification online experience using story board, an interactive media integrated onto the Blackboard learn management system, to provide on-demand training modules. The learning platform allows learners to engage with others, preview modules and share experiences. Revisions enable greater flexibility for program adaptation yet adherence to its core principles. With over 150 trainees, we use REAIM to evaluate effectiveness of modifications and to understand implications for its reach. Part of a symposium sponsored by the Behavioral Interventions for Older Adults Interest Group."} {"text": "Hematopoiesis and bone interact in various developmental and pathological processes. Neurogenic heterotopic ossifications (NHO) are the formation of ectopic hematopoietic bones in peri-articular muscles that develop following severe lesions of the central nervous system such as traumatic cerebral or spinal injuries or strokes. This review will focus on the hematopoietic facet of NHO. The characterization of NHO demonstrates the presence of hematopoietic marrow in which quiescent hematopoietic stem cells (HSC) are maintained by a functional stromal microenvironment, thus documenting that NHOs are neo-formed ectopic HSC niches. Similarly to adult bone marrow, the NHO permissive environment supports HSC maintenance, proliferation and differentiation through bidirectional signaling with mesenchymal stromal cells and endothelial cells, involving cell adhesion molecules, membrane-bound growth factors, hormones, and secreted matrix proteins. The participation of the nervous system, macrophages and inflammatory cytokines including oncostatin M and transforming growth factor (TGF)-\u03b2 in this process, reveals how neural circuitry fine-tunes the inflammatory response to generate hematopoietic bones in injured muscles. The localization of NHOs in the peri-articular muscle environment also suggests a role of muscle mesenchymal cells and bone metabolism in development of hematopoiesis in adults. Little is known about the establishment of bone marrow niches and the regulation of HSC cycling during fetal development. Similarities between NHO and development of fetal bones make NHOs an interesting model to study the establishment of bone marrow hematopoiesis during development. Conversely, identification of stage-specific factors that specify HSC developmental state during fetal bone development will give more mechanistic insights into NHO. Heterotopic ossification (HO) is an abnormal development of bone tissue within soft tissue. HO can be hereditary such as Fibrodysplasia Ossificans Progressiva (FOP) or acquired following traumatic injuries and burns . Among aACVR1 gene encoding a type I BMP receptor . The patIt is currently admitted that NHOs are the result of an endochondral ossification process although intramembranous ossification has also been suggested . Foley eThe development of heterotopic bones in muscles after severe CNS trauma raises interesting stem cell biology questions particularly regarding the cells-of-origin of NHO. Adult skeletal muscles contain two major types of progenitor cells participating in muscle regeneration. Myogenic satellite cells (SCs) are CD56 expressing stem cells located between the basal lamina and myofiber plasma membrane. To regenerate damaged myofibers, activated SCs proliferate, differentiate into myoblasts and fuse to form multinucleated myofibers with the support of macrophages, endothelial cells (ECs), fibroblasts and pericytes or FAPs (via a Prrx1 gene enhancer transgene) are specifically labeled, we find that following SCI, NHO are derived from Prrx1 expressing FAPs, not from Pax7 expressing SCs and central (SCI) neurologic lesions have an effect on FAPs, inducing STAT3 activation, high IL-6 secretory activity and abnormal proliferation . FurtherThe presence of ectopic hematopoietic bones developing in muscles following CNS injuries is puzzling for the hematologist since, in adults, hematopoiesis is physiologically restricted to the BM of skeletal bones.During fetal development, blood formation occurs in discrete anatomical extraembryonic and intraembryonic niches, generating different hematopoietic cell (HC) types . First HSchofield first used the term \u201cniche\u201d to describe a putative HSC-specific environment in the BM that \u201cpreserved the reconstituting ability of stem cells\u201d . SuccessWithin these niches, HSCs are maintained quiescent by a complex molecular interplay between cells from mesenchymal origin, ECs, neuronal cells and HSC progenies, such as megakaryocytes and macrophages. Diffusible factors including inflammatory cytokines and extra-cellular matrix components perfect this molecular network, subtly controlling the fate of HSCs .Apart from stromal cells, macrophages are essential to HSC regulation within niches. They are the most abundant HCs in the dorsal aorta when the number of intra-aortic hematopoietic cluster peaks, and are suggested to promote definitive HSC formation from the dorsal aorta hemogenic endothelium through pro-inflammatory signaling cascades . Among tIn the context of NHO, it is noteworthy to integrate the role of the nervous system as an important regulator of bone remodeling and hematopoiesis homeostasis. Since the discovery of skeleton innervation by Besides its role in energy homeostasis, leptin plays a major role in neuroendocrine regulation and bone metabolism. The expression of leptin receptor on adult MSCs, osteoblasts and chondrocytes, suggests direct effects on bone growth and metabolism. Leptin can also indirectly modulate bone formation through effectors downstream of the hypothalamus such as estrogen, cortisol, IGF-1 and parathyroid hormone, and through activation of local adrenergic signaling at the osteoblast level via \u03b22 adrenergic receptors (AR) . SensoryAs reported above, HSCs are mainly located in perivascular areas of the adult BM, comprising both sinusoidal and arteriolar blood vessels. The arteriolar structures are highly innervated by SNS fibers. The neuroreticular complex formed by SNS nerves and perivascular MSCs has been reported to be a central regulator of HSC quiescence within BM niches mice that lack osteoblasts and osteolineage cells, the vasculature within the nascent bones and bone marrow can sustain multilineage proliferative progenitors but not long-term HSCs. As a result, wild-type HSC transplanted in Osx embryos engraft the liver but not the nascent BM. Therefore, interactions with osteoblasts within fetal bone regulate HSC quiescence and homing ability (Cxcl12 or Kitl gene from Osx+ osteoprogenitors has more effect on hematopoietic progenitors than on proper HSCs (Lepr+ MSCs (that form osteoprogenitors) for HSCs to be maintained (In Osterix-null (Osx ability . In the per HSCs . In contintained . These rUnderstanding the development of hematopoiesis in an adult osteogenic muscle environment as observed in NHO could help gain further insights on the role of bone forming cells in this process. Identification of stage-specific factors that orientate HSC developmental state during fetal bone development must be harnessed to gain more mechanistic insights into NHO development. Similarly, understanding the cellular origin of NHO, the role of inflammation and muscle environment might contribute to a better understanding of the impact of specific niche components on fetal BM HSC properties.In the recent few years, knowledge about NHO pathogenesis has been considerably improved as accredited by the rapidly increasing number of publications in the field. These progresses were mainly due to the development of more suitable animal models and to the availability of patient samples thanks to well organized cohorts. The current review focusing on the hematopoietic features of NHO ossifications, attempts to recapitulate how a favorable environment for the development of bone with HSC niches can develop in adult muscles following central neurological lesions. It emphasizes the role of a persistent inflamed muscle environment driving FAPs to an osteogenic fate initiating the development of ossification followed by the establishment of a mature hematopoietic bone tissue.However, there are still numerous questions in respect to the molecular mechanisms underlying this complex and multifactorial pathological process. Among those, the potential differences between normal endochondral ossification and neurogenic HO in terms of signaling events, cell type involvement and environment remains unanswered. Likewise, how an inflamed adult muscle environment becomes pro-osteogenic and thereafter hematopoietic, and what is the influence of altered nervous and neuroendocrine systems as well as hypoxia in this process? Does the neoformation of hematopoietic bones in muscles mimic what happens during development and can we learn from NHO for a better identification of stage-specific factors that specify HSC developmental state during fetal bone development? Is the impaired mobility of patients a trigger in the development of NHO and does an early and adequate mobilization of patients can avoid or at least reduce its evolution?Gathering surgeons, clinicians, specialists in physical medicine/rehabilitation and researchers within a European/International consortium would be a provocative initiative for developing translational collaborative projects to better understand NHO pathogenesis and, armed with this knowledge, enable the identification of new targets to treat and if possible prevent NHO development. Moreover, such knowledge may also provide new insights for cell therapy needs and for improving treatment of blood and bone disorders.DG, FT, EO, KA, JG, H-WT, MS, J-PL, M-CL, and SB wrote the manuscript. DG, EO, M-CL, and SB prepared the figures. All authors revised the manuscript and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Family caregivers often manage complex medical/nursing tasks (MNTs) for older adults returning home after a hospitalization. The purpose of this qualitative study was to describe caregivers\u2019 experiences leveraging diverse resources to manage MNTs for older adults receiving post-acute home health care services (HHC). In-depth telephone interviews were conducted with 20 caregivers of older adults who received HHC following hospitalization. Interviews were digitally audio-recorded, transcribed, and analyzed using directed content analysis. The Theory of Dependent-Care informed the analytical framework. We organized codes using three theoretical constructs related to managing older adults\u2019 MNT care needs (\u201ctasks related to the other\u201d), accessing existing social/environmental resources (\u201ctasks related to the situation of care\u201d), and working with the healthcare system (\u201ctasks related to the system of care\u201d). Caregivers\u2019 descriptions of MNTs included the complexity and socioemotional impact of assisting in these tasks . When needed, caregivers\u2019 accessed social and environmental resources to help address the older adults\u2019 care needs. Caregivers also identified challenges and strategies for navigating and coordinating care and services within HHC and the larger healthcare system. Caregivers assisting with complex MNTs in the post-acute HHC setting need additional training and support. HHC providers can actively engage caregivers by tailoring training and support strategies, assessing social and environmental contexts and resources, and facilitating caregivers\u2019 navigation of the healthcare system. Future research could elucidate social and environmental factors associated with successful collaborative relationships among providers, older adults and their caregivers in the post-acute HHC setting."} {"text": "Research demonstrates reciprocal relationships between personality and depression as well as the important role interpersonal conflicts play, but rarely explores these risk factors in older adults. This study aimed to examine relationships of personality traits, processes, and the impact of emotional involvement and distress during an interpersonal conflict on depression in older adults. The study also investigated whether emotional involvement or interpersonal distress moderate the relationship between personality pathology and depression. Depressed middle and older adult inpatients completed self-reports and interview-based assessments regarding personality traits , interpersonal problems (IIP-25), and depression (GDS). Narrative responses regarding an interpersonal conflict were obtained and rated for contamination themes as well as emotional involvement and distress. Overall, findings indicated that living with others predicted higher depression (p= .046) and was related to higher neuroticism and interpersonal problems. Personality traits (Neuroticism) and processes , as well as higher levels of emotional distress and involvement in an interpersonal conflict were also tied to depression in bivariate but not multivariate analyses. The moderating effects of emotional involvement or distress on the relationship between personality and depression were not supported. Depressed older inpatients who live with others appear at higher risk of depression. Personality traits and processes may be more distal risk factors for depression. Findings are discussed in relation to stress generation as well as clinical implications targeting emotional regulation."} {"text": "Dear Editor th, they confirmed that they had identified a new coronavirus, which is a family of microRNA respiratory viruses including the common cold, and viruses such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). This new virus was temporarily named \u201c2019-nCoV\u201d. Wuhan city is a major international transport hub. This report to World Health Organization (WHO), raised global public health concern because this is the third coronavirus \u2013associated acute respiratory illness outbreak. On 31 December 2019, Chinese authorities reported the increase in incidence of severe pneumonia in Wuhan city, Hubei province of China. One week later, on January 7Currently, up to the date of submitting this letter, 4593 cases of 2019-nCoV infections have been confirmed globally, both in China and outside of China (56 confirmed in 14 countries.). WHO risk assessment of 2019-nCoV infection is Very High in China and High in other countries or severe pneumonia, Acute Respiratory Distress Syndrome (ARDS), sepsis and septic shock. Patients with pre-existing medical comorbidities develop a more severe disease and have higher mortality rates compared to patients who do not have any comorbidity.Clinical care of patients with suspected 2019-nCoV should focus on early recognition, immediate isolation (separation), implementation of appropriate infection prevention and control (IPC) measures and provision optimized supportive care. At the triage of an Emergency room, early recognition of suspected patients allows for timely initiation of IPC. 2019-nCoV should be considered as a possible etiology of influenza like illness (ILI) under certain situations according to case definitions of WHO or non-invasive ventilation (NIV) should be used in selected patients with hypoxemic respiratory failure. Hypoxemic respiratory failure due to ARDS among these patients commonly results from intrapulmonary ventilation-perfusion mismatch or shunt and usually requires mechanical ventilation. Thus, rapid sequence intubation should be performed using airborne precautions. Implementation of mechanical ventilation using lower tidal volumes (4-8 ml/kg predicted body weight) and higher positive end-expiratory pressure (PEEP) is suggested. Patients with SARI should be treated cautiously with intravenous fluids when there is no evidence of shock, because aggressive fluid resuscitation may worsen oxygenation. For resuscitation of septic shock in adults, at least 30 ml/kg of isotonic crystalloid should be infused in the first 3 hours of shock identification and in children rapid bolus of 20 ml/kg as loading dose and up to 40-60 ml/kg of isotonic crystalloid infusion in the first hour of shock identification is needed. Vasopressor should be administered when shock persists during or after fluid resuscitation. If signs of poor perfusion persist despite reaching mean arterial pressure (MAP) target (i.e. >65 mmHg) with fluids and vasopressor, consider administering an inotrope such as dobutamine. Empiric antimicrobials should be initiated within one hour of identification of sepsis to treat all likely pathogens causing SARI. Empiric antibiotic treatment should be based on the clinical diagnosis of severe pneumonia or sepsis, local epidemiology and susceptibility data as well as treatment guidelines. If influenza is also a concern and there is a local circulation of influenza virus, a neuraminidase inhibitor should be adjoined to empiric therapy. Empiric antibiotic therapy should be de-escalated on the basis of microbiology results and clinical judgment. Systemic corticosteroids should not be routinely adding to therapy unless indicated for another reason. Collection of clinical specimens for laboratory diagnosis is suggested in early outbreak period and after that it is only advised for investigational purposes. If laboratory diagnosis is considered, serology is recommended only when RT-PCR is not available. Otherwise, HCW should collect specimens from both the upper respiratory tract and lower respiratory tract for testing 2019-nCoV via RT-PCR should be developed and implemented in the emergency departments, as the frontline of treating human infections of 2019-nCov in the hospitals."} {"text": "Increased systolic blood pressure (SBP), pulse pressure and carotid-femoral pulse wave velocity (cfPWV) are strong predictors of cardiovascular events. The aorta and carotids are both elastic arteries susceptible to arterial stiffening and its deleterious complications. The relative importance of ascending aortic and carotid stiffness on central arterial stiffness remains unclear.Our aim was to study the relationship of local arterial stiffness in the carotid and ascending aorta to central arterial stiffness assessed by cfPWV and peripheral BP.We studied 22 healthy subjects . Central arterial stiffness was determined using carotid and femoral tonometry and transit surface distances (cfPWV). Distensibility of the ascending aorta was calculated as the ratio of its transverse area change on MRI to the central pulse pressure from radial tonometry arterial waveforms using a transfer function. Carotid distensibility was calculated as the ratio of transverse area change by sonography to carotid pulse pressure by tonometry. Local stiffness indexes of carotid and aorta were calculated from distensibility by the reverse Moens-Korteweg equation. Peripheral SBP and pulse pressure were averages of 6 brachial measurements. Linear regression was used to study correlations between aortic and carotid stiffness and cfPWVAortic stiffness has a significantly stronger correlation than carotid stiffness with: age , peripheral SBP , pulse pressure , and cfPWV . In multivariate analysis with simultaneous adjustment for age, body mass index, SBP, pulse pressure, aortic stiffness and carotid stiffness, aortic stiffness is the strongest independent determinant of cfPWV (p = 0.013), SBP (p = 0.005) and pulse pressure (p = 0.01).Stiffness of the ascending aorta is a stronger predictor of cfPWV and peripheral SBP and pulse pressure than carotid stiffness among healthy individuals. This is consistent with heterogenous age-related stiffening of large arteries."} {"text": "This study reviews the existing literature on psychiatric interventions for individuals affected by the COVID-19 epidemic. My article cumulates previous research on how extreme stressors associated with COVID-19 may aggravate or cause psychiatric problems. The unpredictability of the COVID-19 epidemic progression may result in significant psychological pressure on vulnerable populations. Persons with psychiatric illnesses may experience worsening symptoms or may develop an altered mental state related to an increased suicide risk. The inspected findings prove that psychological intervention measures for patients affected by the epidemic should be designed and personalized adequately. Preventive measures seek to decrease infection rates and cut down the risk of the public healthcare system to eventually be overburdened. Throughout the COVID-19 crisis, people with psychiatric illnesses may confront a decrease in mental health services. As limitations in the current review, by focusing only on articles published in journals indexed in Web of Science, Scopus, and ProQuest, I inevitably disregarded other valuable sources. Subsequent research directions should clarify the effectiveness of online mental health services in providing remote psychiatric interventions to individuals affected by the COVID-19 epidemic. COVID-19 has placed a significant strain on health systems on a large scale . There mAdequate conformity to spatial distancing in addition to home confinement, self-isolation, and quarantine may have the repercussion of social disconnection with adverse effects for psychological wellbeing . The manOn The COVID-19 epidemic has generated extreme stressors that may aggravate or cause psychiatric problems, affecting the brain or generating immune reactions. Emotional responses comprise intense psychosocial distress and insecurity. Such patients need timely, precise information concerning approaches for diminishing risk.COVID-19 pandemic-related, compulsory self-isolation, home confinement, and quarantine are related to poor psychological and physical health . Taking On Infectious disease outbreaks such as COVID-19 bring about mental health conditions as individuals\u2019 emotional reactions tend to comprise extreme fear and confusion, while their anxious responses may lead to socially disruptive behaviors. Symptoms such as anxiety, nervousness, and insomnia may occur in COVID-19 infected patients with psychiatric disorders.The level of risk of COVID-19 spread among persons having a severe mental illness may be more significant than that in the general population, as a consequence of constant unhealthy behaviors and standards of living . IndividAs On People with mental health disorders may be more considerably affected by the emotional reactions generated by the COVID-19 epidemic. Affected individuals are exposed to mental health disorders and suicidal ideation and behavior, resulting in pervasive emotional distress and heightened risk for psychiatric disorders. Social relationships are pivotal in suicide prevention.The swift spread of COVID-19 and important death rate may aggravate the risk of mental health issues and intensify current psychiatric symptoms, damaging their proper functioning and cognition to a greater extent . The conThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} {"text": "Long-term care residents with and without cognitive impairment may experience undertreatment of persistent pain . Certified nursing assistants (CNAs) are important sources of information about resident pain as they provide the majority of residents\u2019 hands-on care. Therefore, assessing the accuracy of CNAs\u2019 pain assessments and potential influencing factors may provide insight regarding the undertreatment of pain. Informed by prior research, this study examined resident pain catastrophizing and cognitive status as predictors of CNAs\u2019 pain assessment accuracy. CNA empathy was examined as a moderating variable. Analyses confirmed a relationship between pain catastrophizing and CNA pain rating accuracy , reflecting lower accuracy of ratings for residents higher in catastrophizing. Hypotheses predicting a relationship between resident cognitive status and CNA pain rating accuracy and moderating effects of empathy were disconfirmed. Challenges of conducting research in long-term care are discussed."} {"text": "Objective: Using the stress-coping theory, the aims of the present study were to test what levels of caregiving intensity posed the most negative influence on caregiver burden as well as how social support moderated such associations among dementia caregivers. Methods: Data from the baseline assessment of the Resources for Enhancing Alzheimer\u2019s Caregiver Health (REACH II) (N = 637) were used. Caregiver burden , caregiving intensity (caregiving hours), and social support were the main measurements. Separate multivariate regression models were conducted with Stata 16. Results: The results showed that the relationships between caregiving hours and caregiver burden were nonlinear after controlling all of the socio-demographic variables. Further analyses showed that when caregiving hours reached 13.50 hours per day, the levels of burden were the highest. In addition, received social support, satisfaction with social support, and social network significantly moderated the relationship between caregiving hours and caregiver burden among dementia caregivers when they were examined separately. However, only social network played a significant moderator role when examining the four social support indicators simultaneously. Discussion and conclusion: These findings suggest the need for programs and practices on educating caregivers regarding how to identify, approach, and gain social support/s, especially in how to broaden the caregivers\u2019 social network while caring for a family member with dementia."} {"text": "Carefully maintained and precisely inherited chromosomal DNA provides long-term genetic stability, but eukaryotic cells facing environmental challenges can benefit from the accumulation of less stable DNA species. Circular DNA molecules lacking centromeres segregate randomly or asymmetrically during cell division, following non-Mendelian inheritance patterns that result in high copy number instability and massive heterogeneity across populations. Such circular DNA species, variously known as extrachromosomal circular DNA (eccDNA), microDNA, double minutes or extrachromosomal DNA (ecDNA), are becoming recognised as a major source of the genetic variation exploited by cancer cells and pathogenic eukaryotes to acquire drug resistance. In budding yeast, circular DNA molecules derived from the ribosomal DNA (ERCs) have been long known to accumulate with age, but it is now clear that aged yeast also accumulate other high-copy protein-coding circular DNAs acquired through both random and environmentally-stimulated recombination processes. Here, we argue that accumulation of circular DNA provides a reservoir of heterogeneous genetic material that can allow rapid adaptation of aged cells to environmental insults, but avoids the negative fitness impacts on normal growth of unsolicited gene amplification in the young population. E. coli and asexual yeasts reveal that strains with high mutation rates outperform those with low mutation rates, showing that mutation provides an adaptive advantage to several megabases are highly focused in aged cells and are suggested to drive premature ageing and shortened lifespan , and is instead generated from chromosomal DNA at such a high rate that simple asymmetric retention of the newly generated copies in the mother cell is sufficient for CUP1 accumulation , the most transcribed protein-coding gene in muscle tissue, is also the largest producer of circular DNA per gene (Moller et al. Excitingly we have observed that the rate of copy number variation events including circular DNA formation is not completely random, which may improve this cost\u2013benefit balance for aged cells (Hull et al. By itself, an adaptive phenotype in an individual aged cell is of little use if the causal circular DNA is selfishly retained in the mother cell, as would be the case if asymmetric segregation is maintained, and we must consider how circular DNA accumulation is translated into a heritable advantage. First, once circular DNA has accumulated, segregation can be relaxed under stress allowing circles with replication origins to propagate at high copy number in the population Fig.\u00a0, step 5aThe idea that a sub-population trades short-term growth for adaptive capacity is formalised in bet-hedging (concisely reviewed in (Levy et al."} {"text": "The primary impact of ventilation and ventilatory efforts on left ventricular (LV) function in left ventricular dysfunction relate to how changes in intrathoracic pressure (ITP) alter the pressure gradients for venous return into the chest and LV ejection out of the chest. Spontaneous inspiratory efforts by decreasing ITP increase both of these pressure gradients increasing venous blood flow and impeding LV ejection resulting in increased intrathoracic blood volume. In severe heart failure states when lung compliance is reduced, or airway resistance is increased these negative swings in ITP can be exacerbated leading to LV failure and acute cardiogenic pulmonary edema. By merely reversing these negative swings in ITP by the use of non-invasive continuous positive airway pressure (CPAP), these profoundly detrimental forces can be immediately reversed, and cardiovascular stability can be restored in moments. This forms the clinical rationale for the immediate use of CPAP for the treatment of acute cardiogenic pulmonary edema. Increasing ITP during positive pressure ventilation decreases the pressure gradients for venous return and LV ejection decreasing intrathoracic blood volume. In a hypovolemic patient even with LV dysfunction this can result in hypotension due to inadequate LV preload. Minor increases in ITP as occur using pressure-limited positive-pressure ventilation primarily reverse the increased LV afterload of negative swings in ITP and if fluid overload was already present, minimally alter cardiac output. The effect of changes in lung volume on LV function are related primarily to its effects on right ventricular (RV) function through changes in pulmonary vascular resistance and overdistention (hyperinflation). In acute lung injury with alveolar collapse, positive pressure ventilation may reduce pulmonary vascular resistance if alveolar recruitment predominates. Hyperinflation, however, impedes diastolic filling while simultaneously increasing pulmonary vascular resistance. Thus, increasing lung volume can reduce RV afterload by reversing hypoxic pulmonary vasoconstriction or increase afterload by overdistention. Hyperinflation can also impede RV filling. All of these processes can be readily identified at the bedside using echocardiography. Understanding the hemodynamic coupling of the heart and lungs plays a significant role in managing patients in the critical care setting. The basic heart-lung physiology has been discovered earlier in the collection of papers. Understanding diastolic and systolic left heart failure is of upmost importance when treating patients with a variety of other common medical conditions such as sleep apnea, ARDS and COPD as these conditions are deeply intertwined. These interactions are magnified in the setting of decreased left ventricular (LV) function. Here we seek to explain how clinical presentations affect the left ventricle and how management of these conditions can have a profound effect on LV function. For simplistic sake, the forces that cause clinically relevant heart-lung interactions are illustrated in There are multiple aspects of cardiopulmonary physiology that affect patients with heart failure. Lung volume and hyperinflation affect autonomic tone and pulmonary vascular resistance. In 1966 de Burgh Daly et al. showed that the correlation between systemic vascular resistance and ventilation was secondary to reflexes from intrapulmonary receptors altered by changes in lung volume. Lung inflation by either negative or positive intrathoracic pressure (ITP), in the setting of blocked carotid sinus and aortic arch baroreceptors, led to an immediate decrease in systemic vasomotor tone . FurtherHere we will discuss the importance of heart-lung interactions in various clinical scenarios including acute cardiogenic pulmonary edema (ACPE), ventilatory weaning, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), and acute respiratory distress syndrome (ARDS).Left heart failure can be characterized by systolic dysfunction, diastolic dysfunction, or both. In developed countries, systolic ventricular failure is most commonly associated with ischemia and hypertension, which also contributes to diastolic dysfunction. In other parts of the world, Chagas disease and rheumatic heart disease are more prevalent causes. Understanding heart lung interactions is essential for the management of all left heart failure patients. Negative intrathoracic pressure leads to increased LV transmural pressure increasing LV afterload. In patients with left heart failure, negative swings in intrathoracic pressure can markedly decrease LV ejection leading to rapid increases in LV filling pressure and secondary (hydrostatic) pulmonary edema. The spontaneous breathing efforts also represent a metabolic stress on the body. During periods of increased work of breathing, spontaneous ventilation increases oxygen demand of respiratory muscles as well as of the myocardium and may induce circulatory insufficiency and visceral organ ischemia .Based on these principles the primary treatment of acute cardiogenic pulmonary edema should be the immediate abolishment of negative swings in ITP. While hypovolemic patients may decrease their cardiac output when positive pressure ventilation is initiated due to the decrease in preload (moving leftward on the ventricular function curve), these effects are minimized if continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) are used in patients with acute heart failure, because the spontaneous inspiratory efforts remain but the negative swings in ITP are markedly diminished or abolished. Thus, CPAP and BiPAP selectively reduce LV afterload shifting the ventricular function curve upward in patients with acute heart failure without decreasing venous return. Numerous clinical trials have shown the immediate beneficial cardiovascular effects of initiating CPAP or BiPAP. These findings were reinforced by a meta-analysis by Weng et al. showing less need for endotracheal intubation and a trend toward reduced mortality when non-invasive ventilation is initiated on patients presenting with acute cardiogenic pulmonary edema . UnfortuPatients subjected to hyperinflation and increased juxtacardiac pressure will experience a drop in biventricular volumes. Furthermore, some of these effects, including decreased vasomotor tone, may be affected by induction of anesthesia during initiation of mechanical ventilation. Lung inflation with volumes less than 10\u00a0mL per kilogram of body weight leads to vagal tone withdrawal and, consequently, an increase in heart rate. This is known as respiratory sinus arrhythmia. On the other hand, lung hyperinflation with volumes greater than 15\u00a0mL per kilogram of body weight leads to vagal tone activation and sympathetic tone withdrawal. In such cases, patients exhibit a decrease in blood pressure secondary to vasodilation from a decrease in systemic vasomotor tone. Many patients with LV failure are also hypervolemic owing to increased antidiuretic hormone activation. Thus, in volume overloaded patients with heart failure, initiation of mechanical ventilation and some degree of lung hyperinflation will decrease preload, cause vasodilation and, thereby, decrease intrathoracic blood volume. In those settings, the slight decrease in LV afterload may augment LV ejection keeping cardiac output constant despite a sustained increase in ITP. These are the reasons why patients with LV failure usually tolerate intubation and positive-pressure ventilation well without secondary post-intubation hypotension .Weaning patients from positive pressure ventilation results in several processes occurring simultaneously. First, respirations change from positive swings in ITP to negative swings in ITP. This must increase venous return and LV afterload. The combined effects of these two processes lead to an increase in intrathoracic blood volume. Second, metabolic demand increases as respiratory muscles resume their normal activity. Patients with increased work of breathing during weaning will experience sympathetic hyperactivation and catecholamine surge leading to increased heart rate and hypertension, which in turn will increase myocardial oxygen demand. If the work of breathing is excessive or LV functional reserve is too limited, then the patient will fail weaning. Weaning failure will manifest as acute cardiovascular collapse, hypotension, tachycardia, and even acute cardiogenic pulmonary edema. These hemodynamic changes can be ameliorated by restricting fluids, having the patients slightly hypovolemic and treating bronchospasm prior to extubation. Optimizing bronchodilation, avoiding volume overload and controlling afterload prior to weaning trials will facilitate liberation from mechanical ventilation .Patients with COPD can also have LV failure. Both COPD and obesity are associated with terminal airway collapse with increased shunt. COPD patients are more likely to experience hyperinflation owning to the increased airway resistance combined with increased lung compliance. These patients experience limitations in expiratory flow secondary to airway collapse. Both hyperinflation and dynamic hyperinflation can increase pulmonary vascular resistance and compress the heart within the cardiac fossa. The combined effects can worsen RV dysfunction by minimizing RV end-diastolic volume (EDV) while simultaneously increasing RV afterload. Patients with LV failure need a higher LV filling pressure and EDV to sustain LV stroke volume. Since hyperinflation compresses the heart, LV end-diastolic volume also decreases, and thus cardiac output often decreases during acute exacerbations of COPD in patients with LV dysfunction .Commonly, patients with LV failure develop RV failure. In such cases, increases in transpulmonary pressure secondary to lung hyperinflation lead to increased RV afterload and decreased RV ejection and RV stroke volume leading to systemic hypotension. In these circumstances, patients may experience acute cor pulmonale and RV ischemia. COPD exacerbations can cause hypoxemia, hypercapnia and increased sympathetic tone. Passive increases in pulmonary artery pressure due to increased LV filling pressure rarely cause enough increases in pulmonary artery pressure to result in acute RV failure. These three mechanisms increase pulmonary vasomotor tone. Patients with COPD may also have chronic pulmonary hypertension leading to RV hypertrophy. Increasing RV afterload increases RV end-systolic volume and, by extension, RV EDV. Clinically, these patients may present with increased jugular venous distension during spontaneous inspiration (Kussmaul\u2019s sign) and the shift in the intraventricular septum will decrease LV end diastolic compliance leading to decreased cardiac output Mooney . LimitataCO2 beyond the apneic threshold. Furthermore, episodes of hypoxia and waking from sleep lead to sympathetic activation, which further increases LV afterload and contributes to an increase in myocardial oxygen demand. Patients with OSA have intermittent hypoxemia and formation of free radicals and inflammatory molecules that lead to vascular remodeling. The negative swings in ITP during OSA lead to a combined increase in LV afterload and systemic hypoxemia. Thus, at the time that LV wall stress is increasing, myocardial oxygen delivery is being compromised. Over months, these repetitive OSA events lead to the development of congestive heart failure and a downward shift in the ventricular function curve. Acutely, the negative swings in ITP, hypoxia, and sympathetic surge lead to increased LV afterload and reactive systemic hypertension leading to increased myocardial metabolic demand. Chronically, these factors worsen LV hypertrophy, which in turn affects LV diastolic function. OSA has been associated with LV remodeling and increased incidence of cardiovascular disease . Nocturnal CPAP or BiPAP have been shown to improve outcomes in patients with disordered sleep. Specifically, OSA patients with heart failure demonstrate improvement in daytime off-CPAP LV function if the CPAP treatment abolishes the obstructive breathing patterns .Noncardiogenic pulmonary edema or ARDS is characterized by decreased lung volumes secondary to alveolar collapse and pulmonary congestion, increased dead space ventilation, hypoxemia and increased work of breathing. Often hypoxemia is not responsive to non-invasive ventilation and intubation with positive end-expiratory pressure (PEEP) is required to sustain gas exchange and minimize receptive alveolar collapse at end-expiration. The resultant higher mean and end-inspiratory airway pressure often further increase dead space ventilation. Dead space ventilation along with hypoxic pulmonary vasoconstriction secondary to alveolar collapse lead to increased pulmonary vascular resistance. This must impede RV ejection and increase RV EDV, which in turn decreases LV diastolic compliance by the process of ventricular interdependence. Indeed, Jardin et al. demonstrated many years ago that when ARDS patients were given high levels of PEEP their LV stroke volume decreased despite a high pulmonary artery occlusion pressure, used as a surrogate of LV EDV. However, when these same patients were fluid resuscitated to restore their LV EDV to their pre-PEEP levels, LV stroke volume also returned to its pre-PEEP value even though PEEP was still being used. This seminal work clearly demonstrated that lung hyperinflation and high levels of PEEP impair LV filling by decreasing LV diastolic compliance through the process of ventricular interdependence and increased juxtacardiac ITP. These points are described elsewhere in this series in greater detail .2 and optimal cardiac output for a given blood volume. Titrating PEEP based on RV systolic function and lung compliance is an important technique to monitor for developing RV failure and preventing PEEP too low that would worsen alveolar collapse and hypoxia or PEEP too high that would worsen PVR and RV afterload and, consequently, worsen LV diastolic filling and overdistention (increasing resistance). This elusive \u201csweet spot\u201d mean airway pressure that balances these two opposing effects is often equated to the point where PEEP maximizes lung compliance. Clinical studies suggest that the highest PEEP associated with the best value of lung compliance is also associated with better RV systolic function as measured using transesophageal echocardiography, least dead space ventilation, assessed as end-tidal CO filling .aCO2 levels are all predictive of the development of cor pulmonale in ARDS. Clearly, all these effects are predictable based on the above logic. Driving pressure is a surrogate of lung stress due to its effect on hyperinflation and pulmonary vascular resistance. Likewise, higher PaCO2 levels are indicative of increased dead space and lead to pulmonary vasoconstriction and increased pulmonary vascular resistance. Mitigating these factors is critical to avoid right heart failure, RV dilation and, consequently, poor LV diastolic filling and low output heart failure (Other investigators looked at variables that are prominent in patients with ARDS that develop cor pulmonale. These investigators concluded that pneumonia being the etiology of ARDS, driving pressure, worsening P:F ratio and rising P failure .Heart-lung interactions play a crucial role in understanding and managing patients with left heart failure under most conditions independent of ventilatory mode."} {"text": "Behavioural supersensitivity may be a result of increased glutamate sensitivity of D2-MSN and reduced sensitivity to dopamine. We propose that clozapine may address behavioural supersensitivity by modulating glutamate activity which may partially explain its unique effectiveness in the setting of treatment resistant schizophrenia. The mainstay of schizophrenia treatment is chronic antipsychotic medication to prevent relapse of a psychotic episode. These antidopaminergic drugs reduce D2 dopamine receptor-mediated transmission. It has been proposed that relapse rates following antipsychotic discontinuation may be due to withdrawal phenomenon rather than due to illness recurrence . The leai intracellular signalling, behavioural supersensitivity was reversed [Kruyer et al. studied the mechanism of antipsychotic-induced behavioural supersensitivity and did not find any change in D2-receptor expression or function in mice administered chronic haloperidol, in the ventral striatum, dorsal striatum or midbrain and concluded neither D2-receptor expression nor the hypothesized increased function of the receptor could explain behavioral supersensitivity . Insteadreversed .Based on the above, Kruyer et al. propose D2-medium spiny neurons hyperexcitation in the nucleus accumbens core underpins neuropathology during chronic antipsychotic treatment, antipsychotic discontinuation and behavioural supersensitivity, such that chronic antipsychotic treatment possibly reduces modulatory dopaminergic input making D2-medium spiny neurons hyperexcitable to incoming excitatory transmission from glutamate . BehavioAntipsychotic-induced behavioural supersensitivity is postulated to reduce the efficacy of antipsychotic medication leading to increasing antipsychotic doses, tolerance and treatment resistance. It has also been possibly linked to the development of tardive dyskinesia which is a motor disorder known to be caused by prolonged antipsychotic exposure . A recenClozapine is a unique medication acting upon multiple receptors , and is 14and may also potentiate glutamate transmission by regulating glutamate transport [It has been hypothesised that clozapine may specifically modulate brain glutamate and that this effect could contribute to its unique efficacy for patients with treatment-resistant schizophrenia , 15. Gluransport . Tanahasransport also demransport . Clozapiransport . In an aransport and thisransport . Glutamaransport . Deficitransport .However, despite the evidence for glutamatergic dysfunction in schizophrenia, specific pharmacological strategies have so far been largely unsuccessful . These aThere is indirect evidence to support that the efficacy of clozapine in refractory schizophrenia may be related to its modulatory effect on glutamate activity \u201330. HoweThe efficacy of clozapine in reversal of tardive dyskinesia can provide indirect links to understand this mechanism further. Antipsychotic-induced behavioral supersensitivity has been considered a possible aetiological factor for the development of both treatment resistant schizophrenia and tardive dyskinesia . Meta-anKruyer et al., show antipsychotic-induced behavioural supersensitivity may be a consequence of hyperexcitation of D2 medium spiny neuron in the nucleus accumbens core, due to enhanced glutamatergic transmission . TherefoKruyer et al., have suggested the potential role of deep brain stimulation and transcranial magnetic stimulation, in reducing and preventing excitatory plasticity in D2 medium spiny neuron . HoweverUnderstanding the mechanistic basis for antipsychotic-induced behavioural supersensitivity may lead to better prevention efforts (reducing both antipsychotic dose and usage) as well as facilitate targeted treatments for supersensitivity psychosis and tardive dyskinesia. Future research should specifically investigate clozapine\u2019s role in antipsychotic-induced behavioural supersensitivity and the mechanism by which clozapine (and other therapeutic approaches) may modulate glutamate-induced excitability specifically within the striatum and the nucleus accumbens. Future controlled trials should be conducted studying the effect of clozapine, electroconvulsive therapy, deep brain stimulation, transcranial magnetic stimulation and other glutamate modulating compounds for the treatment of supersensitivity psychosis with concomitant assessment of glutamate activity within the striatum and nucleus accumbens. These studies may also help identify biomarkers for treatment resistant schizophrenia and possible predictors of clozapine response.The aetiology of treatment resistant schizophrenia is likely complex and treatments that just target either dopamine or glutamate transmission are less likely to be successful . There i"} {"text": "IntroductionIn 2019, the Centers for Medicare & Medicaid Services (CMS) combined all autologous breast flap procedures under one billing code, effective from December 31, 2024. This change will result in equal insurance reimbursement rates for popular flap options, such as transverse rectus abdominis muscle (TRAM) and deep inferior epigastric perforator (DIEP) flaps, which were previously billed separately using S-codes based on complexity.MethodsThis study aimed to analyze insurance code changes for autologous breast reconstruction flap procedures. Data were collected from the American Society of Plastic Surgeons' annual plastic surgery statistics reports, including specific insurance codes and case volumes from 2007 to 2020. A comprehensive analysis was conducted to assess recent trends in flap utilization rates, documenting any modifications or additions to the existing codes and their implementation years.ResultsThe study analyzed billing codes and case volumes for autologous breast reconstruction procedures, with a focus on the DIEP flap and other alternatives. Non-autologous breast reconstruction procedures showed consistently higher case volumes compared to autologous procedures from 2007 to 2020. Notably, the popularity of the DIEP flap surpassed that of other flap options after 2011.ConclusionThe removal of S-codes for autologous breast reconstruction by CMS and the subsequent potential decrease in insurance coverage for the DIEP flap may lead to a decrease in its utilization and a shift toward\u00a0more invasive options, like the TRAM flap. This change could result in financial burdens for patients and widen socioeconomic disparities in breast reconstruction, limiting access to preferred reconstructive methods and impacting patient autonomy and overall well-being. In 2019, the Centers for Medicare & Medicaid Services (CMS) implemented a protocol to combine all autologous breast flap procedures under a single billing code, 193464 [Currently, most plastic surgeons receive reimbursement from insurance companies for specific flap reconstruction procedures with S-codes, such as S2068 for DIEP flap surgery, S2066 for the superior gluteal artery perforator (SGAP) flap surgery, and S2067 for stacked flap surgery, where multiple flaps are stacked on top of one another to accommodate for lack of flap volume with a single flap .\u00a0This diData collectionThe primary objective of this study was to comprehensively analyze insurance code changes concerning flap procedures for autologous breast reconstruction. To achieve this, we employed a meticulous data collection approach that involved gathering relevant information from multiple reliable sources.Sources of dataWe collected the necessary data from the annual plastic surgery statistics reports, which are published by the esteemed American Society of Plastic Surgeons . These rInsurance code identificationTo ensure a robust analysis, we first identified and compiled a comprehensive list of specific insurance codes associated with autologous breast reconstruction flap procedures . This liCase volume recordsThe case volume data for the autologous flap procedures were meticulously gathered from the annual plastic surgery statistics report . These cData analysisAfter obtaining the insurance codes and corresponding case volumes, we performed a detailed analysis to assess the impact of insurance code changes on the utilization of the DIEP flap procedure. First, we identified instances of insurance code changes related to the DIEP flap procedure by comparing the codes recorded in consecutive annual plastic surgery reports. Any modifications or additions to the existing codes were noted, and the corresponding years of implementation were documented. To examine the effect of code changes on the utilization of the DIEP flap, we compared the case volumes before and after each identified code change. This allowed us to assess any fluctuations in procedure frequency and identify potential trends related to insurance code modifications.Billing codes assessed through the annual plastic surgery statistics reportThe analysis focused on the insurance codes and case volumes associated with the DIEP flap procedure and other autologous flap alternatives, as obtained from the CMS . Table 1Case volume of autologous and non-autologous breast reconstructionNon-autologous breast reconstruction procedures had a higher case volume compared to autologous breast reconstruction procedures 168,652 cases) , \"stacked\" flaps, DIEP, and superficial inferior epigastric artery (SIEA) flaps. The findings are summarized in Table In 2021, the CMS discontinued S-codes for autologous breast reconstruction, making the 193464 billing code the sole source of insurance reimbursement for reconstructive breast procedures. In anticipation of these changes, several insurance companies have pre-emptively ceased coverage for the DIEP flap under S2068; other insurance companies are expected to follow [With the removal of appropriate additional reimbursement for the DIEP flap procedure, there is concern that breast reconstruction surgeons will decrease their DIEP flap case volume and potentially revert to utilizing more invasive autologous options, such as the TRAM flap ,7. WhileThere has been an increase in the frequency of DIEP flaps performed following the introduction of S-codes . This trWithout the additional reimbursement provided by S-codes, there is fear that surgeons cannot cover the DIEP procedure costs . For theFurthermore, these insurance changes may broaden the socioeconomic disparities in breast reconstruction . PatientSociodemographic factors currently represent disparities in autologous breast reconstruction and implant-based reconstruction ,20. PatiImplant-based reconstruction is another standard method for breast reconstruction. Some individuals prefer autologous tissue options due to their more natural feel and appearance. Additionally, increased reports and awareness of breast implant illness (BII) and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has decreased interest in implant-based reconstructive options . The decLimitationsDespite the rigorous data collection and analysis, certain limitations must be acknowledged. The reliance on aggregated case volume data from annual reports might have introduced sampling bias, and the lack of individual patient data limited our ability to explore patient-specific factors. Additionally, the focus on a specific time frame (2007 to 2020) and the potential variability in insurance coding practices should be considered when interpreting the results. Nonetheless, our research serves as a foundation for further exploration and underscores the importance of monitoring insurance code updates in the realm of plastic surgery practices.Limiting access to alternative autologous reconstructive options for those recently afflicted by a life-threatening breast cancer diagnosis revokes patient autonomy and heightens socioeconomic health disparities. Introducing and popularizing the DIEP flap was a productive step forward in the field of breast reconstruction. In recent years, the usage and popularity of the DIEP flap have skyrocketed; however, recent changes in reimbursement can potentially result in an inflection point in the number of cases performed in the future. Limiting access to this option only to those who can pay out-of-pocket may dramatically impact\u00a0our patients' physical, mental, and overall well-being."} {"text": "Spatial transcriptomics technologies developed in recent years can provide various information including tissue heterogeneity, which is fundamental in biological and medical research, and have been making significant breakthroughs. Single-cell RNA sequencing (scRNA-seq) cannot provide spatial information, while spatial transcriptomics technologies allow gene expression information to be obtained from intact tissue sections in the original physiological context at a spatial resolution. Various biological insights can be generated into tissue architecture and further the elucidation of the interaction between cells and the microenvironment. Thus, we can gain a general understanding of histogenesis processes and disease pathogenesis, etc. Furthermore, in silico methods involving the widely distributed R and Python packages for data analysis play essential roles in deriving indispensable bioinformation and eliminating technological limitations. In this review, we summarize available technologies of spatial transcriptomics, probe into several applications, discuss the computational strategies and raise future perspectives, highlighting the developmental potential. Human organs and systems are comprised of distinct cell subpopulations whose physiological processes and functions are deeply correlated with their spatial distributions and cellular interactions. To gain a deeper understanding of tissue architecture as well as heterogeneity and to subsequently obtain biological insights into intercellular communication and microenvironment, it is crucial to decipher the disparities among tissue regions and cells in their original spatial context. Previously developed single-cell RNA sequencing (scRNA-seq) has provAlthough current cutting-edge spatial transcriptomics techniques are confronted with some drawbacks such as relatively low resolution and comparatively insufficient sequencing depth , they arSpatial transcriptomics technologies have been continuously making significant progress. Multiple technologies have emerged in recent years, and their applications and advantages and disadvantages are comprehensively reviewed. In this article, we summarize the landscapes of available spatial transcriptomics technologies, present the employment of spatial techniques in extensive fields of biomedical research and focus on the status quo of computational strategies of data analysis.Since the initial spatial transcriptomics workflow was established in 2016 , this fiLaser capture microdissection (LCM) is a micJunker and colleagues devised In summary, microdissection-based methods provide a competent approach to obtaining regions of interest from tissue samples with high sensitivity. These techniques enable focused research into the microanatomical structures and gene expression information of specific regions. However, Geo-seq, which integrates LCM and scRNA-seq (Smart2-seq), offers only a ten-cell resolution due to the limitations of microdissection-based techniques. During the laser-capturing and tissue segregation procedures of LCM, the quality of RNA molecules and the intactness of obtained cells may not be fully maintained. Additionally, microdissection is time-consuming and labor-intensive, limiting the throughput and the capacity to handle large tissue samples. Despite these shortcomings, microdissection-based technologies can still provide robust methods for gene expression profiling.In situ hybridization is a strategy that enables the visualization of RNA molecules within their original context via probes complementary to the objective transcripts rather than extracting them from tissue sections. An early iteration of in situ hybridization technique termed single-molecule fluorescent in situ hybridization (smFISH) is compeTo overcome the drawbacks of accumulating errors, Chen and colleagues devised in-situ-hybridization-based techniques allow for the visualization of RNA molecules within their original tissue context by hybridizing probes with complementary targets. This enables the detection of target genes for biological validation of bioinformatic analysis results and the study of gene expression patterns. However, the nature of FISH methods imposes an intrinsic limitation on throughput. Additionally, specific probes must be synthesized before the hybridization process, necessitating the use of ready-made kits to overcome this challenge [Overall, hallenge .In situ sequencing (ISS) method developed by Ke and colleagues enables To examine transcripts without prior knowledge of tissue, Lee and colleagues devised in-situ-sequencing-based methods enable spatial-level gene expression analysis and avoid the bias introduced by transcript extraction. However, these techniques still face challenges. For example, prior knowledge of the tissue may be required to design specific padlock probes, and read length may be limited. Additionally, in situ sequencing may not be feasible for unconventional or rare cell types and genes. Potential applications of these methods include studying gene expression regulation within tissues or cells and localizing gene variants.In contrast to traditional sequencing methods that separate cells from their spatial context, St\u00e5hl and colleagues proposedImprovement of the resolution of spatial barcoding strategies has been continuously pursued. In 2019, Rodriques and colleagues developeSlide-seq, HDST and Seq-Scope introduced above can provide much higher and even subcellular resolutions, generating more refined spatial distribution information. The approaches to improving the resolutions of Slide-seq and HDST are similar, involving bead arrays with 10-\u03bcm- and 2-\u03bcm-diameter beads, respectively , 45. It Overall, spatial-barcoding-based techniques allow for the simultaneous acquisition of gene expression and spatial location information. However, selecting the appropriate resolution requires careful consideration. Low resolution may obscure the intrinsic tissue structure and require further decomposition analysis to gain comprehensive insights, while high resolution may introduce those aforementioned challenges. Additionally, capture efficiency may be relatively low. Despite these limitations, spatial-barcoding-based techniques are widely used to study tissue architecture, tumor heterogeneity, the tumor microenvironment, etc.Spatial transcriptomics technologies are potent tools for studying the intricate structure, the dynamics of tissue and organ systems and inherent mechanisms within their original context. These technologies can provide valuable biological insights by revealing tissue architecture, developmental patterns and diseases, among which tumor biology may be one of the most extensive applications of spatial transcriptomics. Primary application scenarios of implementing spatial transcriptomics techniques are presented Fig.\u00a0 and seveDecoding intercellular interaction and identifying cell subpopulations are of fundamental significance in delineating tissue architecture and defining structural components through the establishment of a transcriptome atlas of a specific tissue or organ, thus facilitating the perception of tissue dynamics. Hildebrandt and colleagues managed Furthermore, spatial transcriptomics technologies are generally utilized in developmental biology to reveal spatiotemporal gene expression patterns and uncover tissue morphogenesis throughout the entire development course or multiple pivotal stages. Asp and colleagues profiledBeyond the above insights about tissue architecture and development, spatial transcriptomics techniques have a robust capacity for clarifying disease microenvironments and pathogenesis. Boyd and colleagues combinedA substantial part of disease research is the study of tumor biology which could be the most extensive application of spatial transcriptomics. Significant challenges in devising tumor treatment procedures are induced by tumor heterogeneity. Moncada and colleagues utilizedTo comprehensively interrogate the tissue sections, bioinformatic analyses have to be performed to unravel the intertwined and multiplexed bioinformation and minimize the impact of current technological limitations and subsequently derive biological significance more accurately from raw spatial transcriptomics data. These bioinformatics analyses range from spatially-variable genes identification and clustering analysis to gene imputation, etc., which can be handily effectuated through a substantial number of computational strategies devised in recent years. Herein, circumstantial comparisons of algorithms and usages among the existing R or Python packages are presented Table .Table 4CDistinguishing cell types and subpopulations is a fundamental task in the bioinformatic analysis of spatial transcriptomics data. This can be resolved with the help of clustering analysis where spatially-variable genes can be discovered and data dimensions can be reduced through approaches such as principal component analysis (PCA), t-distributed stochastic neighbour embedding (t-SNE) and uniform manifold approximation and projection (UMAP). These methods calculate similarity among barcode spots and define clusters within a tissue. A robust clustering procedure is provided by a widely-distributed R package Seurat , on whicWithin a certain tissue, some genes exhibit conspicuous spatially-variable expression whereas some other genes such as housekeeping genes are expressed equally among the cells. The specific pattern in which the expressions of genes spatially vary can convey indispensable bioinformatic insights into identifying cell types and subpopulations and corresponding spatial information and underlying spatial functions. Some program packages perform outstandingly in identifying spatially-variable genes. Svensson and colleagues describeA common issue in spatial transcriptomics technology is that a single barcode-capturing spot may be overlaid by multiple cells. Thus, the detected expression is an aggregation of a heterogeneous set of cells within the spot, which may impact the efficiency and accuracy of identifying cell subpopulations and delineating tissue atlas. For example, 10\u2009\u00d7\u2009Genomics Visium offers a resolution of 55\u00a0\u03bcm meaning the diameter of each capturing spot is 55\u00a0\u03bcm which is several-fold larger than a typical tissue cell. The spatial decomposition process through various deconvolution algorithms can address this discrepancy, which is to disentangle the mixture of mRNAs and subsequently predict the proportions of each cell type in one capturing spot. A spatial decomposition method devised by Ma and colleagues is termeGene imputation refers to the task of inferring lost gene expression information or \u201cdropouts\u201d caused by factors such as low protocol sensitivity, mitigating errors during gene measurement and facilitating deconvolution. Biancalani and colleagues introducThe aforementioned strategies, including spatial decomposition and gene imputation, have demonstrated considerable efficacy in enhancing the resolution of spatial transcriptomics data and compensating for lost gene expression information. Nevertheless, certain limitations persist. These approaches are based on computational models for predicting cell locations and gene information and therefore, their predictions may be subject to error, potentially resulting in imprecise and spurious results. Further investigation and refinement are necessary to more effectively leverage these technologies and derive more reliable biological insights.Cellular interaction operated within the microenvironment where cells are adjacent to each other can convey significant perceptions into tissue dynamics and the way the communication networks change when experiencing conditions such as disease. A Graph Convolutional Neural networks for Genes (GCNG) method was introduced to infer extracellular interactions from gene expression by depicting a cellular relationship graph transformed from spatial transcriptomics data and subsequently encoding gene expressions, and the graph is then convolved with expression information . Cang anCopy number variation (CNV) refers to the increase or decrease in the copy number due to gene segment rearrangements. Typically, CNVs involve segments longer than 1000 base pairs and are mainly manifested as submicroscopic deletions or duplications. CNVs are a common form of genetic variation in the human genome, with 5%\u2009~\u200910% of the genome affected by CNVs, which is much higher than other forms of genetic variation. Ascertaining the transition from benign to malignant tissue forms the foundation for improving early cancer diagnosis, as genomic instability in histologically benign tissue can signal an early event in cancer evolution. Furthermore, the spatial distribution and activity of CNVs can impact phenotype, making mapping their spatial distribution valuable for comprehending, diagnosing, and treating diseases. Previously, gene expression was utilized to infer CNVs in individual cells, successfully identifying regions of chromosomal gain and loss . EricksoGene expression within a tissue is influenced by the spatial position of cells in the tissue microenvironment. Spatial transcriptomic data can provide valuable insights into tissue regions, as they contain information on spatial position matrices, HE region staining of sections, and relative distances between individual cells, which can be used to delineate spatial regions. MULTILAYER is an algorithm that utilizes agglomerative clustering and community detection methods for graphical partitioning, enabling digital imaging of spatial transcriptomic analysis . This alSpatial trajectory analysis is an analytical method frequently employed in spatial transcriptomics to uncover dynamic cellular evolution and differentiation processes. This approach infers evolutionary trajectories and differentiation relationships between cells by analyzing their spatial positions and gene expression levels within tissue sections. The stLearn package can visualize spatial trajectories in tissue slices and infer biological processes from transcriptional state gradients across tissues . SimilarBoth spatial transcriptomics and scRNA-seq are effective methods for obtaining biological insights into tissues and diseases. However, each method has its limitations. By integrating spatial transcriptomics and scRNA-seq data, these methods can complement each other to provide comprehensive biological information. For instance, RCTD generates spatial decomposition by assigning cell types to spatial transcriptomics spots , whereasMethods for analyzing spatial transcriptomics data are generally similar and can be divided into data preprocessing and downstream analysis. Data preprocessing typically involves quality control and normalization to improve data quality for downstream analysis and obtain more reliable biological information. For spatial-barcoding-based methods, quality control aims to remove low-quality spots and genes from spatial transcriptomics data. Quality control parameters can be adjusted based on tissue type, research requirements, and other factors. These parameters may include removing spots with fewer than a certain number of transcripts, removing genes expressed in fewer than a certain number of spots, and removing spots with a high proportion of mitochondrial genes. Normalization accounts for the difference in sequencing depth among different spots. Since differences among spots in spatial transcriptomics data can be relatively large, effective normalization is essential.After preprocessing, downstream analysis can be performed. The data should first undergo dimensionality reduction and clustering analysis to distinguish spots with different features. Biological information can then be interpreted through these clusters in subsequent analysis. Algorithms such as PCA, t-SNE, and UMAP can be used for this purpose and are available in many data analysis packages. Next, gene expression patterns in the data can be analyzed, including differential expression analysis and spatially variable gene analysis, which can be performed using packages such as Seurat and SpatialDE, respectively. Additionally, cell information from tissue slices can be annotated onto spatial transcriptomics data. Since the sequencing unit of some spatial transcriptomics technologies may contain more than one cell, spatial decomposition can infer the proportion of various cells in each sequencing unit based on the data to obtain cell locations in the spatial context. This step can be achieved using packages with deconvolution algorithms such as RCTD and cell2location. Gene imputation can also predict the positions of low-expressed or missing genes in space due to possible dropout using packages like Tangram. Furthermore, personalized analysis can be conducted based on research objectives. For instance, packages such as Giotto can be used to analyze the communication between cells or spatial regions, including receptor-ligand interactions. SpatialInferCNV can perform copy number variation analysis at the spatial level, while stLearn and SPATA can be used for spatial trajectory analysis and MULTILAYER for spatial region identification. These analytical methods and packages provide excellent visualization during data analysis, facilitating step-by-step comprehension of current analytical outcomes to guide subsequent analysis. Moreover, it is essential to integrate spatial transcriptomics data with scRNA-seq data and other omics data to obtain a more comprehensive understanding of biological information.Explosive advances in spatial transcriptomics technologies have been made in recent years to expand our understanding of miscellaneous tissues and organs. However, current spatial transcriptomics methods are confronted with some challenges of low resolution, sensitivity, throughput, etc., hindering our precise perception of normal and abnormal tissues, which calls for further innovations in technologies to overcome these deficiencies. Given that each technology bears its biological strengths, we envision the integration across these technologies which complement each other in the drawbacks before a novel and robust technology is launched. With future technology revolutions, intercellular signaling could be resolved at higher and even single-cell resolution. In addition, larger-scale tissue specimens may be investigated to allow for depicting organ-level tissue topography, enabling a more holistic and consecutive interpretation of tissue structures, which latently poses challenges for accelerating bioinformatic analysis with higher efficiency and accuracy and more powerful information processing capacity. Beyond the prospective advancement in refining and optimizing current protocols of spatial transcriptomics, we also envisage the integration with multi-omics including epigenomics, proteomics, and metabolomics to shed light on the intrinsic convoluted mechanisms of cellular interactions and disease and better probe into tumor progression and growth course. In addition to advances in spatial transcriptomics technologies, innovations in data analysis strategies are also anticipated. As deep learning technology continues to progress, its application in spatial transcriptomics data analysis is expected to become more widespread. In the future, more deep-learning-based methods may be developed to process and analyze spatial transcriptomics data to improve data resolution and interpretation reliability. Furthermore, as data scale and complexity increase, visualization and interactive analysis will become important tools for spatial transcriptomics data analysis. Future spatial transcriptomics data analysis methods will need to integrate visualization and interactive analysis technologies to better understand and interpret data.Since some spatial transcriptomics techniques, especially some widespread spatial-barcoding-based techniques, are not capable of offering single-cell resolution at the spatial level and scRNA-seq cannot reflect the spatial distribution of each cell, we envision a more organic and efficient alignment of single-cell datasets and corresponding spatial information. The alignment can be achieved by mapping single cells to spatial data, where each cell is matched with a spatial location in an ideal condition. Nevertheless, current methods for integration cannot generate precise matching due to technological limitations, which calls for further breakthroughs in the effectiveness and efficiency of data integration algorithms. By integrating both datasets, we can decipher potential intercellular communication pathways, including ligand-receptor interactions and juxtacrine and paracrine signaling. This may provide insights into previously unclear physiological and disease mechanisms and help discern more refined classifications of certain diseases, facilitating precise and individualized medical treatment. Additionally, publicly-available datasets can be interrogated retrospectively with the integration of spatial transcriptomics and scRNA-seq data to obtain novel biological cues which may be concealed in the raw data before.Moreover, we anticipate the translational medicine research into the clinical significance of spatial transcriptomics, particularly with the compatibility of the 10\u2009\u00d7\u2009Genomics Visium platform with FFPE tissue blocks allowing retrospective analysis into previously opaque tissue specimens to glean more sufficient information on clinical diagnostics and prognostics as well as therapeutic methods and targets. For example, research into human DLPFC distinguished the layer-enriched genes that may be associated with schizophrenia and autism spectrum disorder, implicating the potential of neuropsychiatric disorders progression in those bearing the risk gene expression . In tumo"} {"text": "The clinical spectrum of atrial fibrillation means that a patient-individualized approach is required to ensure optimal treatment. Cardiac computed tomography can accurately delineate atrial structure and function and could contribute to a personalized care pathway for atrial fibrillation patients. The imaging modality offers excellent spatial resolution and has been utilised in pre-, peri- and post-procedural care for patients with atrial fibrillation. Advances in temporal resolution, acquisition times and analysis techniques suggest potential expanding roles for cardiac computed tomography in the future management of patients with atrial fibrillation. The aim of the current review is to discuss the use of cardiac computed tomography in atrial fibrillation in pre-, peri- and post-procedural settings. Potential future applications of cardiac computed tomography including atrial wall thickness assessment and epicardial fat volume quantification are discussed together with emerging analysis techniques including computational modelling and machine learning with attention paid to how these developments may contribute to a personalized approach to atrial fibrillation management. Atrial fibrillation is conventionally classified according to a single domain - the temporal pattern of the arrhythmia. Whilst the use of classification systems has increased our understanding of atrial fibrillation to some extent, such an approach can overlook the importance of the interplay of factors related to the patient, their symptom severity, risk factors and the atrial electrophysiological substrate underpinning atrial fibrillation. Given these interactions, the management of atrial fibrillation necessitates the delivery of a coordinated patient-individualized care pathway to ensure optimal treatment. Whilst more research to explore the patient-specific pathophysiological basis of atrial fibrillation is necessary, the principles of patient-individualized care have been encapsulated in the 4S-AF scheme which aims to provide a structured, pathophysiology-based characterisation of a patient's atrial fibrillation comprising four domains - stroke risk, symptom severity, severity of atrial fibrillation burden and substrate severity.Within this framework, computed tomography may provide useful information to guide atrial fibrillation management by enabling assessment of cardiac structure and function. Advances in computed tomography temporal and spatial resolution have strengthened its utility in the field of electrophysiology.This review will discuss the current state-of-the-art for computed tomography in atrial fibrillation management together with potential future applications that form part of ongoing research .Fig.\u00a01Th22.1In atrial fibrillation, cardiac computed tomography has been used prior to direct current cardioversion, radiofrequency catheter ablation and left atrial appendage closure to investigate for contraindications, delineate anatomy and guide procedures.In the context of atrial fibrillation ablation procedures, pre-procedural atrial imaging can define patient-specific atrial anatomy.Prior to percutaneous left atrial appendage occlusion, pre-procedural imaging is utilised to guide left atrial appendage occluder device selection and sizing, and to facilitate procedure planning.2.2In patients with sub-therapeutic anticoagulation (missed anticoagulant doses or short duration of therapy), investigation for left atrial appendage thrombi prior to direct current cardioversion or atrial instrumentation is required.,Computed tomography can be used to differentiate between left atrial appendage thrombus and slow blood flow by comparing early arterial and delayed phase images.2.32) score. In a recent simulation study by Qureshi et\u00a0al., it has been demonstrated that left atrial appendage morphology may affect coagulation dynamics in blood flow during sinus rhythm and atrial fibrillation, and subsequent risk of thrombus formation.Cardiac computed tomography can be used to accurately characterize left atrial appendage morphology . Left at2.4Prior to radiofrequency catheter ablation of the pulmonary veins in atrial fibrillation, an awareness of a patient's left atrial and pulmonary vein anatomy can enable accurate targeting and planning through the measurement of ostial diameter, characterization of variants in pulmonary vein anatomy such as accessory pulmonary veins or common pulmonary vein ostia, and the identification of anomalies such as anomalous pulmonary venous return, pulmonary vein occlusion or the presence of a persistent left superior vena cava.Variations in pulmonary vein anatomy are common and can be easily assessed with computed tomography.2.5Pulmonary vein stenosis is a recognized complication of atrial fibrillation ablation close to or within the pulmonary vein ostia. Symptoms typically take weeks to months to manifest and include shortness of breath, dry cough and, in some instances, chest pain.2.6Injury to extra-cardiac structures is a recognized, but fortunately rare, complication of atrial fibrillation ablation. The esophagus lies adjacent to the posterior wall of the left atrium leaving it vulnerable to injury during radiofrequency catheter ablation.Methods to reduce risk of atrio-esophageal fistula formation such as active esophageal coolingThe proximity of the right and left phrenic nerves with the right superior pulmonary vein and left atrial appendage roof respectively also leaves these structures vulnerable to injury during ablation.3Advances in computed tomography image acquisition and analysis provide the opportunity for its role in atrial fibrillation assessment to expand. Techniques including computational modelling, artificial intelligence-based imaging, atrial wall thickness assessment and epicardial adipose tissue characterisation may enable an individualized precision-cardiology approach to atrial fibrillation management. This section summarizes these approaches and suggests areas where future research developments using computed tomography may address knowledge gaps in the management of atrial fibrillation.3.1The ability of cardiac computed tomography to accurately delineate atrial structure can enable the acquisition of complex three-dimensional human atrial geometry which can form the basis of computational organ-level atrial models .45 TheseComputational models could be used to characterize an individual's substrate severity and lead to personalized atrial fibrillation ablation therapy. Hwang et\u00a0al. used cardiac computed tomography to create atrial models which could be used to compare different ablation strategies for atrial fibrillation.ClinicalTrials.gov, #NCT05057507) study will aim to use computational modelling to define patient-specific mechanisms of atrial fibrillation.Computational modelling for personalized atrial fibrillation procedure planning is an area of active research, offering the potential to better understand arrhythmia pathophysiology and improve clinical arrythmia prevention, risk stratification and treatment.Future research developments using computational models will require three-dimensional anatomical geometry and cardiac computed tomography is therefore likely to play a role in the generation of these models. A key advantage of cardiac computed tomography in this setting is the high spatial resolution of image acquisition which enables accurate anatomical assessment of wall thickness and left atrial appendage morphology. Previous studies using magnetic resonance imaging to evaluate the role of computational modelling in atrial fibrillation therapy have been unable to include variations in left atrial wall thickness or appendage morphology.3.2Machine learning is likely to be beneficial for personalized atrial fibrillation care in the future.Improved image quality with machine learning-based reconstruction algorithms may improve the ability to assess thin structures such as the atrial wall.The ability of cardiac computed tomography to characterise atrial structure may prove to be of prognostic importance as structural parameters such as left atrial volume3.3Changes in the structure and electrical behavior of the left atrium are associated with conditions which predispose to atrial fibrillation, although it is also recognized that these changes may occur in response to atrial fibrillation itself.Furthermore, we have developed reference values for left atrial wall thickness measurements on computed tomography, measured left atrial wall thickness at two locations (roof and floor) using computed tomography in 100 persistent atrial fibrillation patients., measured thickness around the pulmonary vein antra in patients undergoing repeat ablation procedures and found that antral wall thickness was higher in areas of pulmonary vein reconnection., found no association between left atrial wall thickness measurements and pulmonary vein isolation success rates.Studies have also been performed to examine for an association between left atrial wall thickness measurements and atrial fibrillation ablation success rates. Zuo et\u00a0al.The use of computed tomography to assess atrial wall thickness and provide non-invasive substrate determination may enable us to identify areas where the risk of recurrence is potentially higher and personalize therapy to improve outcomes. The utility of computed tomography-derived left atrial wall thickness in guiding catheter ablation approach has been demonstrated by Teres et\u00a0al., who found that personalized ablation approaches adapted to left atrial wall thickness allowed pulmonary vein isolation with lower radiofrequency delivery, fluoroscopy, and procedure times.3.4Cardiac computed tomography enables a three-dimensional assessment of the volume, thickness, and attenuation of the epicardial adipose tissue C.71 Some,Several studies have shown that patients with atrial fibrillation have increased epicardial adipose tissue thickness, mass and volume compared with patients without atrial fibrillation . A meta-,,,Recently, assessment of the pericoronary adipose tissue attenuation has gained attention due to its association with subsequent cardiac events.Notably these studies have considered only single-plane analysis or peri-atrial fat attenuation limited to the posterior left atrium. Furthermore, cut-off values to accurately define abnormal epicardial adipose tissue attenuation have not been defined and vary between research studies. Further mechanistic studies are therefore needed to study the role of global peri-atrial fat and fat attenuation in atrial fibrillation pathogenesis.In a study by Zhang et\u00a0al., it has been shown that the radiomic characteristics of epicardial adipose tissue may improve the identification of patients who have atrial fibrillation compared to quantification of epicardial adipose tissue volume.At present it is unknown whether changes in epicardial adipose tissue are a cause or consequence of atrial fibrillation. Epicardial adipose tissue, which contains ganglionated plexi, actively secretes cytokines and adipokines which may lead to inflammation and atrial remodelling. The secretion of pro-fibrotic factors by epicardial adipose tissue may contribute to atrial myocardial fibrosis and this may act as a substrate for atrial fibrillation.4Cardiac computed tomography can provide important anatomical information for patients with atrial fibrillation and has been used in the pre-, peri- and post-procedural stages of management. New techniques such as computational modelling and machine learning are improving our understanding of the development of atrial fibrillation and responses to therapy. In the future information such as atrial structure, atrial wall thickness, and epicardial adipose tissue from computed tomography may be used to provide a personalized approach for the management or prevention of atrial fibrillation.MCW has given talks sponsored by Canon Medical Systems, Siemens Healthineers and Novartis. SN receives research funding from Siemens for computed tomography image analysis. SEW has consulting agreements with EPD/Phillips, GSK and Biosense Webster."} {"text": "Most mental disorders, when examined individually, are associated with an increased risk of cardiometabolic complications. However, these associations might be attributed to a general liability toward psychopathology or confounded by unmeasured familial factors.To examine whether the associations between psychiatric diagnoses and increased risk of cardiometabolic complications are attributable to a general liability toward psychopathology, or confounded by unmeasured familial factors.We conducted a cohort study in Sweden and identified all individuals and their siblings born in Sweden 1955-1962 with follow-up through 2013. After excluding individuals who died or emigrated before 1987, the final sample consisted 672 823 individuals. We extracted ICD-coded diagnoses (recorded 1973-1987) for ten psychiatric conditions and criminal convictions when participants were aged 18-25 years, and ICD-coded diagnoses (recorded 1987-2013) for five cardiometabolic complications when the participants were 51-58 years old. Logistic regression models were used to estimate the bivariate associations between psychiatric conditions or criminal convictions and cardiometabolic complications in individuals. A general factor model was used to identify general, internalizing, externalizing, and psychotic factors based on the psychiatric conditions and criminal convictions. We then regressed the cardiometabolic complications on the latent general factor and three uncorrelated specific factors within a structural equation modeling framework in individuals and across sibling pairs.Each psychiatric conditions significantly increased the risk of cardiometabolic complications; however, most of these associations were attributable to the general factor of psychopathology, rather than to specific psychiatric conditions. There were no or only small associations between individuals\u2019 general psychopathology and their siblings\u2019 cardiometabolic complications, suggesting that the associations were not attributable to genetic or environmental confounding factors shared within families. The same pattern was evident for the specific internalizing and psychotic factors.Individuals with mental disorders in early life had an increased long term risk of cardiometabolic complications, which appeared attributable to a general liability toward psychopathology. Sibling analyses suggested that the elevated risk could not be attributed to confounds shared within families.This highlights the importance of transdiagnostic and lifestyle based interventions to reduce the risk of cardiometabolic complications, particularly in patients with several mental disorders.None Declared"} {"text": "Transcranial magnetic stimulation (TMS) is a non-invasive FDA-approved therapy for major depressive disorder (MDD), specifically for treatment-resistant depression (TRD). Though offering promise for those with TRD, its effectiveness is less than one in two patients . Limits on efficacy may be due to individual patient variability, but to date, there are no established biomarkers or measures of target engagement that can predict efficacy. Additionally, TMS efficacy is typically not assessed until a six-week treatment ends, precluding interim re-evaluations of the treatment. Here, we report results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation indexed by functional magnetic resonance imaging (fMRI). Among responders, synchronized rTMS produces two systematic changes in brain dynamics: a reduction in global cortical excitability and enhanced phase entrainment of cortical dynamics. These effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly biomarker tracking enables efficacy prediction and dynamic adjustments through a treatment course, improving the overall response rates. This innovative approach advances the prospects of individualized medicine in MDD and holds potential for application in other neuropsychiatric disorders."} {"text": "BMC Cardiovascular Disorders invites authors to submit articles investigating what drives and affects Cerebrovascular disorders to improve patient care.Cerebrovascular disorders pose a global health concern. Advances in basic and clinical research, including induced pluripotent stem cell models and multi-omic approaches, have improved our understanding and management of these disorders. However, gaps in our knowledge remain. BMC Cardiovascular Disorders welcomes submissions to its new \u201cCerebrovascular Disorders\u201d collection to help further our understanding of such conditions and open new avenues for risk stratification and therapeutic intervention.Cerebrovascular disorders comprise a range of distinct pathologies, including ischaemic and haemorrhagic stroke, transient ischaemic attack, and other intracranial vascular disorders , and significantly increase the risk of vascular dementia. Cerebrovascular disorders represent a significant medical and economic challenge anticipated to rise due to the increasing age of the global population . The pasHDAC9 large-vessel stroke risk to screen for histone deacetylase (HDAC) small molecule inhibitors ) We look forward to the \u201cCerebrovascular Disorders\u201d article collection bringing together basic and clinical research to develop our understanding of what drives and affects such conditions to improve patient care."} {"text": "Climate change poses new threats to plant production as environmental stresses increase significantly. Biotic and abiotic stress that have adverse effects on plant growth and crop productivity and can be major constraints on yield. This will particularly affect major food crops, including legumes and cereals. Biotic and abiotic stresses, such as salinity, drought, chemical toxicity, extreme temperatures and oxidative stress are often interrelated and become serious threats to agriculture. These extreme conditions induce cellular damage and disruption of plant growth and development by a series of morphological, physiological, biochemical and molecular changes. For example, these extreme stresses are often leading to oxidative damage and excessive creation of reactive oxygen species (ROS) in plant cells. Usually, plants interact with these extreme conditions by their innate antioxidative defense system that including enzyme and non-enzyme elements . HoweverTherefore, enhancing the productivity of these important crops is important for the food security of growing populations worldwide. High heterozygosity imposes severe limitations on breeding new varieties of major food crops with desired traits. Conventional plant breeding and genetic research have significantly evolved in recent decades. However, to meet the growing human population\u2019s food demand, especially for major staple cereal and legume crops, genetic gain must be enhanced, making it necessary to exploit genetic diversity within cultivated crops and wild relatives. With modern technologies, plant breeders can use these additional resources of diversity to address problems like biotic and abiotic stresses and yield by combining methods from genomics, and advanced analytics in cereal and legume breeding programs on a massive scale. This topic explores how the recent advances in genomics and plant biotechnology approaches are helping researchers to answer questions related to crop improvement. Therefore, we encouraged contributions to this Research Topic to advance and disseminate knowledge across various facets of this critical field. Our goal is to illuminate the molecular mechanisms that underlie biotic and abiotic stress tolerance, enhance comprehension of plant stress biology, with a particular focus on legumes and cereals. This effort ultimately contributes to bolstering sustainable agriculture and global food security. In this topic, recent advances in genomics and stress tolerance studies of cereals and legumes are presented in six publications, contributed by 52 authors.2+), which plays a crucial role in transmitting signals and regulating numerous physiological processes. This is accomplished through Ca2+ sensors and their target proteins, as highlighted by previous research IQM genes using genome-wide bioinformatics analysis and molecular biology techniques. They discussed the phylogenetic relationships, gene structure, conserved motifs, chromosome location, evolutionary pattern analysis, yeast two-hybrid analysis, and expression profile in response to abiotic stress and hormones of the soybean IQM family. Their results provide a theoretical basis for subsequent functional analysis of soybean IQM genes and insights into improving soybean resistance to biotic and abiotic stresses. Furthermore, Hu et al. indicated that the multiple members of CDPKs in wheat (Triticum aestivum) have diverse and vital functions in plant growth, development regulation and stress responses. They reported that every TaCDPKs member has a specific function. Their results clearly provide an important foundation for in-depth exploring the function and the signaling pathways of CDPK family members, especially the interactions between TaCDPKs and TaNOXs in wheat.Many complex signaling pathways are involved in the response of plants to biotic and abiotic stresses . For exaresearch . SpecifiXue et\u00a0al. performed a research toward deep RNA sequencing to depict long non-coding RNAs (lncRNAs) profiles in rice associated with BPH feeding using the resistant Near-Isogenic Line (KW-Bph36-NIL). They elaborated insightful information on the genome-wide differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) expression profiles of rice under BPH invasion by high throughput sequencing. They suggested that NILs could be used in BPH resistance breeding programs.Insect pest infestation is a serious threat to cereal crops and causes extensive damage to crop production annually. The brown planthopper (BPH) is a major threat to rice production. Host-plant resistance is a key component of pest management strategies to reduce the damage caused by BPH in rice production worldwide. Maanju et\u00a0al. to determine the genetic diversity and population structure of corn leaf aphid (CLA) Rhopalosiphum maidis (Fitch) resistance in barley to identify sources of resistance against R. maidis that considered as a common pest of cereals worldwide. In this study, 10 aphid specific simple-sequence repeats (SSR) markers were used to investigate the genetic diversity and population structure of 109 barley genotypes against R. maidis. Cluster analysis from the agro-morphological features grouped all the germplasm in four subpopulations and approximately 87.52% of the 109 barley genotypes shared a common major allele at any locus and finally they identified two genotypes having high resistance against CLA which highlighted their potential for inclusion in the future CLA resistance breeding programs.A study was undertaken by Park et\u00a0al. analyzed the transcriptome changes associated with the callus formation process in soybean under the influence of wounding signals and phytohormones. They identified key genes associated with transcription factors, biosynthesis, transporters, and signaling pathways related to phytohormones. The obtained results demonstrated the importance of the coordinated interplay of wounding, auxin, cytokinin, and brassinosteroid signaling pathways to activate the genes involved in determining the fate of meristematic cells. This study provides insights into the regulatory network of callus formation in soybean.With the aim of uncovering facts related to the biological mechanism underlying soybean callus induction and developmental process, Wu et\u00a0al. reported the analysis of the sugar beet WD40 proteins. They identified 177 bvWD40 from sugar beet and analyzed their evolutionary characteristics, protein structure, gene structure, protein interaction network and gene ontology. They concluded that BvWD40-82 gene is a salt-tolerant candidate gene. Transgenic Arabidopsis thaliana seedlings expressing BvWD40-82 showed enhanced tolerance to salt stress by elevating the contents of osmolytes and antioxidant enzyme activates, maintaining intracellular ion homeostasis and increasing the expression of genes related to salt overly sensitive (SOS) and abscisic acid (ABA) pathway. The obtained results hypothesized the importance of BvWD40-82 as a promising candidate gene for improving crop stress resilience.Salinity is a major environmental stress on crop productivity. Understanding the molecular and physiological mechanisms underlying salt stress tolerance will facilitate efforts to improve crop performance under salinity. In line with this aim, Biotic and abiotic stresses will remain major concerns for future food production and sustainability. The use of the most recent technologies in leveraging genomics, phenomics, machine learning approaches and plant biotechnology along with conventional breeding strategies is the most appropriate way to identify multifactorial interactions networks involved in plant defenses against stress conditions towards improving abiotic and biotic stress tolerance in major crops.PL: Writing \u2013 review & editing. MH: Writing \u2013 review & editing. RT: Writing \u2013 review & editing. MR: Writing \u2013 review & editing. HS: Writing \u2013 review & editing. H-JJ: Writing \u2013 review & editing."} {"text": "Saccharomyces cerevisiae has been studied in hopes of understanding its causes and identifying conserved pathways that also drive aging in multicellular eukaryotes. While the short lifespan and unicellular nature of budding yeast has allowed its aging process to be observed by dissecting mother cells away from daughter cells under a microscope, this technique does not allow continuous, high-resolution, and high-throughput studies to be performed. Here, we present a protocol for constructing microfluidic devices for studying yeast aging that are free from these limitations. Our approach uses multilayer photolithography and soft lithography with polydimethylsiloxane (PDMS) to construct microfluidic devices with distinct single-cell trapping regions as well as channels for supplying media and removing recently born daughter cells. By doing so, aging yeast cells can be imaged at scale for the entirety of their lifespans, and the dynamics of molecular processes within single cells can be simultaneously tracked using fluorescence microscopy.For several decades, aging in Key featuresThis protocol requires access to a photolithography lab in a cleanroom facility.Photolithography process for patterning photoresist on silicon wafers with multiple different feature heights.Soft lithography process for making PDMS microfluidic devices from silicon wafer templates. Saccharomyces cerevisiae, the traditional method of manual microdissection of mother and daughter cells in order to count replicative lifespan has been largely supplanted by the use of microfluidic devices, which efficiently trap individual mother cells in place while removing newly budded daughter cells . As a reference, yeast cells growing in the device can be seen in Paxman et al. (2022). Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with challenges to proteostasis. eLife ("} {"text": "Plasmodium malaria parasites [P. falciparum and highlight critical future questions to answer.Isoprenoid precursor synthesis is an ancient and fundamental function of plastid organelles and a critical metabolic activity of the apicoplast in arasites \u20133. Over arasites , due in arasites ,6. In th Malaria parasites retain a non-mevalonate/methylerythritol phosphate (MEP) pathway for isoprenoid precursor synthesis in the apicoplast organelle. This pathway synthesizes two 5-carbon isoprene subunits, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), whose sequential condensation is critical for making diverse longer-chain isoprenoids required for a variety of key cellular functions that include protein prenylation, dolichol synthesis for protein glycosylation, and biosynthesis of mitochondrial ubiquinone and heme A . Core enPlasmodium therefore requires the apicoplast and the pathways that support and maintain this key organelle.Within the apicoplast, isoprenoid precursor synthesis requires the support of several additional metabolic pathways. The final 2 enzymes in the MEP pathway, IspG and IspH, contain essential Fe-S cluster cofactors that receive electrons from apicoplast-targeted ferredoxin, which also contains an Fe-S cluster. These critical Fe-S cofactors are produced by the apicoplast Suf pathway, which is therefore essential for isoprenoid synthesis \u201310. One Plasmodium focused almost exclusively on cellular roles for isoprenoids outside of the apicoplast, since exogenous IPP can rescue parasites from loss of the apicoplast and the attendant ablation of endogenous IPP synthesis. Nevertheless, multiple prior papers reported that MEP pathway inhibitors like fosmidomycin (FOS) blocked apicoplast biogenesis and prevented elongation of the organelle in blood-stage parasites . Sev. Sev4]. The foundational discovery that exogenous IPP could rescue parasites from apicoplast-specific dysfunctions and organelle loss enabled many opportunities to probe the functional properties of the apicoplast and its constituent proteins . BecauseP. falciparum [Plasmodium will be required for organelle maintenance due to a critical role in IPP synthesis and/or in other aspects of apicoplast biogenesis apart from IPP synthesis. Future studies of apicoplast functions can test this prediction and extend or revise its validity to different parasite stages in distinct host environments, where additional apicoplast pathways like type II fatty acid synthesis can produce essential outputs [Current knowledge specifies IPP and coenzyme A (CoA) as the only biosynthetic outputs of the apicoplast that are essential for blood-stage lciparum ,19,20. Ulciparum ,19. Base outputs ,22 that Plasmodium, this paradigm of metabolic interdependence does not appear to hold throughout the phylum Apicomplexa. Toxoplasma gondii parasites express 2 PPS homologs but neither appears to localize to the apicoplast [T. gondii, loss of isoprenoid precursor synthesis has no apparent impact on apicoplast biogenesis [Plasmodium and Toxoplasma presumably reflect the differing selective pressures that guided evolution of these parasites over the 600 Myr timeline of their divergence from a common ancestor. Multiple PPS homologs are also retained by other hematozoan parasites that are more closely related to Plasmodium than Toxoplasma, but a possible role for PPS in apicoplast biogenesis is unexplored in these organisms. Understanding the similarities and differences in isoprenoid metabolism between broader apicomplexan parasites can unveil and unravel the biochemical forces that have spurred evolution of intracellular parasitism along distinct pathways.The MEP pathway for isoprenoid precursor synthesis is a hallmark of apicoplast retention in apicomplexan parasites . Althougicoplast ,23,24. Aogenesis ,25. ThesP. falciparum parasites that we hope will stimulate future studies in these areas.Below, we lay out several key questions at the frontier of our understanding of the apicoplast and isoprenoid metabolism in Why does apicoplast biogenesis require long-chain linear isoprenoids? We hypothesize that these lipids are critical to tune the biophysical properties and flexibility of apicoplast membranes, such that their deficiency impairs membrane expansion during organelle biogenesis. It remains unknown if these isoprenoids are enriched in specific or all apicoplast membranes and/or serve other roles in organelle biogenesis. It may be possible to test our hypothesis with small-molecule dyes whose fluorescence properties are sensitive to variations in membrane fluidity, together with chemical rescue experiments using a homologous series of progressively longer-chain polyprenols to bypass loss of PPS.How are isoprenoids transported into and out of the apicoplast? Isoprenoid precursors synthesized in the apicoplast, including IPP and DMAPP, are required and utilized outside the organelle. Chemical rescue experiments suggest that IPP and longer isoprenoids can enter the apicoplast. Charged metabolites face an unfavorable energetic barrier to diffuse across the 4 hydrophobic membrane bilayers that encircle the apicoplast, but specific protein transporters that enable their passage into and out of the organelle remain undefined.What prenyl synthase supports the biosynthesis of ubiquinone required in the Plasmodium mitochondrion? Ubiquinone, which has a polyprenyl tail, is critical for function of the mitochondrial electron transport chain. A mitochondrial-targeted polyprenyl synthase has been identified in T. gondii [Plasmodium remain obscure and poorly studied. Apicoplast PPS was proposed to play this role in Plasmodium [. gondii , but theasmodium , but theasmodium .Are there additional metabolic uses of isoprenoids by malaria parasites beyond currently defined products? Plasmodium lacks enzyme homologs for terpene and carotenoid biosynthesis, and recent work found no evidence to support IPP incorporation into carotenoids [otenoids ,3,15. Ne"} {"text": "Patients with traumatic brain injury (TBI) or head trauma present challenges for emergency physicians and neurosurgeons. Traumatic brain injury is currently a community health issue. For the best possible care, it is crucial to understand the various helpful therapy techniques in the pre-operative and pre-hospital phases. The initial rapid infusion of large volumes of mannitol and a hypertonic crystalloid solution to restore blood pressure and blood volume is the current standard of care for people with combined hemorrhagic shock (HS) and traumatic brain injury. The selection and administration of fluids to trauma and traumatic brain injury patients may be especially helpful in preventing subsequent ischemic brain damage because of the hemodynamic stabilizing effects of these fluids in hypovolemic shock. Traumatic brain injury is an essential factor that may lead to disability and death in a patient. Traumatic brain damage can develop either as a direct result of the trauma or as a result of the initial harm. Significant neurologic problems, such as cranial nerve damage, dementia, seizures, and Alzheimer's disease, can develop after a traumatic brain injury. The comorbidity of the victims may also be significantly increased by additional psychiatric problems such as psychological diseases and other behavioral and cognitive sequels. We review the history of modern fluid therapy, complications after traumatic brain injury, and the use of fluid treatment for decompressive craniectomy and traumatic brain injury. The term \"traumatic brain injury\" (TBI) is most often used to describe brain dysfunction brought on by external trauma. Many types of traumatic injuries happen worldwide, and traumatic brain injury is one of the most contentious health issues in modern society . The CenAn essential part of surgical treatment is administering perioperative fluids, although this process is frequently not completely understood and is still primarily empirical. There are lingering concerns regarding its effectiveness and potential consequences ,11. FluiMethodologyWe undertook a\u00a0search through PubMed, CENTRAL and other government sources in November 2022 using keywords such as \"traumatic brain injury\", \"fluid resuscitation\", \"brain injury\", \"brain trauma\", and \"colloid solutions\"((( traumatic brain injury [Title/Abstract]) OR (\"traumatic brain injury\" [MeSH Terms]), (\"fluid resuscitation\" [Title/Abstract])) OR (\"fluid resuscitation\" [MeSH Terms]), ((\"brain injury\" [Title/Abstract]) OR (\"brain injury\" [MeSH Terms]) AND (\"brain trauma\" [Title/Abstract]) OR (\"brain trauma\" [MeSH Terms]). One reviewer independently checked the papers retrieved based on title and abstract against the inclusion criteria before moving on to the full texts. Another reviewer also reviewed 20% of these studies to validate inclusion studies. The selection of studies Figure dependedThe evolution of modern fluid therapyThe importance of intravenous fluid therapy in treating cholera initially emerged in the 1830s, thanks to William Brooke O'Shaughnessy's findings on the blood observations of his suffering cholera patients ,25. It wCrystalloidsSmall, water-soluble molecules that make up a crystalloid fluid can quickly diffuse across semi-permeable barriers. These solutions' tonicity and sodium content (which affects how they are distributed throughout the body compartments) together greatly influence their features . They reColloidsColloids are liquids that impose oncotic pressure on semi-permeable membranes because they are composed of larger, more soluble molecules that are difficult to penetrate. Through osmosis, water is retrieved from the interstitial and international classifications of functioning based on their shape, molecular weight, capillary permeability, and ionic charge. They exit the intravascular region and act for a specific time . All colTraumatic brain injury and fluid therapyOedema development is not significantly impacted by clinically appropriate fluid restriction. The first investigation on human fluid therapy showed that decreasing the standard maintenance volume by 50% for neurosurgical patients causes an increase in serum osmolality over about a week . TherefoFluid treatment for decompressive craniectomyBased on experience, it is suggested that decompressive craniectomy in traumatic epidural hematoma patients improves these patients' outcomes . The genPhysiological reactions in the perioperative stageThe effects of surgery alone and the resulting adjustments to the hormonal environment inside the body are exacerbated in critically ill patients by a systemic inflammatory response that leads to capillary leak development. As a result, the interstitium endures losses that are challenging to balance and frequently display oedema. Additionally, nutritional support and actions that alter acid-base homeostasis can actively or inadvertently influence the fluid and electrolyte imbalances that result in severe illness . The effTable Traumatic brain injury (TBI) is a greater community or social health problem that increases mortality and disability. Traumatic brain injuries can result from physical attacks, sports-related injuries, traffic accidents, etc. The development of therapeutic procedures for TBI recovery has been ongoing for many years, even though there is currently no effective treatment for TBI rehabilitation. For the best possible care, it is crucial to understand the various helpful therapy techniques in the pre-operative and pre-hospital phases. There are still questions concerning the benefits and dangers of perioperative fluid therapy. The rapid infusion of large crystalloids to restore blood volume and blood pressure is now the standard treatment for patients with combined traumatic brain injury (TBI) and hemorrhagic shock (HS). Crystalloid fluid therapy is more effective than colloid fluid therapy in patients with TBI. There are no standards of care or evidence-based guidelines for managing fluid treatment in patients having decompressive craniectomy."} {"text": "Suicide is a major health problem, mostly related to mental health disorders. However psychological autopsies have revealed the presence of unexpected suicide factors such as dietary patterns particularly folate intake. Which is a naturally occurring form of B9 essential for neurogenesis, nucleotide synthesis and methylation of homocysteine.The aim of our study is to identify the link between folate intake and suicidality.Our literature review was based on the PubMed interface and adapted for 2 databases: Science Direct and Google Scholar using the following combination ( suicide [MeSH terms]) AND (folate [MeSH terms]) AND (prevention [MeSH terms]).Stress-induced neuronal dysfunctions interact with genetic and environmental factors, including diet, to precipitate mental health disorders in vulnerable or predisposed individuals especially mood disorders.In one hand, studies showed delayed onset of clinical improvement even treatment resistance in depressive patients treated with fluoxetine associated with low folate levels.In the other hand Folate depletion has been linked to serotoninergic metabolism disturb.Moreover, co-administration of methylfolate, a highly absorbable form of folic acid, has been found to augment the effects of SSRIs .A duration-response analysis (1-mg dosage) revealed a 5% decrease in suicidal events per month of additional treatment.Accumulating data have shown that these nutrients can enhance neurocognitive function, and may have therapeutic benefits for depression and suicidal behaviors . But the pathological mechanism remains unclear that\u2019s why further studies are needed for a better comprehension and efficiency.None Declared"} {"text": "Other distinct clinical features include keratocystic odontogenic tumors, dyskeratotic palmar and plantar pitting, and skeletal abnormalities. Clinicopathological findings of the syndrome are very diverse, and many symptoms manifest during a certain period of life. We present the compelling whole-body bone scan and"} {"text": "Synthetic glucocorticoids (sGCs) are a well-investigated and standard drug therapy for disorders associated with CNS inflammation. Less is known about treating psychiatric disorders associated with neural autoantibodies. Our aim is to elucidate the repositioning of sGCs in psychiatric diseases that co-exist with neural autoantibodies. We used PubMed to identify articles for this narrative review. To our knowledge, no randomized, placebo-controlled trials have yet been conducted on applying sGC to treat neural autoantibody-associated psychiatric disorders. We describe initial results of cohort studies and single cases or case series often associated with autoantibodies against membrane-surface antigens demonstrating a largely beneficial response to sGCs either as monotherapy or polytherapy together with other immunosuppressive agents. However, sGCs may be less efficient in patients with psychiatric diseases associated with autoantibodies directed against intracellular antigens. These results reveal potential benefits of the novel usage of sGCs for the indication of neural autoantibody-associated psychiatric disease. Further large-scale randomized, placebo-controlled trials are needed to discover whether sGCs are safe, well tolerated, and beneficial in subgroups of neural autoantibody-associated psychiatric diseases. The term drug repurposing refers to employing old drugs for a new purpose, as for another disease category. Two additional subconditions of drug repurposing beyond its superordinate concept are distinguished, namely, drug repositioning and drug reformulation. Drug repositioning means employing an old formula for a new indication, whereas drug reformulation requires either the application of a novel dosage or a novel route, or even both. In our review, we focus on the drug repositioning of steroids in psychiatric disease limited to those patients presenting serum and/or CSF neural autoantibodies. In our review article, we refer only to synthetic glucocorticoids as they are currently applied in treating diseases involving CNS inflammation. sGCs orchestrate various cellular functions, such as inflammation application. We excluded patients with neurological disorders apart from dementia, internal medicine diseases, such as pancreatitis, autoimmune encephalitis with a mixed neuropsychiatric or no pure psychiatric symptoms, and psychiatric syndromes associated with non-neural antibodies, such as thyroid antibodies. The efficacy of sGCs has been proven in patients with autoimmune encephalitis associated with membrane-surface autoantibodies antibodies]. Concerning autoimmune encephalitis following the Graus criteria . There is evidence that the origin of neural autoantibody-associated psychiatric disease is organic, as in autoimmune encephalitis antibodies and partly responsive to polyimmunotherapy, including sGCs who underwent this therapy for autoimmune dementia of patients Table , whereasA large recent chart review study by Endres et al. showed tDifferent sGC mechanisms with a major impact on neural autoantibody-associated psychiatric disease should be mentioned. First, sGCs can enhance emotional memory by increasing hippocampal activity during the encoding of emotional stimuli , our review data point to a new direction in psychiatry that has emerged in recent years and should be pursued further. However, the use of sGCs must be seriously reconsidered when potent alternative immunotherapeutic drugs such as IVIGs and plasmapheresis are available, in case side effects such as exacerbation of psychiatric symptoms should occur. In every case, a critical risk\u2013benefit evaluation should be made especially in cases with isolated psychiatric syndromes and lacking neural autoantibody detection in CSF."} {"text": "Waiting and stopping are essential and distinct elements of appropriate behavioral control with its dysfunction implicated in various impulsivity related mental disorders. Although rodent and human studies have investigated both phenomena, the role of preparing to stop in waiting impulsivity has rarely been investigated. Furthermore, convergent evidence from multi-modal investigation tools remains a poorly utilized approach in addressing such questions.Here, we conducted two separate, but hierarchical studies, using functional magnetic resonance imaging (fMRI) to map the neural circuit involved in waiting impulsivity and proactive stopping, and subsequently provide mechanistic and causal evidence of disruption of this circuit by transcranial magnetic stimulation (TMS). In the second study, based on our fMRI study data, we attempted to investigate possible causation between the LIFG and waiting impulsivity by modulating LIFG, i.e. non-invasively producing a \u201cvirtual lesion\u201d with an inhibitory transcranial magnetic stimulation (TMS) protocol called continuous theta burst stimulationWe recruited 41 healthy volunteers who performed an adapted version (1CSRT) of the well-established 5 choice serial reaction time task to capture waiting impulsivity. We developed a novel task measuring proactive inhibition. We scanned participants while completing these two tasks. Our fMRI data showed a strong association between LIFG activity and waiting impulsivity on the 1CSRT task. We conducted a single-blind, randomized, between-subjects design of cTBS of the LIFG on a sample of 51 healthy volunteers who completed an adapted version of the 1CSRT task (2CSRT task). Our a priori hypothesis was that cTBS would transiently decrease local cortical activity of the LIFG and increase the frequency of premature responses on both fixed and delayed cue-target interval trials on the 2CSRT task.We first show a shared neural network comprising the pre-supplementary motor area and bilateral anterior insula underlying both waiting impulsivity and proactive stopping. We further demonstrate activity in dorsomedial prefrontal cortex and left inferior frontal gyrus (LIFG) negatively correlated with waiting impulsivity in trials with additional target onset delay. We demonstrate active stimulation significantly increased waiting impulsivity.In these two studies, we validated a novel task measuring proactive inhibition. We further validated the significance of task structure for assessing distinct aspects of impulsivity, which is of translational interest. We further established a causal role of lIFG for waiting impulsivity thus highlighting the integrity of LIFG and related neural circuitry required in waiting impulsivity.None Declared"} {"text": "In November 2022, the Centers for Disease Control and Prevention updated a 2016 practice guideline for opioid prescription.The 2022 Centers for Disease Control and Prevention guideline reiterates that clinicians should prescribe opioids at the lowest effective dose for the expected duration of pain warranting opioid use. The guideline also endorses patient-centered approaches to the initiation or taper of opioids. Clinicians should discuss benefits and risks of opioids and consider patient preference. The 2022 guideline further suggests that clinicians \u201cevaluate benefits and risks with patients within 1-4 weeks of starting opioid therapy for subacute or chronic pain or of dosage escalation.\u201d This recommendation is particularly relevant to the chronic management of patients who begin opioids for hidradenitis suppurativa, erosive lichen planus, or chronic ulcerating conditions, or even in the emergency department, where opioids are frequently prescribed for cellulitis and abscess.Postsurgical pain management comprises the majority of opioid prescriptions among dermatologists.An added 2022 recommendation outlines the use of prescription drug monitoring or high-sensitivity screening questions to mitigate opioid prescriptions to patients at higher risk for substance use. This recommendation is accompanied with the caveat that prescription drug monitoring data should be used with \u201call patients rather than differentially on the basis of assumptions about what [clinicians] will learn about specific patients.\u201d The 2022 guideline also uses five new guiding principles, which emphasize an individualized, flexible, and multidisciplinary approach to opioid prescription. The fifth guiding principle encourages culturally informed communication to promote access to affordable, diversified pain management regimens and recognizes the role of bias in pain management. The 2022 guideline update is an important step toward thoughtful, safe, and patient-centered opioid stewardship. Dermatologists should continue to build on this national policy update and consider more specific opioid appropriateness recommendations for chronic, nonsurgical dermatologic conditions.None disclosed."} {"text": "N-glycans stabilized the ligand-binding domain dimer via cation/anion binding and modulated receptor gating properties using electrophysiology. Our findings provide vital structural and functional insights into the unique KAR gating mechanisms.Kainate receptors (KARs) belong to the family of ionotropic glutamate receptors (iGluRs) and are tetrameric ligand-gated ion channels that regulate neurotransmitter release and excitatory synaptic transmission in the central nervous system. While KARs share overall architectures with other iGluR subfamilies, their dynamics are significantly different from those of other iGluRs. KARs are activated by both full and partial agonists. While there is less efficacy with partial agonists than with full agonists, the detailed mechanism has remained elusive. Here, we used cryo-electron microscopy to determine the structures of homomeric rat GluK2 KARs in the absence of ligands (apo) and in complex with a partial agonist. Intriguingly, the apo state KARs were captured in desensitized conformation. This structure confirms the KAR desensitization prior to activation. Structures of KARs complexed to the partial agonist domoate populate in domoate bound desensitized and non-active/non-desensitized states. These previously unseen intermediate structures highlight the molecular mechanism of partial agonism in KARs. Additionally, we show how"} {"text": "Magnetic resonance imaging (MRI) has several advantages over computerized tomography (CT) in the treatment planning of central nervous system (CNS) malignancies. The adoption of hybrid MRI and linear accelerators (MRLs) has allowed for more effective tumor control and reduced unnecessary neurotoxicity through precise daily adaptations. In this review, we provide a summary of the evidence for MRLs in the management of various CNS tumors. Additionally, we discuss the potential of multiparametric MRI and genomically guided radiotherapy to enhance patient outcomes.Magnetic resonance imaging (MRI) provides excellent visualization of central nervous system (CNS) tumors due to its superior soft tissue contrast. Magnetic resonance-guided radiotherapy (MRgRT) has historically been limited to use in the initial treatment planning stage due to cost and feasibility. MRI-guided linear accelerators (MRLs) allow clinicians to visualize tumors and organs at risk (OARs) directly before and during treatment, a process known as online MRgRT. This novel system permits adaptive treatment planning based on anatomical changes to ensure accurate dose delivery to the tumor while minimizing unnecessary toxicity to healthy tissue. These advancements are critical to treatment adaptation in the brain and spinal cord, where both preliminary MRI and daily CT guidance have typically had limited benefit. In this narrative review, we investigate the application of online MRgRT in the treatment of various CNS malignancies and any relevant ongoing clinical trials. Imaging of glioblastoma patients has shown significant changes in the gross tumor volume over a standard course of chemoradiotherapy. The use of adaptive online MRgRT in these patients demonstrated reduced target volumes with cavity shrinkage and a resulting reduction in radiation dose to uninvolved tissue. Dosimetric feasibility studies have shown MRL-guided stereotactic radiotherapy (SRT) for intracranial and spine tumors to have potential dosimetric advantages and reduced morbidity compared with conventional linear accelerators. Similarly, dosimetric feasibility studies have shown promise in hippocampal avoidance whole brain radiotherapy (HA-WBRT). Next, we explore the potential of MRL-based multiparametric MRI (mpMRI) and genomically informed radiotherapy to treat CNS disease with cutting-edge precision. Lastly, we explore the challenges of treating CNS malignancies and special limitations MRL systems face. Central nervous system (CNS) tumors pose unique and significant challenges for oncologists. As the understanding of CNS tumors continues to improve, innovative approaches and advancements in radiotherapy techniques are needed to take advantage of these insights to improve patient outcomes. The integration of magnetic resonance imaging (MRI) with linear accelerators (MRLs) has allowed for adaptive magnetic resonance-guided radiotherapy (MRgRT), which has emerged as a promising modality for increased personalization in radiation therapy for treating CNS tumors.MRI plays a central role in both the diagnosis and evaluation of CNS tumors due to its excellent soft tissue imaging and ability to visualize the boundaries between the tumor and normal tissues ,2. High-2 fluid-attenuated inversion recovery (FLAIR) sequence and a true fast imaging with steady-state free precession (TRUFI) sequence [The advent of MRLs marked a revolutionary step in the field of MRgRT for CNS tumors ,7. In adsequence of a heaIn the subsequent sections, we discuss the unique challenges and limitations associated with treating adult patients with CNS tumors using traditional radiotherapy methods and how MRgRT offers a potential solution to address these issues. Specifically, we explore the role of MRgRT in the treatment of glioblastoma (GBM) and the unique ability of MRLs to detect subtle soft tissue changes and plan adaptation to improve tumor targeting and reduce dose to surrounding healthy tissue . FurtherIn accordance with the guidelines established by the Radiation Therapy Oncology Group (RTOG), the postoperative GBM target includes both the surgical cavity and the adjacent edema . This apAlthough conducting MRI scans throughout RT to account for these changes would be ideal, it is not feasible due to limited scanner availability and cost constraints. Unfortunately, CT-guided radiotherapy (CTgRT) does not adequately account for parenchymal changes because of its inadequate soft tissue contrast. MRLs may offer a solution, as they allow for superior soft tissue contrast to detect subtle geometric changes and for online plan adaptation to account for tumor and post-operative bed changes during therapy. The need for geometric plan adaptation is highlighted in a prospective study involving 61 GBM patients who underwent chemoradiotherapy (CRT) and received diagnostic brain MRIs at planning, fraction 10, fraction 20, and one-month post-CRT. Significant anatomical changes were observed throughout therapy . The stup = 0.036) versus 20.6 Gy (p = 0.005), respectively [A recent study investigated the potential benefits of adaptive radiotherapy for GBM patients using an MRL system . The stuectively . MultiplIn summary, treatment of GBMs with MRLs is associated with improvements in dosimetry and treatment planning due to its ability to detect subtle soft tissue changes and facilitate plan adaptation. Additionally, MRLs can account for changes in the tumor and tumor bed throughout treatment to ensure better target coverage while minimizing unnecessary dose to normal brain parenchyma. Future studies are needed to determine if this translates into better disease control durability and if better normal tissue sparing results in quality-of-life improvements for these patients.SRT is an important modality in the management of brain metastases and other intracranial tumors . An MRL Several studies have explored the dosimetric feasibility of MRgRT for intracranial SRT ,18,19,20Another study examined the dosimetric feasibility of direct post-operative MRL-based SRT for resection cavities of brain metastases, concluding that direct post-operative MRL-based SRT is dosimetrically acceptable, with benefits including increased patient comfort and logistics . StreamlCollectively, the above studies indicate that MRgRT using an MRL has the potential to offer dosimetric and logistical advantages over conventional linear accelerators for intracranial SRT treatment. However, further clinical investigations are necessary to evaluate the clinical benefit of this technology.Spine SRT plays a critical role in managing metastatic disease by alleviating pain, preventing pathological fractures, and reducing neurological morbidity. Stereotactic body radiotherapy (SBRT) has been shown to provide improved efficacy compared with conventional radiotherapy methods . For spiMRLs offer several advantages over CTgRT, including MR imaging in treatment position to allow for easier fusion with the planning CT and superior spinal cord delineation during setup compared with cone-beam CT (CBCT) ,23. DosiSeveral clinical trials are currently investigating the use of MRL in spine SRS/SBRT. These studies will provide valuable insights into the feasibility and effectiveness of this technique for spine treatment. For example, a phase I/II trial is examining the use of Stereotactic MR-guided Adaptive Radiotherapy (SMART) for treating various disease sites, including the spine (NCT04115254). Additionally, the Pilot Study of Same-session MR-only Simulation and Treatment with SMART for Oligometastases of the Spine (NCT03878485) focuses specifically on spine treatment.As more clinical data emerge from these studies, the potential benefits of MRL in spine SRT will become clearer. The integration of MRI with linear accelerators for spine treatment may lead to improved tumor targeting, reduced normal tissue exposure, and better patient outcomes. Ultimately, these advancements may help optimize radiotherapy for patients with metastatic spine disease and contribute to the ongoing evolution of spine SRT techniques.HA-WBRT is a promising technique that aims to achieve the local control benefits of whole brain RT for both macro- and micro-metastatic lesions, while reducing neurotoxicity by specifically avoiding the hippocampus . HA-WBRTParticularly for patients with numerous brain metastases of radioresistant histology, HA-WBRT with a simultaneous integrated boost to gross disease may be an effective strategy ,56, one One of the fundamental goals of radiotherapy is maximizing the dose to target tissue while minimizing the dose to surrounding OARs. In a significant first step towards this aim, MRLs have facilitated treatment plan adaptation to observable anatomic changes throughout therapy. MRLs, however, may be able to enable biological plan adaptation by leveraging MRI\u2019s capability to track biological and physiological changes through advanced mpMRI techniques. These techniques may allow radiation oncologists further insight into a tumor\u2019s biology as it responds to RT over the course of treatment.The treatment paradigm of radiotherapy has traditionally been based on empirical large cohort data rather than individual biology, resulting in a one-size-fits-all approach. However, recent advancements in genomics and radiomics have begun to pave the way towards a more personalized approach based upon individual tumor biology. The synergy between genomically informed radiotherapy, treatment of high-risk sub-volumes based on extraction of radiographic data, and daily mpMRI-guided plan adaptation has the potential to usher in a new treatment paradigm in radiation oncology. Pre-treatment genomic and radiomic analyses of the tumor may improve patient selection for MRL-based dose escalation ,57,58. DThe currently active phase II Habitat Escalated Adaptive Therapy (HEAT), With Neoadjuvant Radiation for Soft Tissue Sarcoma (NCT05301283) is an example of a cutting-edge study utilizing genomic and mpMRI radiomic biomarkers to guide the initial treatment and adaptive treatment approach for high-grade soft tissue sarcomas. Utilizing a similar approach for CNS tumors appears to be technically feasible currently. For example, genomic-adjusted radiation therapy (GARD) could be similarly utilized to identify GBM patients who could benefit from higher doses with MRIMRL is poised to take a central role at the forefront of this paradigm shift to allow for plan adaptation based not only upon geometric shifts but also on a tumor\u2019s evolving treatment response throughout therapy. An ultra-personalized treatment approach like this allows for total dose, dose distribution , and fractionation changes throughout the course of therapy to improve clinical outcomes for patients. Historically, daily MRgRT plan adaptation has been utilized to manage interfractional geometric changes. However, MRI is also capable of assessing biological and physiological information using advanced mpMRI techniques ,67,68,69One such technique is diffusion-weighted imaging (DWI), which enables the detection of water mobility changes . These a1 relaxation time following a bolus injection of gadolinium [1, T2, and ADC [Dynamic contrast-enhanced (DCE) MRI is another functional imaging technique that investigates perfusion by dynamically evaluating changes in the Tdolinium ,83. Thisdolinium . DCE hasdolinium . As a redolinium . DCE has and ADC . While D and ADC .Additional MR-based techniques, such as magnetic resonance spectroscopic imaging (MRSI) , chemicaAlthough none of the CNS-specific trials within Genomics provides another powerful avenue towards personalized radiation treatment, which when combined with the advances in image guidance listed above, may provide an even more sophisticated approach for challenging malignancies such as GBM. Several such signatures have been introduced as a potential means for genomically guided RT ,109,110.In summary, MRL can be leveraged by incorporating genomically guided RT and mpMRI radiomics to enable a biologically adaptive RT paradigm. Various mpMRI techniques, including DWI, DCE, MRSI, and CEST, have the potential to offer valuable insights into tumor biology and physiology, ultimately leading to more personalized and effective treatment strategies. Using these technologies to identify intratumoral heterogeneity and tumoral sub-volumes at risk may allow for focal dose escalation or avoidance, respectively. As research and development continues in this area, we expect significant advancements in the application of these techniques, potentially revolutionizing the management of CNS tumors.MRgRT offers significant advancements for image-guided radiation therapy (IGRT) and personalized oncology in CNS tumor treatment, but there are certain limitations to be considered. These include substantial financial and time investments for training and operation, development of MR-safety protocols, and unique physical challenges related to the concurrent use of MR and external beam radiotherapy ,116,117.Treating CNS tumors on an MRL presents several unique challenges. The complex anatomy of the CNS, with its highly radiosensitive normal tissues, requires precise targeting and dose delivery. The proximity of critical structures, such as the optic nerves, brainstem, and spinal cord, demands meticulous treatment planning and delivery. Furthermore, CNS tumors often exhibit infiltrative growth patterns, making it almost impossible to accurately delineate tumor boundaries.MRL systems suffer the same limitations as diagnostic MRIs. As such, they\u2019re sensitive to the magnetic susceptibility artifacts that arise from air\u2013tissue and boneGeometric distortion represents one of the most difficult challenges to account for with any MRgRT. Geometric distortion occurs due to imperfections in the magnetic field, gradient nonlinearities, and magnetic susceptibility differences at tissue interfaces . This caTreatment of CNS tumors on MRLs represents a promising direction for the advancement of personalized cancer care. MRLs provide excellent soft tissue visualization, real-time monitoring of targets and normal tissues with gating capabilities, and the ability for daily plan adaptation. These unique advantages hold the potential to improve radiation delivery to patients with intracranial or spine tumors. Clinical trials are currently underway and seek to clarify the role of MRLs in the treatment of CNS malignancies. Future clinical studies are needed to explore the integration of mpMRIs and genomics to develop a biologically adapted radiation therapy paradigm for CNS tumors."} {"text": "Fungal infections are increasingly associated with critical illness, especially in major burn injury. The risk factors of invasive fungal infections include central venous catheter (CVC) placement, mechanical ventilation, broad-spectrum antibiotics, renal replacement therapy (RRT), and total parental nutrition. Critically ill burn patients have additional risk factors including extensive wounds, impaired immune system, and repeated surgical intervention. Despite significant morbidity and mortality caused by invasive fungal infections, efforts to prevent them with antifungal prophylaxis have not improved outcomes. In patients who develop invasive fungal infection, appropriate empiric antifungal therapy is imperative to reduce morbidity and mortality especially in the setting of delayed culture and sensitivity data. The purpose of this study was to characterize risk factors associated with the development of invasive fungal infection, invasive fungal infection organisms and surgical and pharmacological management.A retrospective chart review was completed of adult patients admitted to the burn ICU found to have an invasive fungal infection . The primary outcome was to identify common fungal organisms. Secondary outcomes included susceptibility pattern of the organism, location of infection, surgical management including debridement and amputation, pharmacological management, median ICU and hospital length of stay, and in hospital mortality.A total of 10 patients of a goal of 100 patients with a median 54% TBSA burns were evaluated at this time. The most common yeast species included candida albicans; mold species included a variety of organisms such as fusarium, zygomycete and paecilomyces. Common risk factors among these patients included CVC access (57%), mechanical ventilation (43%), and RRT (43%). Yeast infections were primarily treated with anidulafungin and fluconazole, while mold infections were managed with systemic amphotericin as backbone in addition to voriconazole or isavuconazole. Patients underwent aggressive surgical debridement for source control. Median ICU stay was 53 days with a median hospital stay of 63 days, and 42% mortality.Fungal infections among critically ill burn patients are associated with the high morbidity and mortality rates. Therefore, mitigation of modifiable risk factors is of utmost importance. This retrospective review of common fungal growth in our unit will inform future empiric antifungal management for patients with concern of invasive fungal infections.Fungal infections present a clinical challenge for burn practitioners, especially in geographically moist areas. Prevention and informed surgical and pharmacological management are key to overcoming this infectious disease threat."} {"text": "Obesity has become a global health epidemic with profound implications for various medical specialties, including reproductive medicine. This comprehensive review focuses on the anesthetic evaluation and management of obese patients undergoing in vitro fertilization (IVF) procedures. Obesity, as defined by BMI, is associated with infertility and poses unique challenges for anesthetic care. The review also addresses the timing of anesthesia concerning IVF procedures, the impact of obesity on IVF success rates, and the importance of emotional and psychological support for obese patients undergoing IVF. Challenges and future directions in the field are highlighted, focusing on ongoing research, emerging technologies, and the role of multidisciplinary teams in managing these complex cases. In conclusion, this review underscores the critical role of tailored anesthesia and perioperative care in optimizing outcomes for obese patients undergoing IVF. It provides valuable insights for anesthetic providers, reproductive specialists, and healthcare teams, emphasizing the need for a patient-centered approach to address the unique challenges posed by obesity in the context of assisted reproductive technology. Obesity has emerged as a global health epidemic, affecting millions of individuals worldwide and presenting a significant public health challenge. In 2005, approximately 1.6 billion adults globally were overweight BMI: 25-30 kg/m2), and at least 400 million were obese (BMI: >30 kg/m2). By 2015, these numbers had escalated to 2.3 billion and 700 million, respectively [0 kg/m2, Obesity and IVF: an overviewDefinition of Obesity and Its ClassificationObesity is a complex health condition marked by excessive adipose tissue accumulation in the body. BMI is the most commonly used metric for defining and categorizing obesity, as classified by the WHO in Table Prevalence of Obesity and Its Association With InfertilityThe global prevalence of obesity has witnessed a concerning and continuous rise in recent decades, emerging as a significant public health issue. Research indicates that this surge in obesity rates has far-reaching consequences, including its profound impact on reproductive health, both in men and women. The association between obesity and infertility is a growing concern within the medical community, as it sheds light on the intricate interplay between body weight and reproductive function .In womeImportance of IVF as a Fertility Treatment OptionOvercoming ovulatory disorders: Obesity is often intricately linked with ovulatory disorders, such as PCOS, which can hinder natural conception. IVF is particularly advantageous as it effectively bypasses these ovulatory challenges. Through IVF, eggs are directly harvested from the ovaries, ensuring a steady supply of eggs for fertilization, thereby circumventing the irregular ovulation associated with PCOS .ControlAnesthetic evaluation of obese women patientsPreoperative Assessment and Patient HistoryEvaluation of comorbidities: The preoperative assessment of comorbid conditions is paramount, particularly in obese patients undergoing surgical procedures. Obesity is often accompanied by a higher prevalence of medical comorbidities, necessitating a thorough evaluation to manage patient risks comprehensively. Conditions such as diabetes, hypertension, cardiovascular disease, and obstructive sleep apnea (OSA) are frequently encountered in the obese population and can significantly influence anesthesia management. Assessing these comorbidities' nature, severity, and control is critical in determining the patient's perioperative risk profile. This assessment is a foundation for tailoring anesthetic strategies and optimizing patient safety .MedicatPhysical Examination in Obese PatientsAssessment of airway anatomy: Obese patients often present unique challenges related to their airway anatomy. Limited neck mobility, short and thick necks, and excess tissue in the oropharyngeal and supraglottic areas may characterize their airways. These anatomical variations can complicate airway management significantly during anesthesia induction and intubation. Anesthesiologists must carefully consider these factors and employ suitable airway management strategies, such as specialized equipment or alternative airway approaches, to mitigate potential difficulties and ensure safe ventilation .EvaluatLaboratory Tests and InvestigationsComplete blood count (CBC): Rather than delving into the definition of a CBC, it is pertinent to elucidate the changes observed in CBC counts within the obese population. Such insights can prove invaluable for healthcare professionals, especially physicians, as they navigate the challenges presented by obesity. In this context, the CBC becomes an essential tool that scrutinizes various blood components, including RBCs, WBCs, and platelets. Each component within the CBC bears crucial information for anesthesia providers during the preoperative evaluation process. For instance, the RBC count and hemoglobin levels are pivotal in assessing the patient's oxygen-carrying capacity. Low values may indicate anemia, a condition that, if left unaddressed, can adversely impact tissue oxygenation during surgery. WBC counts offer insights into the patient's immune status. Deviations from the normal range may indicate underlying infections or inflammatory conditions, necessitating preemptive action before surgery. Platelet counts, vital for normal blood clotting, help in assessing bleeding risks and guiding decisions regarding blood transfusions or medications such as anticoagulants. By examining these hematological parameters and understanding their variations within the obese population, anesthesia providers can make informed decisions to mitigate bleeding risks, optimize oxygen delivery, and ensure a safer perioperative experience .CoagulaAnesthetic Risk StratificationFollowing the comprehensive preoperative assessment, anesthetic risk stratification should be performed. This involves categorizing patients into risk groups based on their comorbidities, physical status, and the nature of the surgical procedure. Standard classification systems include the American Society of Anesthesiologists (ASA) Physical Status Classification and the Charlson Comorbidity Index . AnestheAnesthetic management strategiesPreoperative OptimizationWeight loss and lifestyle modification: Preoperative weight loss and lifestyle modification are proactive and potentially transformative strategies for obese patients embarking on elective surgery, including IVF procedures. These initiatives are driven by the recognition that obesity can engender complex health concerns and perioperative challenges. Here, we delve deeper into the multifaceted aspects of preoperative weight loss and lifestyle modification, elucidating their manifold benefits .ImproveGlycemic ControlCrucial for surgical success: Elevated blood glucose levels in patients with diabetes can heighten the risk of surgical complications, including impaired wound healing, increased infection susceptibility, and cardiovascular events. Achieving and maintaining optimal glycemic control before surgery can mitigate these risks, promoting a smoother and safer perioperative experience .ImplicaAnesthetic choicesGeneral Anesthesia vs. Regional AnesthesiaTable Sedation OptionsPatient comorbidities: Comorbid conditions like cardiovascular disease or OSA should be carefully considered when choosing sedation options. Some medications used for sedation may have hemodynamic effects or exacerbate respiratory compromise, necessitating a tailored approach that minimizes these risks. Additionally, anesthetic providers must monitor vital signs and promptly address adverse reactions .Airway Equipment considerationsSpecially Designed Operating Room Tables and EquipmentBariatric operating tables: Bariatric operating tables are designed to support the weight and dimensions of obese patients effectively. They offer enhanced stability and durability, which is essential during surgical procedures. These tables are more comprehensive and feature robust mechanisms for adjusting patient positioning. This ensures that patients are adequately supported, minimizing the risk of complications related to positioning, such as pressure ulcers or nerve injuries .More coAirway management challengesAdvanced Airway Management SkillsAnesthesia providers should possess advanced airway management skills, allowing them to adapt to the anatomical nuances of obese patients. This includes expertise in various intubation techniques and strategies for optimizing ventilation. Providers should be prepared to handle scenarios where conventional intubation methods may prove challenging .Video LaryngoscopesVideo laryngoscopes are invaluable tools in managing obese patients with difficult airways. These devices incorporate a camera at the tip of the laryngoscope blade, offering a clear view of the airway and vocal cords. This visual aid enhances the accuracy of intubation attempts, even in cases where direct laryngoscopy may be challenging due to anatomical factors .Supraglottic Airway DevicesSupraglottic airway devices, such as the laryngeal mask airway (LMA), are crucial in securing the airway in obese patients. These devices are inserted above the vocal cords and are particularly useful in scenarios where endotracheal intubation is challenging. LMAs provide a secure airway for positive pressure ventilation and can be a bridge to definitive airway management if needed .Comprehensive TrainingAnesthesia providers should undergo comprehensive training in advanced airway management tools and techniques, especially when caring for obese patients. Regular simulation exercises and ongoing education help maintain proficiency and ensure readiness to address airway challenges effectively .Medication dosing in obese patientsInduction AgentsAdjusting for altered pharmacokinetics: Obesity is associated with significant drug distribution and metabolism changes. In particular, the increased adipose tissue content and expanded volume of distribution can lead to prolonged drug effects. As a result, dosing of induction agents like propofol and etomidate should be cautiously approached in obese patients .Consideration of ideal body weight or lean body mass: To prevent the risk of overdosing and subsequent prolonged sedation or respiratory depression, anesthesia providers often base dosing on ideal body weight or lean body mass rather than total body weight in obese patients. Ideal body weight is calculated based on a healthy BMI, which allows for a more accurate alignment of drug dosing with the patient's physiological characteristics .Maintenance AgentsCareful titration based on patient response: Maintenance agents, including inhalational anesthetics and intravenous infusions, require precise titration based on the patient's response. Continuous monitoring of the depth of anesthesia is essential throughout the procedure. Technologies like bispectral index (BIS) monitoring provide real-time feedback on the patient's level of consciousness, enabling anesthesia providers to adjust maintenance agent dosages as needed .Balancing anesthesia depth: The primary goal is to achieve a balanced anesthetic state that ensures patient comfort while minimizing the risks associated with excessive or inadequate anesthesia depth. Overly deep anesthesia can result in delayed emergence, whereas insufficient depth may lead to intraoperative awareness .Neuromuscular Blocking AgentsHigher dosing requirements: Due to the increased volume of distribution in obese patients, higher initial doses of neuromuscular blocking agents (NMBAs) like rocuronium or vecuronium may be necessary to achieve the desired level of muscle relaxation for surgical procedures. This adjustment is crucial to ensure the effectiveness of NMBA-induced paralysis .Monitoring neuromuscular blockade: Train-of-four (TOF) monitoring is paramount when administering NMBAs to obese patients. TOF monitoring assesses the depth of neuromuscular blockade, aiding anesthesia providers in precise dose titration. This approach ensures that the degree of paralysis aligns with the requirements of the surgical procedure, preventing both inadequate blockade and excessive paralysis. Continuous monitoring continues throughout the surgery to guide the administration of reversal agents when necessary, facilitating a smooth recovery .AnalgesicsWeight-adjusted dosing: Pain management is crucial for obese patients during and after surgery. The dosing of analgesics, whether opioids or non-opioid alternatives, should be adjusted to account for weight-related factors. This adjustment ensures that analgesic effects are adequate to control pain effectively while minimizing the risk of overdose .Multimodal analgesia: In obese patients, a multimodal analgesic approach is often favored to reduce reliance on opioids and mitigate their associated side effects, including respiratory depression and postoperative nausea and vomiting. This approach may encompass non-opioid analgesics, regional anesthesia techniques, and adjunct medications like non-steroidal anti-inflammatory drugs (NSAIDs). By combining multiple analgesic modalities, anesthesia providers can enhance pain control and improve the overall safety profile of pain management in obese patients .Ventilation strategiesRisk of Hypoventilation and Respiratory ComplicationsIncreased vulnerability: Obese patients have unique anatomical and physiological characteristics that make them more susceptible to hypoventilation, oxygen desaturation, and postoperative respiratory complications. These challenges stem from decreased lung compliance, reduced functional residual capacity, and a propensity for upper airway obstruction .Positive end-expiratory pressure (PEEP): PEEP\u00a0is often employed to address these concerns. PEEP helps maintain lung volume by preventing alveolar collapse during expiration. This technique aids in improving oxygenation and mitigating atelectasis, which is a common issue in obese individuals during anesthesia and surgery .Monitoring oxygen saturation: Continuous monitoring of oxygen saturation (SpO2) is essential throughout the surgical procedure to promptly detect any declines in oxygen levels. Obese patients may experience rapid desaturation during periods of hypoventilation, making vigilant monitoring crucial for patient safety .Monitoring end-tidal CO2 (ETCO2): Continuous monitoring of end-tidal carbon dioxide (ETCO2) levels, known as capnography, is a fundamental component of anesthesia for obese patients. ETCO2 monitoring provides real-time feedback on ventilation and allows anesthesia providers to detect hypoventilation early. Rising ETCO2 levels can be an early sign of inadequate ventilation, enabling timely intervention to prevent hypercapnia and associated complications .Elevation of the Head of the BedImproved ventilation: During surgery, elevating the head of the bed in obese patients can help improve ventilation. This adjustment assists in reducing the risk of upper airway obstruction, which is more prevalent when patients are supine. Proper positioning is critical to optimize lung mechanics and maintain effective ventilation .Positioning and Pressure Sore PreventionProper patient positioning is crucial to ensure access to the surgical site and prevent pressure sores, especially in obese patients with limited mobility. Pressure-relieving pads and regular position changes should be employed to minimize the risk of skin complications during prolonged procedures. A thorough understanding of these anesthetic management strategies tailored to obese patients is essential for anesthesia providers and healthcare teams to ensure safe and effective care during IVF procedures .Intraoperative and postoperative considerationsHemodynamic MonitoringContinuous surveillance of hemodynamics is paramount in the care of obese patients undergoing IVF procedures. A higher prevalence of cardiovascular comorbidities, such as hypertension, coronary artery disease, and heart failure, often accompanies obesity. As a result, meticulous attention to hemodynamic parameters is essential to detect and manage potential perioperative cardiovascular issues .Blood Pressure MonitoringClose and continuous blood pressure monitoring, including systolic and diastolic measurements, is crucial. Automated non-invasive blood pressure cuffs should be appropriately sized to ensure accurate readings. This ongoing assessment enables anesthesia providers to detect and respond promptly to changes in blood pressure, whether due to surgical manipulation, anesthesia effects, or underlying cardiovascular conditions .Heart Rate MonitoringContinuous heart rate monitoring is vital to detect any arrhythmias or hemodynamic fluctuations promptly. Anesthesia providers must be prepared to address bradycardia or tachycardia as needed during the surgery, ensuring that the patient remains stable throughout the procedure .Cardiac Output AssessmentIn certain high-risk or complex cases, assessing cardiac output may be necessary. This can be achieved through various techniques, including thermodilution or less invasive methods like pulse contour analysis. Monitoring cardiac output provides valuable insights into the patient's circulatory status and helps guide fluid management and vasopressor/inotropic support when indicated .Temperature managementMaintaining normothermia is of paramount importance in the intraoperative care of obese female patients undergoing IVF. These patients present unique considerations due to their larger body surface area and altered thermoregulation. Such factors elevate their susceptibility to perioperative hypothermia, a condition that can have detrimental consequences, including coagulopathy, heightened vulnerability to surgical site infections, and increased cardiovascular stress .To safeguard the well-being of these patients, it is imperative to employ active warming measures specifically tailored to their needs. One widely utilized method involves the use of forced air warming blankets, which deliver warm air directly to the patient's body, helping to counteract the challenges posed by their altered thermoregulation. Furthermore, warmed intravenous fluids can be employed as an effective means to maintain the core body temperature within the desired range for this patient population. Continuous temperature monitoring throughout the IVF procedure is essential, enabling immediate intervention in case of any deviations from the optimal normothermic range .Fluid managementIn fluid management during surgical procedures, particularly for obese patients, two crucial considerations demand attention. Firstly, obese patients are at a heightened risk of overhydration, which can result in severe complications, including pulmonary edema and cardiovascular strain. Therefore, healthcare providers must exercise caution when administering fluids to this patient population. Implementing individualized fluid management strategies tailored to each patient's unique needs is essential. These strategies should be guided by hemodynamic monitoring, and in some cases, invasive measures might be required to ensure precise fluid balance and prevent overhydration .Secondly, preventing complications like pulmonary edema is paramount when caring for obese surgical patients. To achieve this, it is imperative to avoid excessive fluid administration. Instead, the focus should be on optimizing oxygenation levels. Continuous monitoring of oxygen saturation and end-tidal CO2 and a vigilant assessment for early signs of fluid overload, such as crackles during auscultation, must be integral to the surgical team's protocol. By adhering to these meticulous fluid management and monitoring practices, healthcare providers can minimize the risks associated with overhydration and pulmonary edema, ultimately ensuring safer surgical outcomes for obese patients .Postoperative considerationsPostoperative care for obese patients demands a comprehensive and tailored approach to ensure their safety and well-being during recovery. Firstly, transitioning from the operating room to the recovery room necessitates vigilant monitoring. Healthcare providers must closely observe vital signs, oxygen saturation levels, and consciousness levels and remain alert to any signs of postoperative complications, such as respiratory distress or cardiovascular instability. This heightened level of surveillance is crucial in the immediate postoperative phase to promptly address any issues that may arise .Effective pain management is another critical facet of postoperative care for obese patients. Recognizing that they may require higher doses of analgesics due to altered pharmacokinetics, healthcare teams should adopt multimodal analgesic approaches. These approaches should incorporate non-opioid options to minimize the potential for opioid-related side effects while optimizing pain control and ensuring patient comfort .Early mobilization is a cornerstone of postoperative care for obese individuals. Promptly getting patients up and moving helps mitigate the risk of complications associated with immobility, such as atelectasis (lung collapse) and DVT. Collaboration between physical therapists and nursing staff is vital in facilitating early ambulation and encouraging deep breathing exercises, which can significantly contribute to a smoother recovery .Obese patients are particularly susceptible to postoperative complications, notably atelectasis and DVT. Reduced lung compliance and hypercoagulability make them prone to these issues. Therefore, preventive measures should be integrated into the postoperative care plan. This may include using incentive spirometry to promote lung expansion, early ambulation to improve circulation and lung function, and pharmacological thromboprophylaxis to minimize the risk of DVT formation. By implementing these strategies and maintaining a vigilant postoperative care regimen, healthcare providers can help obese patients recover safely and minimize the potential for complications .Special considerations for IVFTiming of Anesthesia and IVF ProceduresThe timing of anesthesia in conjunction with IVF procedures is a critical and intricately coordinated aspect of patient care. Firstly, anesthesia providers must establish a close and seamless collaboration with the IVF team to ensure that anesthesia induction and surgery are perfectly synchronized with the patient's specific IVF protocol. This synchronization is vital to optimize the timing of crucial IVF procedures, including oocyte retrieval, insemination, and embryo transfer, thereby maximizing the chances of a successful outcome .Oocyte retrieval stands out as a pivotal moment within the IVF process. To ensure patient comfort and minimize discomfort during the transvaginal follicular aspiration, anesthesia should be administered before this procedure. The timing and administration of anesthesia at this stage are critical to ease the patient's experience and allow the IVF team to perform the retrieval smoothly and efficiently .Regarding embryo transfer, the anesthesia approach may differ from oocyte retrieval. In many cases, patients may not require general anesthesia for this procedure. Instead, conscious sedation or regional anesthesia techniques may be more appropriate and well-tolerated by patients. The choice of anesthesia should consider the patient's preferences, comfort, and any specific medical considerations. This personalized approach ensures that the patient remains as relaxed as possible during this crucial step of the IVF process, contributing to a positive overall experience .Implications of Obesity on IVF Success RatesReduced oocyte quality: One of the primary consequences of obesity in the context of IVF is the potential for reduced oocyte (egg) quality in obese women. This decline in oocyte quality can manifest as abnormalities, such as irregular chromosome structure and spindle formation. As a result, obese individuals may experience lower fertilization rates and reduced embryo implantation rates during IVF. These challenges can pose significant obstacles to achieving a successful pregnancy .Altered hormonal profiles: Obesity disrupts hormonal profiles in several ways. Notably, it often leads to increased insulin resistance, a condition in which cells become less responsive to the effects of insulin. Additionally, obesity can alter sex hormone levels, causing elevated estrogen and androgen levels while reducing levels of sex hormone-binding globulin (SHBG). These hormonal imbalances can negatively impact ovarian function, potentially leading to irregular menstrual cycles and suboptimal reproductive outcomes .Increased risk of miscarriage: Obese patients undergoing IVF are at an elevated risk of experiencing miscarriages. This heightened risk emphasizes the importance of preoperative health and weight management optimization. Furthermore, during pregnancy, obese individuals require close monitoring to promptly identify and manage any complications that may arise, given the increased risk associated with their condition .Diminished response to medications: Obesity can result in a diminished response to fertility medications used in IVF, particularly gonadotropins. Due to altered pharmacokinetics, obese patients may require higher doses of these medications to stimulate ovarian follicular development effectively. Tailoring medication dosages to individual patient needs is crucial in optimizing IVF outcomes .Increased risk of complications: Obesity is associated with a heightened risk of complications during IVF procedures. Notably, obese individuals may be at an increased risk of developing ovarian hyperstimulation syndrome (OHSS), characterized by enlarged ovaries and fluid accumulation in the abdomen and chest. Additionally, they may face an elevated risk of thromboembolic events, such as blood clots, during the IVF process. Careful management and monitoring are essential to mitigate these risks and ensure the safety and success of IVF procedures in obese patients .Emotional and Psychological Support for Obese Patients Undergoing IVFPatient counseling: Preoperative counseling tailored to IVF's emotional and psychological aspects is essential for obese patients. It's important to create a safe and non-judgmental space where patients can openly discuss their anxieties, body image concerns, and expectations related to fertility treatment. Addressing these issues early can help patients better cope with the emotional rollercoaster often accompanying IVF .Support groups: Obese patients undergoing IVF can benefit immensely from participating in support groups or counseling sessions for individuals facing similar challenges. These groups provide a supportive environment where patients can share their experiences, express their emotions, and receive advice and encouragement from peers who have undergone similar journeys. Connecting with others who understand their unique struggles can be comforting and empowering .Multidisciplinary approach: A holistic approach involving a team of healthcare professionals is crucial. This multidisciplinary team may include psychologists, social workers, dietitians, and reproductive specialists collaborating to provide comprehensive support. Psychologists and social workers can help patients address the emotional impact of infertility and obesity on their mental health, offering coping strategies and emotional resilience tools .Education: Providing patients with accurate and detailed information about the relationship between obesity, IVF, and fertility outcomes is key. Clear and open communication helps patients make informed decisions and manage their expectations realistically. Educating patients about the specific challenges they may face due to obesity and the potential impact on IVF success can help alleviate anxiety and uncertainty .Challenges and future directionsOngoing Research in the FieldObesity-related factors: Researchers are delving into specific obesity-related factors that can influence fertility and IVF outcomes. This includes studying adipokines (hormones produced by fat tissue), inflammatory markers, and genetic predispositions that may impact reproductive health. Understanding the molecular mechanisms underlying these factors can provide insights into potential interventions to improve fertility and IVF success rates in obese patients .Anesthetic techniques: Research in this area evaluates the safety and efficacy of various anesthetic techniques tailored to obese patients undergoing IVF. This may include investigating the benefits and risks of regional anesthesia options, optimizing sedation strategies, and developing drug dosing protocols that account for the altered pharmacokinetics and pharmacodynamics often seen in obese individuals. Finding the safest anesthesia approach can improve patient comfort and procedural outcomes .IVF protocols: Modified IVF protocols designed to address the unique challenges presented by obesity are a critical area of research. Scientists and clinicians are working on optimizing ovarian stimulation regimens to improve oocyte quality and quantity in obese women. Additionally, researchers aim to develop protocols that reduce the risk of complications like ovarian hyperstimulation syndrome (OHSS) in this patient population, ensuring safer and more successful IVF cycles .Long-term outcomes: Research efforts also extend to studying the long-term outcomes of obese patients and their offspring following IVF. This includes assessing the impact of maternal obesity on maternal and neonatal health and investigating potential epigenetic changes that may occur during IVF procedures. Understanding the lasting effects of IVF in obese patients is crucial for providing comprehensive healthcare and counseling to these individuals and their families .Emerging Technologies and TechniquesPrecision medicine: The application of precision medicine in IVF involves tailoring treatment protocols and anesthesia management to each patient's specific genetic and metabolic characteristics. By analyzing an individual's genetic and metabolic profile, healthcare providers can make more informed decisions regarding fertility medications, dosages, and anesthesia techniques. This personalized approach can optimize treatment outcomes and minimize risks for obese patients, who often exhibit unique physiological variations .RoboticThe Role of Multidisciplinary Teams in Managing Obese Patients Undergoing IVFCollaboration: Effective care for obese patients undergoing IVF requires close collaboration among healthcare specialists. This includes anesthesiologists, reproductive endocrinologists, bariatric specialists, nutritionists, psychologists, and other relevant professionals. These experts work together to develop integrated care plans that address both the medical and psychosocial aspects of obesity and fertility treatment. This collaborative effort ensures that all aspects of a patient's health and well-being are considered .TailoreIn conclusion, the anesthetic evaluation and management of obese patients undergoing IVF procedures is multifaceted and demands precision, empathy, and a multidisciplinary approach. This comprehensive review has underscored the significance of addressing obesity's impact on IVF success rates, the importance of tailored anesthesia and perioperative care, and the need for emotional support throughout the IVF journey. Obesity poses unique medical and psychological challenges, necessitating a holistic approach that bridges the realms of anesthesia, reproductive medicine, and patient well-being. As we move forward, ongoing research, emerging technologies, and collaborative efforts among healthcare providers promise to enhance further the care of obese individuals seeking fertility treatments. By refining our practices and understanding, we can empower these patients to achieve the dream of parenthood while ensuring their safety, comfort, and overall success."} {"text": "During the COVID-19 pandemic, clinical trials of vaccines received unprecedented publicity; whether this interest might be transferred to vaccine trials generally is unknown. Enrolment in paediatric COVID19 vaccine trials was slower than uptake of adult vaccine trials, and lessons learned are, therefore, of importance for future recruitment and participant experience. Previous studies have investigated motivations for participation in adult vaccine trials , paediatPreviously, we have observed response rates of 2%-4% for similar trials. We therefore hypothesised that prior vaccine trial experience and exposure might modulate the threshold for trial participation, and descriptively studied motivations and barriers to paediatric vaccine trial participation in this context. Ethical approval and feedback from the Oxford Vaccine Centre Public and Patient Involvement (PPI) group was received. Motivations for trial participation were dichotomised by prior trial participation Table ; self-deThis survey has limitations, being an unvalidated survey instrument, the reliance on self-report, and the inability to ascertain motivations among those who declined to participate. Further research including representative sample of the general UK population and better controlling for social desirability bias may shed further light on the nature and magnitude of differences in motivation, providing a basis for targeting adjustments to enrolment\u2014and improve generalisability especially post-pandemic. Parental motivations for enrolling children in clinical trials are understudied and merit detailed exploration to maximise successful recruitment in future trials.Additional file 1: Supplementary Table 1. Baseline characteristics of 81 respondents. P-values are for chi-squared tests."} {"text": "Catatonia is a complex psychomotor syndrome that often goes unrecognized and, consequently, untreated. Prompt and correct identification of catatonia allows for highly effective treatment and prevention of possible complications. Benzodiazepines and electroconvulsive therapy (ECT) are the most widely studied treatment methods. However, no uniform treatment method has yet been brought forward and no previous attempts to treat catatonia on a patient suffering concomitant major depressive disorder (MDD) with NMDA receptor antagonists have been documented so far.To describe the unknown and novel management of catatonia and MDD with intranasal esketamine, a NMDA receptor antagonist.A 55-year-old woman with a diagnosis of long-standing recurrent major depressive disorder who was admitted to the psychiatric inpatient unit of UniversityHospital Marqu\u00e9s de Valdecilla suffering a complex catatonic, mutative state framed on a severe MDD. Different ineffective therapeutic interventions were deployed during the course of her illness. After failing to improve under conventional pharmacological treatment and ECT, and given the complexity of peripheral venous access on this patient (which disabled the option for iv ketamine use), we decided to initiate compassionate treatment with intranasal esketamine.Intranasal esketamine was effective in the resolution of patient\u2019s complex catatonic state. Clinical response from catatonia was observed after 6 intranasal esketamine administrations (2-week follow-up), reaching full catatonia and MDD remission after 12 sessions in absence of significant adverse eventsEsketamine showed promising effectiveness for the treatment of catatonia in the context of MDD, although further research on this topic is needed.None Declared"} {"text": "Cardiac fibrosis is a pathological response characterized by excessive deposition of fibrous connective tissue within the heart. It typically occurs following cardiac injuries or diseases. However, the lack of suitable models for disease modeling and high-throughput drug discovery has hindered the establishment of an effective treatments for cardiac fibrosis. The emergence and rapid progress of stem-cell and lineage reprogramming technology offer an unprecedented opportunity to develop an improved humanized and patient-specific model for studying cardiac fibrosis, providing a platform for screening potential drugs and synchronously elucidating the underlying molecular mechanisms. Furthermore, reprogramming cardiac fibroblasts into cardiomyocyte-like cells to reduce scar volume and induce myocardial tissue regeneration is a promising approach in treating cardiac fibrosis. In this review, we summarize the current advancements in stem cell technologies applied to study cardiac fibrosis and provide insights for future investigations into its mechanisms, drug discovery as well as therapy method. Cardiac fibrosis is a prevalent pathological alteration observed in the advanced stages of most cardiovascular diseases (CVDs). This debilitating condition is frequently associated with various cardiac disorders, resulting in impaired heart function and potentially life-threatening complications such as heart failure plays a pivotal role in initiating cardiac fibrogenesis in response to mechanical stress Leask , mitogenFollowing myocardial damage, a plethora of signaling molecules such as chemokines, cytokines and growth factors are released, triggering the activation of cardiac fibroblasts through diverse pathways. The RAAS is activated during the process of cardiac fibrosis and interacts with pathways that contribute to fibrosis , including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), have substantially expanded the availability of human cells for modeling cardiac fibrosis and discovering drugs due to their ability to unlimitedly self-renew and differentiate into types of cells within the body (about 40%) derived from hESCs better mimics the pathological process of cardiac fibrosis . The transplantation of hPSC-CMs holds the potential to directly enhance cardiac function in individuals with reduced fibrosis and increased vascular density. Additionally, hPSC-CMs can enhance cardiac tissue regeneration and repair processes by secreting growth factors, cytokines, and other signaling molecules . This feature illustrates the potential to obtain abundant cardiomyocytes for transplantation\u00a0 in the implantation of hPSC-CMs in a subacute myocardial infarction pig model , mesoderm posterior bHLH transcription factor 1 (MESP1), myocardin (MYOCD), and zinc finger protein, multitype 2 (ZEPM2) to convert human fibroblasts into human induced cardiomyocyte-like cells (hiCMs) from mouse and human fibroblasts, which possess multipotency to differentiate into various types of cardiovascular cells using a transgene-free reprogramming approach involving six small molecules: CHIR99021, A83-01, GSK126, Forskolin (an adenylyl cyclase activator), CTPB (a P300 histone acetyltransferase activator), and AM580 (a RAR\u03b1 activator) (Wang et al. Despite the considerable potential of stem cell therapy in addressing cardiac fibrosis, there are still several obstacles need to be overcome. These challenges encompass the selection of appropriate stem cells sources, concerns regarding biosafety during cell transplantation, and the necessity to improve cell survival and retention rates, among other factors. The advantages and disadvantages of stem cell transplantation and cell reprogramming for cardiac fibrosis therapy are summarized in Table In summary, stem cell therapy for cardiac fibrosis is an advancing field with promising prospects for the future. Ongoing research and technological advancements are propelling these therapeutic approaches towards potential success. However, several challenges persist in current stem cell treatments. Further investigation is required to address issues such as the selection of appropriate stem cell sources, biosafety concerns, and the feasibility to monitor treatment efficacy. Moreover, ensuring the successful engraftment and survival of transplanted stem cells into the heart remains to be tackled. Many transplanted cells do not exhibit long-term viability or fail to differentiate into functional cardiac cells, thereby impeding the overall effectiveness of this therapy. To ensure the safety and efficient implementation of these stem cell-based approaches, rigorous clinical studies and repeated validation are indispensable. Efforts are underway to establish a high-throughput drug screening platform for the development of novel therapies. Striking a balance between complexity and user-friendliness is pivotal for this platform. Through comprehensive research and validation, we can surmount these challenges and unlock the full potential of stem cell therapy for cardiac fibrosis in the future."} {"text": "Long-term success of peritoneal dialysis as a kidney replacement therapy requires a well-functioning peritoneal dialysis catheter. With ongoing reductions in infectious complications, there is an increased emphasis on the impact of catheter-related and mechanical complications. There is currently a marked variation in the utilization of various types of catheters , methods of catheter insertion , timing of catheter insertion, location of catheter placement and peri-operative practices. Specialized approaches to catheter placement in clinical practice include use of extended catheters and embedded catheters. Marked variations in patient lifestyle preferences and comorbidities, specifically in high acuity patient populations necessitate individualized approaches to catheter placement and care. Current consensus guidelines recommend local procedural expertise, consideration of patient characteristics and appropriate resources to support catheter placement and long-term functioning. This review focuses on an overview of approaches to catheter placement with emphasis on a patient-centered approach. It is reported that approximately 424,000 patients worldwide utilize peritoneal dialysis (PD) as a method of kidney replacement therapy . A well-Knowledge of best practices in catheter insertion can minimize the risk of catheter complications leading to early PD failure. Guideline committees under the sponsorship of the International Society for Peritoneal Dialysis (ISPD) recommend optimal PD catheter implantation be based on individualized patient factors, facility resources and operator expertise . Currentvia trocar and blind insertion via Seldinger technique at the time of catheter placement , 22. EarAnother strategy for timely initiation of PD is the embedded catheter technique, with the external limb of catheter embedded in subcutaneous tissue until the need for dialysis initiation. This allows for early patient commitment to PD, more predictable operating room scheduling, and immediate utilization of the catheter after exteriorization. However, there is a risk of non-usage of catheters, in addition to catheter dysfunction rates secondary to fibrin accumulation \u201328.No specific catheter placement approach has been proven to produce superior outcomes. Comparison of percutaneous placement, open surgical dissection and basic surgical laparoscopy have shown equivalent patient outcomes , 29\u201331. The goals of PD catheter placement involve a balance between pelvic position of catheter tip to facilitate inflow and outflow of dialysate along with an easily visible and accessible exit site. Operator expertise and experience necessitates selection of appropriate available catheter type suited to patient specific conditions. Placement includes the consideration of body habitus, belt-line, skin creases, prior scars, stomas, gastrostomy tubes, recreational habits and occupation. An ideal exit site is either above or below the beltline, with a lateral and inferior directed exit site . In the via a 2- piece extended catheter system, with a long subcutaneous section, while maintaining optimal catheter tip position. Alternatively, single piece catheters with long intercuff segments are also utilized in certain centers necessitate a specialized approach for successfully conducting PD as a dialysis modality. This includes not only optimal exit site and catheter tip position, but utilization of focused interventions to ensure ideal long term function. Patients with obesity require creation of an easily visible upper abdomen/presternal exit site requiring an extended catheter approach. The catheter should be allowed to heal completely for several weeks prior to PD initiation. Ideally, a laparoscopic approach is recommended, utilizing selective omentopexy along with resection of epiploic appendices of sigmoid colon if needed. The upper abdominal and chest exit sites are located in areas with relatively thin subcutaneous layer, minimizing tubing stresses from mobility of the subcutaneous fat layer with postural changes. Data suggests longer time to first exit site infections in patients with extended catheters . MoreovePatients with autosomal dominant polycystic kidney disease (ADPKD) present a unique set of concerns regarding limited peritoneal space, peritonitis risk and hernias. Several studies have reported the feasibility of PD in ADPKD patients \u201340. WithPatients with cirrhosis present their own unique challenges with regards to potential bacterial peritonitis, nutritional challenges, and concerns for leaks \u201349. SeveSafe and effective placement of PD access is critical to the ultimate outcomes of PD as a home dialysis modality. SK and MR were responsible for preparation, writing and editing of this manuscript. Both authors contributed to the article and approved the submitted version."} {"text": "Furthermore, the SVM model could distinguish MDD patients with different suicidality gradients . In conclusion, we have identified that disrupted brain connections were present in MDD patients with different suicidality gradient. These findings provided useful information about the pathophysiological mechanisms of MDD patients with suicidality.Suicidal behavior is a major concern for patients who suffer from major depressive disorder (MDD). However, dynamic alterations and dysfunction of resting-state networks (RSNs) in MDD patients with suicidality have remained unclear. Thus, we investigated whether subjects with different severity of suicidal ideation and suicidal behavior may have different disturbances in brain RSNs and whether these changes could be used as the diagnostic biomarkers to discriminate MDD with or without suicidal ideation and suicidal behavior. Then a multicenter, cross-sectional study of 528 MDD patients with or without suicidality and 998 healthy controls was performed. We defined the probability of dying by the suicide of the suicidality components as a \u2018suicidality gradient\u2019. We constructed ten RSNs, including default mode (DMN), subcortical (SUB), ventral attention (VAN), and visual network (VIS). The network connections of RSNs were analyzed among MDD patients with different suicidality gradients and healthy controls using ANCOVA, chi-squared tests, and network-based statistical analysis. And support vector machine (SVM) model was designed to distinguish patients with mild-to-severe suicidal ideation, and suicidal behavior. We found the following abnormalities with increasing suicidality gradient in MDD patients: within-network connectivity values initially increased and then decreased, and one-versus-other network values decreased first and then increased. Besides, within- and between-network connectivity values of the various suicidality gradients are mainly negatively correlated with HAMD anxiety and positively correlated with weight. We found that VIS and DMN-VIS values were affected by age ( Major depressive disorder (MDD) is a common psychiatric disorder characterized by an inability to experience pleasure/reward (anhedonia) , affecti. Furthermore, previous studies aver that cortical thickness of ten regions within fronto-temporal-parietal system act as top-ranked classifiers that could differentiate suicide attempts from SI in MDD patients [Neuroimaging and behavioral studies have recently centered on network-based structural and functional alterations of individuals at risk of suicide. Previous studies postulated that fronto-limbic system is the central circuit underlying the suicidal process under depressive conditions \u201315. MDD patients . In addipatients . These fBased on prior studies, we hypothesized that suicidal gradient in MDD patients might arise from disturbances in macroscale brain RSNs and altered brain connections may represent powerful diagnostic biomarkers to discriminate MDD with or without SI and SB. First, the current study mapped the dynamic trajectory of large-scale RSNs roles and their clinical significance with dynamic network-based analysis in MDD patients with suicidality gradient. Second, common and specific network connections associated with different suicidal gradients were identified in MDD patients. Third, the support vector machine (SVM) model was used to explore the role of these abnormal neuroimaging characteristics as objective diagnostic biomarkers in classifying MDD patients with different suicidal gradients. Depression shows gender specificity in which the incidence rate of MDD is approximately twofold higher in women than in men . TherefoAmong the previously mentioned MDD patients, 169 individuals had a medication history; nevertheless, they had refrained from taking medication for a duration of at least three weeks at the time of enrollment. Based on a 17-item HAMD suicide item score, MDD patients were categorized into five categories: a score of 0 was defined as MDD without suicidal ideation (MDDNSI); score of +1 was defined as MDD with mild suicidal ideation (MDDmSI); score of +2 was defined as MDD with moderate suicidal ideation (MDDmoSI); score of +3 was defined as MDD with severe suicidal ideation (MDDSSI); and score of +4 was defined as MDD with SB (MDDSB). HCs were randomly divided into HC and verification groups. Detailed information on all subjects is shown in Table A total of 528 MDD patients and 998 HCs were recruited from the REST-meta-MDD consortium and the All study sites obtained approval from their local institutional review boards and ethics committees. Also, these research protocols were approved by the Ethics Committee of Henan Provincial Mental Hospital Affiliated with Xinxiang Medical University . All participants, their legal guardians, or their legally authorized representatives provided informed consent prior to their involvement in the study.Scan acquisition was completed within 1 week of assessments. Resting-state fMRI and structural T1-weighted MRI brain scans were acquired at each of the 24 participating study sites (see STable These networks comprise the auditory network (AUD), the cingulo-opercular network (CON), the dorsal and ventral attention network (DAN and VAN), the default mode network (DMN), the fronto-parietal network (FPN), the salience network (SAN), the sensorimotor network (SMN), the subcortical network (SUB), and the visual network (VIS). Network connectivity between all pairs of 10 RSNs, as well as between each RSN and all other RSNs were computed.A power atlas was usedp\u2009<\u20090.05 for all tests. In addition, a one-way analysis of variance (ANOVA) test was used to analyze continuous variables, with post hoc least significance difference (LSD) tests for pair-wise comparisons. Chi-squared tests were also used for categorical variables. Notably, each network metric ) was compared across groups using generalized linear model (GLM) analysis adjusted for age, gender, education, and study site as covariables. All p values were adjusted for multiple comparisons using FDR correction.Group comparisons of demographic characteristics and network metrics across MDD subgroups were undertaken using analysis of covariance (ANCOVA) and significance levels were set at p\u2009<\u20090.001.The current study first generated a 226 * 226 connectivity matrix for each subject. Network-based statistical analysis (NBS) method was then used to identify common and differential connections of networks between healthy control (HC) and disease groups, as well as various disease subgroups. Each connection identified by NBS with Bonferroni correction satisfied Due to the potential effects of age and sex in dynamic network analysis, Wilcoxon rank sum tests were used to compare the abnormality of network and clinical variables in sex and age. Specifically, all patients were split into younger (age: 18\u201337) and older (age: 38\u201365) participants or females and males to obtain sex- and age-related alterations in networks and clinical variables, separately.The current study computed Pearson\u2019s correlation between network variables and clinical data.SVM was used in the current study to classify MDD subgroups and HCs in MATLAB based on a library (LIBSVM) . The curAll described analyses were repeated using another set of healthy subjects that included 499 subjects to validate whether network role construction could be replicated and whether selected functional connections could be used for classification.p\u2009<\u20090.001) and subscales scores including anxiety (p\u2009=\u20090.0003), weight (p\u2009<\u20090.0001), retardation (p\u2009<\u20090.0001), and sleep (p\u2009=\u20090.0001), compared with those of MDNSI subjects, indicating that MDD patients R1\u20132 with suicidality had severer depression compared with MDNSI patients. Furthermore, there were no statistically significant differences in additional clinical characteristics upon enrollment, including total disease duration and frequency of episodes among the subgroups of individuals with MDD.Demographic information and characterization of all study subjects are outlined in Table R1\u20133 and pairwise BNC in HC group and suicidality-related MDD patients Fig. . SpecifiTo further map abnormal network connections with significant group differences in within-, between- or one versus other networks of ten RSNs in MDD patients, the current study first established increased and decreased network connections in the suicidality-related MDD patients compared with the HC group as shown in Fig. To understand the clinical significance of abnormal WNC and BNC in MDD subgroups, the current study conducted Pearson\u2019s correlation between FC strength within- and between networks and clinical variables including HAMD total scores and subfactor scores, including HAMD-Anxiety, HAMD-Weight, HAMD-Retardation, and HAMD-Sleep in MDD patients after controlling for covariables of age, gender, education, and study site. Correlation patterns showed group-level associations of WNC and BNC with depressive severity in MDD subgroup patients and established that distinctive network basis was associated with different symptom dimensions in MDD patients with or without suicidality Fig. . These nThe SVM model was used to explore the role of abnormal FC as an objective diagnostic biomarker in MDD patients. Mean FCIs from 31 pairs of network connections were used as input features to the linear support vector classifier (SVC). AUC showed that these FCIs demonstrated a higher capacity to discriminate MDD patients with SB from the HC group (AUC\u2009=\u20090.96). The use of the SVM-trained model as a classifier demonstrated that the SVM-trained model showed better power in separating MDD patients with SI or SB from MDDNSI patients . Furthermore, FCIs also showed greater potential to discriminate suicidality gradient-related MDD patients except for MDDmSI from MDDmoSI patients AUC\u2009=\u20090.73). Detailed information is described in Fig. 3. DetailWilcoxon rank sum tests were used to determine the potential effects of age and sex on large-scale brain networks and clinical variables in females and males, or in younger and older participants, separately. The current study established that age and sex had significantly different impacts on the two variables Fig. . SpecifiThe current study repeated these analyses to validate current findings in independent cohorts that included new 499 HCs and the original 528 MDD patients. More females and lower educational years were found in MDD subgroup patients compared with the new HC group. In addition, large-scale network roles analysis showed similar network dynamics in MDD subgroups compared with the HC validation group . These findings indicate that the use of large-scale network connection approaches to identify more robust diagnostic neuroimaging biomarkers may vary depending on whether the prediction goal pertains to diagnosis. Therefore, the established key features of large-scale network dynamics are crucial for early recognition and timely diagnosis of individuals with suicidality in depression and achieve much greater progress towards understanding and preventing suicide, as well as reducing patients\u2019 risk of morbidity from suicide ideation and attempts and their risks of suicide death. In clinical translational practice, measured imbalanced network links in the current study served as functional endophenotypes to particularly characterize depressive patients who tend to disguise real suicide intent without apparent symptoms. In addition, the current study used this endophenotype to guide informed treatment and monitor if medications target these networks.Several previous studies have established the effects of age and gender on large-scale network dynamics in healthy and depressive disorders \u201362. In mThe current study had some limitations. First, this was a cross-sectional study involving multiple centers. A longitudinal study should be undertaken to validate these findings. Second, the suicidality gradient in depression was assessed using HAMD suicidal factor scores, which may limit findings. Therefore, the use of improved suicidality assessment instruments is necessary to precisely evaluate the severity of suicide in MDD patients in future studies. Third, future studies are needed to establish whether these abnormal networks are long-lasting and how they may interact with environmental and genetic factors.In conclusion, the current study demonstrated that the dynamic trajectory of network roles at a large-scale level was associated with suicidality gradient in MDD patients. Abnormal overlapping network connections were used as neuroimaging biomarkers in the diagnostic identification of subjects who are vulnerable to suicide under depressive conditions. The current study achieved much greater progress towards understanding the pathologic mechanism of suicide and precisely preventing suicidal occurrence via targeting these circuits with effective medical or physical instruments.supplemental material"} {"text": "In recent few years, high-flow nasal oxygenation (HFNO) has been widely used for management of acute hypoxemic respiratory failure and during postextubation periods, including after endotracheal intubation general anesthesia (ETGA). However, HFNO generates positive pressure in the injured airway following removal of endotracheal tube may cause airway leaks. This is the first case report of severe airway leak syndrome following postextubation use of HFNO in surgical patients.This case report describes a 75-year-old female with critical aortic stenosis who underwent an emergency Bentall procedure. HFNO (flow rate of 45\u2009L/min) was applied after weaning from mechanical ventilation and removal of the endotracheal tube.At 6 hours after HFNO application, subcutaneous emphysema in the neck bilaterally and face was noted, and the emphysema extended into the supraclavicular regions.The HFNO cannula was removed soon after and the patient was re-intubated with an endotracheal tube the following day due to progressive respiratory insufficiency. Unfortunately, the patient general condition deteriorated, as the subcutaneous air collections progressed into deep tissue infections of the neck, mediastinal abscesses, and left-sided empyema. Patient received surgical interventions repeatedly to drain the mediastinal abscess and empiric antimicrobial therapy was given.The patient passed away about 2 months later due to uncontrollable sepsis.Air leaks in the upper airway can occur during the use of post-extubation HFNO use, and the resulting subcutaneous emphysema can progress to severe intrathoracic infections in surgical patients who have a sternotomy wound. Therefore, HFNO-induced subcutaneous emphysema should be treated more aggressively in open thoracic or sternotomy surgeries to prevent the development of intrathoracic sepsis. HFNO is currently used to prevent hypoxic events during anesthesia induction, procedural sedation and as an alternative to respiratory support in critically ill patients.,2 A large-scale multi-center clinical trial further demonstrated that HFNO is not inferior to standard noninvasive mechanical ventilation for preventing reintubation and respiratory failure within 72 hours post endotracheal tube removal in high-risk critically ill adults. Compared with conventional oxygen therapy, HFNO also significantly reduces reintubation rates and rates of respiratory support escalation immediately after endotracheal general anesthesia (ETGA) in adult surgical patients. Therefore, HFNO is recommended over conventional oxygen therapy for the management of acute hypoxemic respiratory failure and for postextubation periods in emergency departments, hospital wards, intermediate or step-down units, and intensive care units. Although clinical studies did not find major complications in postextubation use of HFNO,,6 positive pressure in the upper airway from high gas flow may cause air-leaks into the subcutaneous tissues from the injured airway mucosa.,8 This case report describes a patient who was successfully weaned from invasive mechanical ventilatory support day 1 after a Bentall procedure, but developed extensive subcutaneous emphysema and pneumomediastinum within few hours after switching from endotracheal intubation to HFNO.Specially equipped high-flow nasal oxygenation (HFNO) provides a high flow rates (up to 70\u2009L/min) of warm and humidified mixed oxygen/gas to generate continuous positive pressure in the upper airways, wash-out of dead space in the nasopharyngeal cavity, increase alveolar recruitment and functional residual capacity, reduce work of breathing and respiratory muscle fatigue, enhance airway secretion clearance, and improve hypercapnia post endotracheal tube extubation.A 75-year-old woman with a medical history of chronic hypertension and aortic stenosis developed progressive shortness of breath and orthopnea a few days before surgery. She presented to the emergency department with hypotension and low peripheral oxygen saturation. An echocardiographic study showed calcified and severely stenotic aortic valves with a mean transvalvular pressure gradient of 60\u2009mm Hg and left ventricle dysfunction. The proximal aortic root was dilated to a diameter of 10\u2009cm. Acute cardiac failure was evidenced by elevated serum levels of B-type natriuretic peptide (>500 pg/mL) and pulmonary edema on chest radiography. An urgent Bentall procedure, including graft replacement of the ascending aorta and aortic valves was performed under ETGA and cardiopulmonary bypass. An endotracheal tube was inserted smoothly on the first attempt using a video laryngoscope without complications.The whole surgical procedure was completed within 10 hours. After successfully weaning off cardiopulmonary bypass in the operating room, the patient was transferred to intensive care unit for postoperative care under mechanical ventilatory support. Mechanical ventilation was switched from pressure control and pressure support mode when the patient had regained consciousness and had shown effort of spontaneous respiration the morning after her operation. Following a successful spontaneous breathing trial for an hour, the endotracheal tube was removed and HFNO was applied with 40% fraction of inspired oxygen at a flow rate of 45\u2009L/min via a nasal cannula . The patient settled comfortably with HFNO, and adequate peripheral oxygen saturation was maintained. Six hours later, the patient claimed to have insidious attacks of sharp pain and swelling in the neck and face. Subcutaneous crepitus was detected at the neck bilaterally, extending to the lower jaw and the upper chest. HFNO was discontinued and the patient was put on a non-rebreathing mask for oxygen supplementation. A portable chest radiography taken at bedside confirmed the presence of subcutaneous emphysema in the neck and supraclavicular regions with no signs of pneumothorax or pneumomediastinum who were treated with HFNO after endotracheal tube removal. Two of these patients developed pneumothoraxes and one developed pneumomediastinum at 4 to 5 hours after HFNO use. Air leak problems in these pediatric patients were diagnosed by routine chest radiographies rather the presence of subcutaneous emphysema or hypoxic events. There was another case of an adult female with hemophagocytic lymphohistiocytosis who received endotracheal intubation and mechanical ventilatory support due to acute respiratory failure. HFNO therapy was applied at a flow rate of 40\u2009L/min after weaning from mechanical ventilation. Four days later, the patient developed dyspnea and hypoxemia. A series of radiological studies were performed to investigate and found pneumothorax, subcutaneous emphysema, and massive pneumomediastinum. After HFNO cessation, the patient respiratory conditions improved. Air-leak syndrome during postoperative HFNO use after ETGA in surgical patients have not been reported in the literature.It is generally believed that positive airway pressure generated by HFNO in the upper airway and trachea can squeeze air into subcutaneous tissues via micro-tears in the airway mucosa. However, our case progressed rapidly to intrathoracic sepsis and empyema due to gram negative nosocomial pathogen infections and she eventually expired because of uncontrollable sepsis. We speculated that the sternotomy wound might have precipitated the invasion of nosocomial organisms into the mediastinal subcutaneous air collection. Hence, more aggressive empirical antimicrobial treatment should be considered early stages subcutaneous emphysemas are found in surgical patients with a sternotomy or thoracotomy wound.We reported the first fatal air-leak complication following use of postextubation HFNO in a patient with a sternotomy after cardiac surgery. While most of the other case reports were associated with pneumothorax due to distal airway or lung tissue tears, the leak in our case was most likely located in the upper trachea, as the air-leak was not detected before removal of the cuffed endotracheal tube nor after tracheal re-intubation, and pneumothorax was also not found in our case. The initial clinical signs of air-leak syndrome in our patient were focal pain and detection of subcutaneous emphysema as opposed to being clinically asymptomatic or presence of hypoxia at the late stage in other cases. Therefore, detection of emphysema underneath the neck or facial subcutaneous tissues could be an early sign of upper airway leak when HFNO is applied after tracheal extubation. The outcomes of subcutaneous emphysema due to airway leak is usually self-limiting and requires mainly conservative management.In conclusion, the use of postextubation HFNO is generally safe after ETGA, but air-leak syndrome may still happen in unrecognized airway mucosal injuries, as continuous positive pressure is generated by the HFNO. The presence of subcutaneous emphysema can be an early sign of airway leak following application of HFNO and subcutaneous emphysema should be treated more aggressively in open thoracic or sternotomy surgery to prevent the development of intrathoracic sepsis.Conceptualization: Yu-Yang Liao, Hsuan-Yin Wu, Chen-Fuh Lam, Yi-Ming Wang.Data curation: Yu-Yang Liao, Yi-Ming Wang.Supervision: Chen-Fuh Lam, Yi-Ming Wang.Validation: Hsuan-Yin Wu, Chen-Fuh Lam.Writing \u2013 original draft: Yu-Yang Liao, Hsuan-Yin Wu.Writing \u2013 review & editing: Chen-Fuh Lam, Yi-Ming Wang."} {"text": "Dear EditorWe thank Lightner and colleagues for their study on surveillance pouchoscopy in ulcerative colitis patients. The authors reported that neoplasia following ileal pouch-anal anastomosis (IPAA) is rare. They recommended pouch surveillance with random biopsies of the anal transition zone (ATZ) for patients with a personal or family history of colorectal neoplasia (CRN)It is unknown whether routine surveillance improves outcomes of pouch neoplasia, since pouch neoplasia is usually diagnosed after symptom development. As such, all patients in this study had a negative surveillance pouchoscopy in the 2\u2009years prior to pouch carcinoma detectionWe question whether random biopsies lead to earlier detection of (pre)cancerous pouch lesions. The authors reported six pouch carcinomas and none were detected in random biopsies. Moreover, six of seven dysplastic lesions identified with random ATZ biopsies were not confirmed in follow-up biopsies and it could be questioned whether the initial lesions contained \u2018true\u2019 dysplasiaFinally, we disagree with the recommendation of pouch surveillance in patients with a family history of CRN. The authors reported a positive family history in only one of 13 patients and previous studies did not identify this as a risk factor for pouch neoplasia.In conclusion, we only advocate pouch surveillance with random ATZ biopsies in high-risk patients with prior CRN. Nevertheless, current data remain scarce and uniform, widely adopted pouch surveillance guidelines are needed to unify practice.Disclosure. The authors declare no conflicts of interest."} {"text": "The natural amino acid asparagine (Asn) is required by cells to sustain function and proliferation. Healthy cells can synthesize Asn through asparagine synthetase (ASNS) activity, whereas specific cancer and genetically diseased cells are forced to obtain asparagine from the extracellular environment. ASNS catalyzes the ATP-dependent synthesis of Asn from aspartate by consuming glutamine as a nitrogen source. Asparagine Synthetase Deficiency (ASNSD) is a disease that results from biallelic mutations in the ASNS gene and presents with congenital microcephaly, intractable seizures, and progressive brain atrophy. ASNSD often leads to premature death. Although clinical and cellular studies have reported that Asn deprivation contributes to the disease symptoms, the global metabolic effects of Asn deprivation on ASNSD-derived cells have not been studied. We analyzed two previously characterized cell culture models, lymphoblastoids and fibroblasts, each carrying unique ASNS mutations from families with ASNSD. Metabolomics analysis demonstrated that Asn deprivation in ASNS-deficient cells led to disruptions across a wide range of metabolites. Moreover, we observed significant decrements in TCA cycle intermediates and anaplerotic substrates in ASNS-deficient cells challenged with Asn deprivation. We have identified pantothenate, phenylalanine, and aspartate as possible biomarkers of Asn deprivation in normal and ASNSD-derived cells. This work implies the possibility of a novel ASNSD diagnostic via targeted biomarker analysis of a blood draw. ASNS gene occupies 35 kb within chromosome 7q21.3 and is composed of a total of 13 exons glucose to analyze central carbon metabolism, [U-13C]aspartate to assess the specific fate of the ASNS reaction, and [U-13C]glutamine to assess TCA cycle turnover. Additionally, the significant decrements in lactate and central metabolism suggest that in vivo [2H7]glucose metabolic imaging may potentially be utilized to assess the effects of Asn deprivation on brain metabolism [In summary, our findings demonstrate that Asn deprivation leads to a broad-based disruption of the metabolic profiles of patient cells deficient for ASNS. We have identified potential metabolic signatures of Asn deprivation in healthy and ASNSD cells. This observation is of high interest for ASNSD and metabolic research as it warrants future work to establish the relevance of these metabolic signatures and their potential roles as diagnostic and prognostic biomarkers in an in vivo and clinical setting. While our results indicate a certain global metabolic insult caused by Asn deprivation in ASNS deficient cells, further work must be done to discern pathway-specific changes using isotopomer tracer and metabolic flux analysis. The research reported here warrants future studies on ASNSD cell models to assess the utilization of [U-tabolism ."} {"text": "Conversely, no statistically significant difference in oral microbiota composition was observed, thus further revealing a close relationship between ICI response and gut microbiota diversity in NSCLC patients. Extracellular vesicles (EVs) were broadly classified into three main categories based on their biosynthetic or secretory processes: exosomes, microvesicles/particles/extracellular bodies, and apoptotic vesicles due to their association with both nutritional and inflammatory status. vesicles . With tharcinoma . A modelarcinoma . In addiarcinoma . Gao et Using Multi-Omics to Develop New Strategies for Improving Prognosis and Immunotherapy Outcomes in Cancer\u201d serves as a platform for sharing innovative strategies developed through multi-omics to enhance the effectiveness of immunotherapies and improve patient outcomes. These studies integrate data from various layers, providing valuable insights into the molecular structure of tumors and expanding the scope of cancer biology. Although clinical applications of these techniques are still in the early stages, we believe that several of these new approaches will not only advance our understanding of tumor biology but also significantly shape the future of precision cancer therapies.The Research Topic \u201c"} {"text": "Escherichia coli bacteremia. Larvae of Strongyloides stercoralis were also observed in stool smears after a centrifugation concentration method. This diagnosis was confirmed by qPCR detection of Strongyloides spp. using the Allplex GI-Helminth (I) Assay (Seegene) (The definitive diagnosis was disseminated strongyloidiasis with concurrent Seegene) in the tS. stercoralis is a soil-transmitted nematode that is endemic in tropical and subtropical countries, especially in areas with inadequate sanitary conditions, and it is recognized as a neglected tropical disease in the gut, resulting in autoinfection. This unique property allows infection to persist for decades (chronic strongyloidiasis) and cause overwhelming infection if people become immunosuppressed later in life, leading to Strongyloides Hyperinfection Syndrome (SHS) or disseminated infection (Strongyloides infection in patients treated with dexamethasone needs to be considered to avoid precipitating SHS and disseminated strongyloidiasis (nfection , 7. Concnfection , so asym"} {"text": "Plant genotype influences interactions among associated bacteria and fungi;Plant-growth-promoting bacterial communities lead to outcomes exceeding the sum of individual effects; andEnvironmental conditions impact how microbes in communities interact.Soils are home to a wide variety of microorganisms. The collective genome of these organisms is vast, and so individual strains perform some functions that few others can. In addition to the consumption of specific metabolites, many soil microbes excrete unique compounds into their direct environment in soils, at root surfaces, and inside plants as endophytes. The ensuing localized build-up of compounds impacts other organisms by exerting a variety of functions: promoting growth, activating signal transduction, suppressing cellular functions, or changing the physicochemical environment. Microorganisms share soils with plants, whose roots exude cocktails of organic compounds ,2 that fOryza rufipogon wild rice and male parent Oryza sativa cultivated rice had significantly different bacterial and fungal communities than either of the parental lines. Similarly, sorghum lines have different rhizo- and endosphere bacterial communities that contribute to plant performance to different degrees under low nitrogen stress conditions [Plant breeding has focused largely on improved agronomic traits, such as yield and disease resistance, invariably losing some parental traits not selected for. Rhizomicrobiome analysis of modern cultivars versus ancestral accessions has revealed significant differences in the bacterial and fungal communities of rice . The pronditions . Cultivanditions .A unique three-way interaction has been reported among plants, their endophytes, and the associated rhizomicrobial community. Fungal endophytes of Tall Fescue are not only associated with improved biomass yield and stress tolerance, but also with soil fungal community composition and increased diversity . These sStreptomyces [Physicochemical conditions are well known to affect the growth of individual microbial cultures. Invariably, shifts in environmental conditions also impact the fitness of individual species and strains. Farda et al. reviewed the literature on actinomycetes in caves . The scaptomyces . Tarin eptomyces .Various microbial strains isolated from soils have been shown to benefit crop production through mechanisms such as nutrient acquisition or suppression of pathogens. Wang et al. present an analysis of how the consortia of disease-suppressing microorganisms bring about enhanced protection when compared to individual strains . They goThe contributions to this Special Issue all point to the complexity of specific interactions that lead to shifts in microbial communities under specific conditions. Much remains to be done to unravel the specific components of these interactions."} {"text": "Environmental transmission of bacteria, including multidrug-resistant organisms (MDROs), persists within hospitals despite routine cleaning. In prior work, we identified discordance between 16S profiles of room surfaces and culture of MDROs, suggesting unique environments for MDRO persistence within rooms. To build on this work, we used culture-enriched metagenomic sequencing to identify a broad range of viable taxa on surfaces with strain-level assignment and resistome profiling. Additionally, we evaluated the role of room proximity on sharing bacterial taxa and resistance genes between rooms.We selected three intensive care unit (ICU) rooms at the Hospital of the University of Pennsylvania with varying proximity and sampled 12 surfaces per room divided into three composite samples (Table 1). Sampling was repeated for 3 consecutive days. Samples underwent liquid media enrichment, DNA extraction and shotgun metagenomic sequencing. Strain-level assignment was performed with MetaPhlAn 4.0 and resistance genes assigned via the Comprehensive Antibiotic Resistance Database (CARD).Each composite sample represents approximately 350 square inches of surface areaWe identified 40 strain-level assignments, with 18 shared between rooms. Within individual patient rooms, we identified microenvironments of bacterial strains and resistance genes and an increased probability of detecting cephalosporin resistance genes as distance increased from the patient\u2019s bed and neared bathroom sites . Using mixed effects regression, we found that distance between patient rooms was associated with decreased similarity in microbiomes of the distant in-room sites , while an opposite pattern was observed in the bathroom sites .Rooms that were closer had greater similarity of microbiomes at the distant in-room site. Focused interventions on this microenvironment within patient rooms may be highest yield in reducing room-to-room transmission of bacteria. Shared microbiota at the bathroom site may be linked to plumbing infrastructure, but further research is needed to support this hypothesis.All Authors: No reported disclosures"} {"text": "Open Biology, titled \u2018Advances in Quantitative Bioimaging\u2019, proposes an overview of the latest advancements in quantitative bioimaging techniques and their wide-ranging applications. The articles cover various topics, including modern imaging methods that enable visualization on a nanoscale, such as super-resolution microscopy and single-particle analysis. These techniques offer unparalleled insights into complex molecular structures and dynamic cellular processes in situ, such as mapping nuclear pore proteins or tracking single histone deposition events throughout the cell cycle. The articles presented in this edition showcase cutting-edge quantitative imaging techniques coupled with advanced computational analysis capable of precisely measuring biological structures and processes. Examples range from correlating calcium release events to underlying protein organization in heart cells to pioneering tools for categorizing changes in microglia morphology under various conditions. This editorial highlights how these advancements are revolutionizing our understanding of living systems, while acknowledging challenges that must be addressed to fully exploit the potential of these emerging technologies, such as improving molecular probes, algorithms and correlation protocols.This special feature of Recent progress in quantitative bioimaging technologies has empowered us to visualize complex molecular architectures, track individual proteins, compare cellular dynamics with nanoscale precision and single-molecule resolution. This leap forward holds significant potential for driving our understanding into uncharted territory by offering fresh mechanistic insights into living systems. In this special feature issue of . 2et al. discusses the power of combining super-resolution microscopy (SRM) with single-particle analysis (SPA). Several primary research articles in this special edition leverage advanced imaging methods to shed light on important cellular processes: Hurley et al. explore the relationship between calcium signalling events and the structural organization of calcium channels in cardiac muscle cells; Lando et al. use single-particle tracking to understand histone CENP-A molecule deposition in fission yeast; Ragaller et al. propose novel smart probes to measure membrane properties, which are crucial for understanding cellular processes. On the computational front, Martinez et al. have developed machine learning-based tools to characterize morphological alterations and behavioural shifts in microglia during neuroinflammation.This special edition features articles highlighting the ground-breaking applications of quantitative bioimaging techniques in various areas of biology. A review by Mendes et al., in their review entitled \u2018Mapping molecular complexes with super-resolution microscopy and single-particle analysis\u2019, discuss the combined power of SRM and SPA [Mendes and SPA . SRM's aMiriam E. Hurley and her colleagues in their paper \u2018Correlative super-resolution analysis of cardiac calcium sparks and their molecular origins in health and disease' have successfully linked calcium release events, referred to as \u2018sparks\u2019, with the nanoscale arrangement of calcium channels known as ryanodine receptors RyR2) in rat heart cells [ in rat hIn vivo assessment of mechanical properties during axolotl development and regeneration using confocal Brillouin microscopy\u2019 by Riquelme-Guzm\u00e1n et al. used confocal Brillouin microscopy to uncover tissue mechanical changes in vivo throughout development and regeneration in the highly regenerative axolotl, with a particular focus on limb and digit cartilage [The article \u2018artilage . Probinget al., the authors used image analysis tools to examine the morphology and phagocytic behaviour of microglia in healthy and pathological conditions in vitro and in brain tissue [In the article titled \u2018Characterization of microglia behaviour in healthy and pathological conditions with image analysis tools\u2019 by Martinez n tissue . The autet al., in their work \u2018Dissecting the mechanisms of environment sensitivity of smart probes for quantitative assessment of membrane properties', present smart probes\u2014Pro12A, NR12S and NR12A\u2014to assess membrane properties [The research presented in this special issue has important implications for various fields. For instance, Ragaller operties . In thei. 3The studies presented here highlight scientific progress made possible by advanced quantitative bioimaging techniques and image analysis. These tools allow us to better understand the intricate layers of cellular functions and expand our perception of how living systems operate across different scales. Over time, these advancements will help bridge the gap between experimental observation and theoretical vision, progressively tackling the formidable complexity intrinsic to biology."} {"text": "Nitrospirota and Nitrospinota have received significant research attention due to their unique nitrogen metabolisms important to biogeochemical and industrial processes. These phyla are common inhabitants of marine and terrestrial subsurface environments and contain members capable of diverse physiologies in addition to nitrite oxidation and complete ammonia oxidation. Here, we use phylogenomics and gene-based analysis with ancestral state reconstruction and gene-tree\u2013species-tree reconciliation methods to investigate the life histories of these two phyla. We find that basal clades of both phyla primarily inhabit marine and terrestrial subsurface environments. The genomes of basal clades in both phyla appear smaller and more densely coded than the later-branching clades. The extant basal clades of both phyla share many traits inferred to be present in their respective common ancestors, including hydrogen, one-carbon, and sulfur-based metabolisms. Later-branching groups, namely the more frequently studied classes Nitrospiria and Nitrospinia, are both characterized by genome expansions driven by either de novo origination or laterally transferred genes that encode functions expanding their metabolic repertoire. These expansions include gene clusters that perform the unique nitrogen metabolisms that both phyla are most well known for. Our analyses support replicated evolutionary histories of these two bacterial phyla, with modern subsurface environments representing a genomic repository for the coding potential of ancestral metabolic traits.The phyla Bacteria and Archaea are presumed to have retained ancient traits due to the environments being analogous to early-Earth, in some cases isolated from the surface world on geologic timescales . Ge. GeNitroses Fig.\u00a0. Gene clly Figs.\u00a0, 8.Fig. Nitrospirota and Nitrospinota as direct relatives . In. InnxrABota Fig.\u00a0. This susmatales . The verNitrospirota and Nitrospinota are markedly different than the later branching groups that have received much attention due to their ecological prominence, especially in the marine environment, and unique nitrogen-based metabolisms. Despite some differences in particular metabolic functions, the similar evolutionary histories of Nitrospirota and Nitrospinota demonstrate how multiple modes of evolution can shape closely related phyla that occupy similar ecological niches. These data demonstrate that gene loss, de novo origination, or lateral acquisition of new genes is a replicated pattern in later-branching clades of phyla whose extant subsurface-inhabiting members resemble ancestral lineages that initially evolved in a primordial habitat.Here we demonstrate that the ancestral metabolisms of early branching clades for the sister phyla Supplmental Methods and FiguresSupplemental Data 1Supplemental Data 2Supplemental Data 3Supplemental Data 4Supplemental Data 5Supplemental Data 6Supplemental Data 7"} {"text": "Burgeoning evidence demonstrates that effects of environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations1,2. This phenomenon remains controversial because underlying mechanisms have not been identified. Therefore, understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental unanswered question in biology. Here, we used an established murine model of male-specific transgenerational obesity to show that exposure to the obesogen tributyltin (TBT) elicited heritable changes in chromatin interactions (CIs) in primordial germ cells (PGCs). New CIs were formed within theIdegene encoding Insulin Degrading Enzyme in the directly exposed PGCs, then stably maintained in PGCs of the subsequent (unexposed) two generations. Concomitantly,IdemRNA expression was decreased in livers of male descendants from the exposed dams. These males were hyperinsulinemic and hyperglycemic, phenocopyingIde-deficient mice that are predisposed to adult-onset, diet-induced obesity. Creation of new CIs in PGCs, suppression of hepaticIdemRNA, increased fat mass, hyperinsulinemia and hyperglycemia were male-specific. Our results provide a plausible molecular mechanism underlying transmission of the transgenerational predisposition to obesity caused by gestational exposure to an environmental obesogen. They also provide an entry point for future studies aimed at understanding how environmental exposures alter chromatin structure to influence physiology across multiple generations in mammals."} {"text": "Editorial on the Research TopicRecent advances in the assessment and management of thoracic traumaThoracic trauma presents a significant global public health challenge, comprising approximately 25% of all injuries and contributing to up to 50% of trauma-related fatalities . SurvivoHoepelman et al.). This initiative aimed to delve into the clinical outcomes and quality of life experienced by individuals after surgical rib fixation for flail chest injuries. The findings showed a significant trend, with low complication rates and a favourable one-year quality of life, as assessed with the EQ-5D-5l questionnaire. Nonetheless, it is pertinent to note that substantial variability was observed among patients in this context.The majority of the articles included in this compilation scrutinized outcomes following surgical stabilisation of rib fractures in distinct patient cohorts. A noteworthy endeavour was carried out by the NEXT study group, encompassing a prospective cohort study that spanned six institutions across Switzerland and the Netherlands (Zhang et al. embarked on an evaluation of outcomes following surgical stabilisation of rib fractures in elderly patients. Employing a single-centre, propensity score matching analysis, their investigation identified a nuanced dichotomy. Patients who underwent surgery exhibited a modestly prolonged hospital stay by an average of two days when compared with their counterparts receiving conservative treatment. Nevertheless, the surgical cohort demonstrated markedly improved rates of fracture healing and a shorter duration of analgesic regimens, delineating a balance between hospitalisation duration and therapeutic efficacy.Becker et al. contributed a matched pairs analysis by using data from the German trauma registry. Their study focused on determining the optimal timing for rib fracture surgery. The findings highlighted a distinct advantage for surgical stabilisation within the initial 48\u2005h post-trauma, resulting in significantly shorter durations of intensive care unit and hospital stays compared to fixation performed between three and ten days following the injury.van Veelen et al., a unique perspective emerged as the authors explored outcomes after surgical fixation of chest wall fractures incurred during cardiopulmonary resuscitation efforts. It is worth mentioning that this retrospective, single-centre study included 19 patients, representing the largest reported cohort to undergo fracture fixation due to cardiopulmonary resuscitation. The authors reported a lack of complications associated with rib fixation, with only one infection observed following sternal fixation. Furthermore, the long-term follow-up demonstrated a favourable quality of life, as measured with the EQ-5D-5l questionnaire.Shifting our attention to the study by While the studies included in this Research Topic make substantial contributions to the evidence base, it is essential to acknowledge certain limitations. In the domain of thoracic trauma, the predominant body of research is characterized by retrospective observational studies and non-randomized prospective trials. Moreover, there is a pronounced heterogeneity in surgical techniques and outcome reporting, making comparisons between studies a challenging endeavour . RegardiWhile the studies featured in this Research Topic undeniably advance our understanding of the assessment and management of thoracic trauma, they also reveal a multitude of unanswered questions. Key areas requiring further research include the definition of optimal patient selection criteria for surgical stabilisation of rib fractures. Currently, it remains uncertain whether fixation should be extended to include a broader spectrum of non-flail chest fracture patterns. There is also a pressing need for comparative effectiveness studies examining different surgical techniques. The role of thoracoscopic visualization in fracture management is an interesting topic that also requires more comprehensive evaluation. Moreover, the absence of standardized protocols for perioperative analgesia and rehabilitation is conspicuous. In addition, there is a dearth of research into long-term, patient-centred outcomes, such as persistent disability and return to work. Formal cost-effectiveness analyses comparing surgical stabilisation to non-operative management are also relatively absent. To address these knowledge gaps effectively, it is necessary to conduct high-quality randomised controlled trials with standardised treatment protocols and well-defined outcomes. Multicentre studies can facilitate larger sample sizes, leading to improved generalizability. Overall, continued research is crucial in honing best practices for thoracic trauma care and ultimately enhancing outcomes for these patients. The studies presented in this Research Topic are indeed promising strides forward, but they highlight that a plethora of unanswered questions awaits exploration in future research.Thoracic trauma continues to exact a substantial toll on global health, contributing significantly to morbidity and mortality rates. The research shared in this Topic signifies prominent advancements, yet further investigations are imperative to delineate optimal practices more precisely. Persistent research efforts in this pivotal domain are warranted to mitigate the global public health repercussions of chest injuries and ultimately improve patient outcomes."} {"text": "Editorial on the Research TopicArtificial intelligence and advanced technologies in neurological surgerySurgical treatment of neurologic disorders has always benefited from technologic advancements in operative techniques and equipment, imaging, predictive analytics, and many others. In recent years, almost all neurosurgical subspecialties have seen a substantial effort to develop, validate, and utilize artificial intelligence and machine learning models in a clinical manner . Unique In this research topic, we explore recent technologic advancements made in neurosurgery, including supervised machine learning models aimed at predicting postoperative survival in glioma patients, customized 3D printing and laser navigation applied to minimally invasive hematoma evacuation, an advanced cerebrospinal fluid (CSF) drainage method for use in posterior fossa tumor resection, and a novel endoscopic approach for treatment of oculomotor nerve palsy, all of which may help to inspire future work in similar topics of interest.Li et al. at an academic institution in China compared the accuracy of traditional statistical models and supervised machine learning models in predicting patient survival following resection for gliomas. Multivariate Cox proportional hazards regression, support vector machine (SVM), random survival forest (RSF), and tree and component gradient boosting (GB) models were evaluated using patient-specific clinical and biomarker variables and were subsequently compared in performance using concordance indexes. Predictably, the traditional Cox proportional hazards regression model performed poorly in both training and testing sets when compared to the supervised machine learning models, of which the GB models produced superior performance in predicting survival. Time-dependent survival performance was additionally assessed between tree GB and component GB models, which displayed good discrimination (area under the curve >0.8) at all evaluated time points. The authors of this study recognized many important patient variables found to influence survival based on these models, including functional status, tumor size, and resection type, which can be utilized to develop patient-specific perioperative plans with the goal of extending survival and limiting morbidity.At the forefront of advancements in neurosurgical outcomes analysis is artificial intelligence and machine learning. A retrospective cohort study conducted by Yuan et al. studied hypertension-induced intracerebral hematoma external drainage techniques based on two new methods in a retrospective analysis: three-dimensional (3D) printing and laser guidance for navigation during puncture and debridement. In the 3D printing method, computed tomography (CT) image reconstructions were utilized to plan endoscope entry and trajectory into hematomas, which were then 3D printed in combination with patient face molds for customized intraoperative guidance. Laser guidance additionally utilized Xper-CT scans and 3D reconstructed images to emit a continuous focus directed towards the hematoma throughout the duration of the procedure. In direct intraoperative and postoperative comparisons, patients treated with 3D printing assistance were found to have significantly shorter operative durations than those treated with laser navigation assistance. However, outcomes including hematoma clearance rate, Glasgow Coma Sale improvement, and hospitalization time were similar between the two groups. The authors noted advantages to both techniques, including real-time navigation feedback and customized care, but may come at increased costs or extended preoperative setup time. Minimally invasive techniques in neurosurgery can be further improved with advancements in imaging and navigation, such as 3D printing and laser guidance.Beyond predictive analytics, developments in imaging technology have been utilized to improve intraoperative techniques. Recent work done by Roethlisberger et al. In their recent work, the authors utilized image-guided ipsilateral trigonal ventriculostomy for cerebellar pressure control during retrosigmoid craniotomy for cerebellopontine angle (CPA) tumor resection, after which outcomes were evaluated in a cohort of 52 patients. Prior to durotomy, the authors performed ventriculostomy of the ipsilateral trigone of the lateral ventricle using CT or magnetic resonance image (MRI) guidance, advancing an external ventricular drain (EVD) to release CSF and decompress the cerebellum. In the prospectively evaluated cohort, cerebellar swelling was avoided in 98% of cases using this technique. However, authors reported an 8% incidence of postoperative intracerebral or intraventricular hemorrhage without clinical complications. Ultimately, the authors recommended consideration of this technique for large posterior fossa tumors but not for small lesions.Developments in image guidance technology have been additionally explored in cerebrospinal fluid (CSF) diversion approaches to reduce cerebellar contusion, such as in the study described by Wang et al. The authors of this work describe detailed anatomic landmarks encountered in their endoscopic approach, focusing on correct identification of the optic strut triangle, consisting of the internal carotid artery, optic nerve, and superior orbital fissure, in preparation for oculomotor nerve decompression. Hollowing of the optic strut by sequential drilling under endoscopic visualization achieved decompression of the optic and oculomotor nerves, resulting in rapid neurologic symptom improvement in 2 presented patient cases. Although still requiring further trials, the techniques described in this study may introduce alternatives to invasive approaches that arise with often extensive complications.New surgical methodologies for conditions previously lacking standardized treatment plans have been developed with the aid of technological advancements including endoscopic approaches. A novel transnasal endoscopic approach for treatment of traumatic oculomotor nerve palsy associated with superior orbital fissure fracture is described in a recent study by Advancements in clinical and intraoperative technology have enabled neurosurgeons to create patient-specific management plans and improve postoperative outcomes for a range of conditions. In this research topic, four original studies were included that demonstrate the breadth of developments made in artificial intelligence-based predictive analytics, intraoperative imaging and navigation technologies, and novel cranial approaches aimed at improving patient outcomes. Further incorporation of machine learning algorithms, reconstructive software, and minimally invasive technology into daily medical practice will allow future generations of surgeons to provide personalized care to patients based on unique comorbidities and anatomic variations.We certainly live in an era of rapid technologic advancement, but this also comes with great responsibility. As physicians and surgeons, it is our duty to question these technologies and understand their limitations before implementing them in our clinical practice. However, it is also our duty to embrace and use them when they can improve our patients\u2019 lives. As our techniques and devices continue to evolve, we look forward to exploring the positive impacts made to neurosurgery and beyond."} {"text": "The need for high quality evidence is recognized for optimizing practices of parenteral nutrition (PN). The purpose of the present systematic review is to update the available evidence and investigate the effect of standardized PN (SPN) vs. individualized PN (IPN) on protein intake, immediate morbidities, growth, and long-term outcome in preterm infants. A literature search was performed on articles published in the period from 1/2015 to 11/2022 in PubMed and Cochrane database for trials on parenteral nutrition in preterm infants. Three new studies were identified. All new identified trials were nonrandomized observational trials using historical controls. SPN may increase weight and occipital frontal circumference gain and lower the value of maximum weight loss. More recent trials suggest that SPN may easily increase early protein intake. SPN may reduce the sepsis incidence, but overall, no significant effect was found. There was no significant effect of standardization of PN on mortality or stage \u22652 necrotizing enterocolite (NEC) incidence. In conclusion SPN may improve growth through higher nutrient intake and has no effect on sepsis, NEC, mortality, or days of PN. Parenteral Nutrition (PN) is a lifesaving therapy for preterm infants. PN is indicated when oral or enteral nutrition is not possible, insufficient, or contraindicated in order to avoid undernutrition and related adverse consequences. The nutrient stores of very low birth weight and extremely low birth weight preterm infants are low. Bridging PN ensures adequate fluid intake and nutrient supply for weight gain and possibly neurodevelopmental long-term outcome. VLBW infants are vulnerable to postnatal growth failure because the gut is immature, and provision of nutrients is challenging. The evidence showing the beneficial effects of enhanced PN to VLBW infants is accumulating. Providing amino acids and energy immediately after birth with PN is a standard practice to promote positive nitrogen retention . SP. SP18]. However, the currently available commercial SPN solutions may not be the optimum approach. Commercial SPN may need an additional amino acid supply to achieve recommended target intakes and consequently adequate growth defined as intrauterine growth velocity .Beyond improved nutrient intake, the umbrella aim in introduction of SPN is to improve patient safety possibly at the cost of increased PN solution wastage . Due to However, SPN did not significantly prevent hospital associated complications . EspeciaStandard PN Solutions (SPN) Should Generally Be Used over Individualized PN Solutions (IPN) in the Majority of Preterm Infants, Including VLBW Premature Infants .Individually Tailored PN Solution should Generally Be Used When the Nutritional Requirements Cannot Be Met by the Available Range of Standard PN Formulations .It has been estimated that the majority of preterm infants receiving PN via central catheters may actually be treated by SPN, although, the optimum composition is not known ,38. SPN Adequately Powered Randomized Controlled Trials Based on Up-To-Date Parenteral Nutrition Recommendations Are Required to Evaluate the Real Clinical Benefits of SPN vs. IPN .Strengths of the present review are its exhaustive search of the available literature, reproducibility, systematic assessment of evidence and grading of recommendations. However, there are important limitations. Neonatology is rapidly developing and changing. E.g., nutritional recommendations changed several times within the last 20 years. Using historical controls rather than contemporaneous controls carries a high risk of bias and grossly limits the level of evidence. Improvements in nutritional status may rather be a consequence of increased nutritional awareness than a consequence of new developed PN approaches. The observed effects may have been noticed by chance and adequately powered, randomized controlled trials based on up-to-date parenteral nutrition recommendations are urgently required to evaluate the real clinical benefits of SPN bags. Given current parenteral nutrition recommendations a considerable proportion of infants of the reported trials are undernourished. In addition, the composition of SPN and IPN nutritional regimens and consequently the observed nutritional status, varied across and within the different studies, limiting the validity of the results of the meta-analyses. In the clinical experience of the authors, one SPN does not fit all preterm infants. The smaller the infants are, the more often adjustments are required, commercial SPN bags are more expensive than hospital pharmacy produced SPN bags, and finally commercial SPN bags still require pharmacy-based adjustments .We conclude that SPN may improve growth through higher nutrient intake and has no effect on sepsis, NEC, mortality, or days of PN. These observations may have been noticed by chance and adequately powered randomized controlled trials are required to evaluate the real clinical benefits of SPN."} {"text": "Arachis hypogaea is a segmental allotetraploid in the section Arachis of the genus Arachis along with the Section Rhizomataceae. Section Arachis has several diploid species along with Arachis hypogaea and A. monticola. The section Rhizomataceae comprises polyploid species. Several species in the genus are highly tolerant to biotic and abiotic stresses and provide excellent sets of genotypes for studies on differential gene expression. Though there were several studies in this direction, more studies are needed to identify more and more gene combinations. Next generation RNA-seq based differential gene expression study is a powerful tool to identify the genes and regulatory pathways involved in stress tolerance. Transcriptomic and proteomic study of peanut plants under biotic stresses reveals a number of differentially expressed genes such as R genes , pathogenesis related proteins and defense related genes that are the most consistently expressed genes throughout the studies reported so far. In most of the studies on biotic stress induction, the differentially expressed genes involved in the process with enriched pathways showed plant-pathogen interactions, phenylpropanoid biosynthesis, defense and signal transduction. Differential gene expression studies in response to abiotic stresses, reported the most commonly expressed genes are transcription factors , LEA proteins, chitinase, aquaporins, F-box, cytochrome p450 and ROS scavenging enzymes. These differentially expressed genes are in enriched pathways of transcription regulation, starch and sucrose metabolism, signal transduction and biosynthesis of unsaturated fatty acids. These identified differentially expressed genes provide a better understanding of the resistance/tolerance mechanism, and the genes for manipulating biotic and abiotic stress tolerance in peanut and other crop plants. There are a number of differentially expressed genes during biotic and abiotic stresses were successfully characterized in peanut or model plants (tobacco or Arabidopsis) by genetic manipulation to develop stress tolerance plants, which have been detailed out in this review and more concerted studies are needed to identify more and more gene/gene combinations.Peanut Arachis hypogaea L.) is one of the most important legume crops economically worldwide and its seed a source of high quality edible oil, proteins, minerals and vitamins. It is widely cultivated across developing countries from semi-arid tropics to subtropical regions (st and 2nd respectively based on FAOSTAT data for the year 2020 (Peanut ( regions . China aear 2020 . ProductArabidopsis (135 Mb), rice (430 Mb), Medicago (904 Mb) and soybean (1.1 Gb). Large genome size and polyploidy nature is quite large in size in contry nature hamper cArachis comprises many wild species at different ploidy levels that exhibit resistance/tolerance to several biotic and abiotic stresses, which makes it a rich resource of suitable genes for commercial applications. Some wild species were deployed in the experiments with the aim of transferring the genes for tolerance/resistance to different stresses from the related wild species to the cultivated peanut genotypes in crop improvement programs is well-established and versatile technique with application to detects the enriched sequences in specific tissues at specific time points and used to characterize differential gene expression of plant responses to biotic and abiotic stresses . To inveRalstonia solanacearum , late leaf spot (LLS), rust, aflatoxin contamination and bacterial wilt disease by nacearum Figure\u00a01nacearum . To manaCercospora arachidicola [Hori] and Phaeosariopsis personata [Berk & M. A. Curtis] respectively, are the major foliar fungal diseases in peanut, which cause complete defoliation of leaves leading to significant losses in plant productivity upto 50 to 70% protein, transcription factors , peroxidases and genes related to secondary metabolites in the resistant variety upon pathogen invasion, while there was downregulation of genes including F-box, cytochrome p450, LRR protein kinase and terpene synthase that are associated with several biological processes in the susceptible variety. There is another recent report of DEGs of resistant and susceptible peanut cultivars to early leaf spot infection, which revealed the expression of resistance associated genes like CC-NB-LRR (NLR) type resistance gene, Phytoalexin deficient 4 (PAD 4) and polyphenol oxidase (PPO) that play important roles in mediating early leaf spot resistance and late leaf spot (LLS) diseases also collectively known as \u2018Tikka\u2019 disease caused by 0 to 70% . Early l0 to 70% . Advance0 to 70% . Upon pa0 to 70% . Candidasistance . IdentifPheaosariopsis personata (Cercospora personata) is the most devastating disease in peanut and can lead to yield losses up to 70% under favorable conditions . Furthermore, they identified TDFs (transcript derived fragments) that are associated with defense, signal transduction and metabolism, and further reported several genes for proteins involved in hypersensitive cell death, cell wall fortification and defense mechanism. Differential gene expression analysis in wild type and mutant peanut cultivar against late leaf spot pathogen was also reported by There are several methods available to study differential gene expression during plant-pathogen interactions in peanut, such as Genefishing DEG kit, suppression subtractive hybridization (SSH), cDNA-AFLP and cDNA-microarray techniques . These ansferase . In an e pathway . Kumar aR-genes (381) associated with leaf spot disease was predicted by a RGA-PCR based technique , receptor like proteins (RLPs) and receptor like cytoplasmic kinases (RLCKs), which co-ordinate and initiate protection responses against the invading pathogen , as potential resistance (R) genes play important roles in recognition and activation of disease resistance responses and the identification of putative peanut echnique . Furtherpathogen . Recentlpathogen .Puccinia arachidis that often occurs along with leaf spot disease also because of its rain fed nature, which leads to further yield losses. There are several studies on quantitative trait locus (QTL) in cultivated peanut to identify molecular marker or genetic map for rust resistance technique, which is based on next-generation sequencing (NGS) for genotyping and this resulted in the identification of six candidate genes for rust resistance protein were significantly upregulated in the resistant genotype revealing their important roles in plant defense mechanism. These findings will be helpful in understanding the molecular mechanism of peanut plant defense against the rust pathogen and may assist the breeders in the development of resistant varieties through molecular approaches.Rust is another serious foliar disease of peanut caused by sistance , but thesistance . RecentlAspergillus flavus is an opportunistic saprophytic fungal pathogen that infects a number of seed crops and microarray technology. Furthermore, they identified sixty two genes in the resistant cultivar that were upregulated in response to Aspergillus infection including defense related genes like PR10 protein, defensin, calmodulin, metallothionein like protein, Cu/Zn superoxide dismutase etc. and a large number of hypothetical proteins as the complete genome sequence was not available at that point of time. A similar study has reported the identification of Aspergillus resistance genes in peanut cultivars by comparing transcriptome profiles in resistant and susceptible peanut genotypes using microarray technique and identified hub genes positively associated with resistance to A. flavus in peanut. Their analysis also revealed that upregulation of genes encoding pathogenesis-related protein (PR10), MAPK kinase, 1-aminocyclopropane-1-carboxylate oxidase (ACO1), a serine/threonine kinase, cytochrome P450, pectin esterase, SNARE protein SYP121, pentatricopeptide repeat (PPR) protein and disease resistance response proteins in the esistant peanut cultivar that play major roles in resistance to infection from A. flavus. These studies provide new insights into the molecular mechanism of peanut defense against aflatoxin contamination and further the safety and management of peanut products for human consumption.on etc.) and prodon etc.) . Peanut nditions that cauechnique . Their rchnology . This grRalstonia solanacearum) is the most devastating soil borne disease in peanut (Arachis hypogaea L.) leading to significant yield losses because of reduced plant stand on the field at the seedling stage of the crop. Molecular mechanism of peanut response to R. solanacearum remains unnknown and needs to be studied in detail. In an attempt to explore the molecular mechanism of bacterial wilt resistance in peanut using Genefishing DEG kit, several differentially expressed candidate genes encoding a cyclophilin, ADP-ribosylation factor, antibacterial peptide and disease resistance response proteins were identified by studying the differences in gene expression between inoculated and control peanut seeds into six groups as resistant/susceptible response genes, which included PAMPs induced resistant/susceptible response genes and type III effectors (T3Es) induced resistant/susceptible response genes. Further more, KEGG enrichment pathway analysis of differentially expressed genes showed that MAPK signaling, plant-pathogen interaction, and plant hormone signal transduction pathways were upregulated. WRKY Transcription factors play an important role in plant disease resistance. Differential gene expression analysis of WRKY genes in cultivated peanut displayed different expression patterns in resistant and sensitive peanut cultivars infected with R. solanacearum. The identification of candidate WRKY genes with possible role in peanut resistance to R. solanacearum infection may contribute in the improvement of a resistant peanut variety , pathogenesis related proteins , defense related genes , glutathione S-transferase) and the genes involved in phenylpropanoid pathway are the most commonely expressed ones (Arabidopsis) through genetic manipulation and successfully developed biotic stress resistant plants for functional characterization of genes that integrated into the corresponding genome. There are limited reports on differentially expressed peanut genes for further characterization using genetic engineering to develop stress tolerance plants. The transgenic plants that were developed for functional characterization of diffrentially expressed peanut genes are given in Several peanut genes, which were differentially expressed during biotic stress conditions were further characterized by transgenic approach. Presently, genetic engineering technique such as Cyclophillin (AdCyp) gene that was differentially expressed in wild peanut A. diogoi during late leaf spot infection was incorporated into tobacco genome under a constitutive promoter through the Agrobacterium method and this resulted in enhanced resistance to Ralstonia solanacearum and reduced susceptibility toward Phytophthora parasitica var. nicotianae. Further, the resistance phenomenon was associated with the up-regualtion of various defense related genes genotype enhanced resistance to late leaf spot pathogen and this expression was associated with the co-expression of resistance-related genes, CC-NB-LRR and some protein kinases, while heterologous expression in tobacco enhanced its resistance against Phytophthora parasitica var. nicotianae, Alternaria alternata var. nicotianae and Rhizoctonia solani like cell death and positively regulated defense response genes. Furthermore, ectopic expression of AdVPE in tobacco resulted in enhanced resistance against Phytophthora parasitica var. nicotianae, Alternaria alternata var. nicotianae and Rhizoctonia solani (AdZADH2) was also differentially upregulated in Arachis diogoi, a wild peanut upon challenge with the late leaf spot (LLS) pathogen. Transient over-expression of AdZADH2 under an estradiol inducible promoter (XVE) exhibited hypersensitive response (HR)-like cell death in tobacco leaf and the cell death was associated with the upregulation of antioxidative enzymes such as SOD, CAT and APX and pathogenesis-related (PR) proteins (Vacuolar processing enzymes (VPEs) are cysteine proteases exhibiting caspase-1-like activity, which mediate cell death and upregulated during pathogen infections . AdVPE wa solani . A novelproteins .R gene products, which can directly or indirectly recognize pathogen effector proteins and induce signaling pathways for resistance against the impending pathogen in Nicotiana benthamiana and AhRLK1 overexpression in transgenic tobacco significantly enhanced resistance to R. solanacearum by triggering EDS1 and PAD4 in the R gene signaling pathway that possibly contributed to defense responses against the pathogen protein was found to be upregulated in both approaches . Wang etranensis .Soil salinity is another major abiotic stress factor that affects plant growth and development reducing crop productivity. Peanut is considered to be a moderately salt sensitive species, which makes salinity a liming factor for peanut cultivation. In general, plants respond to salt stress by changing their gene expression, which leads to an increase in the concentrations of several metabolites to protect themselves against high salinity. Transcriptome study has become an important tool for studying the possible mechanism and elucidating signal pathways underlying salt stress tolerance in plants. However, limited information is available about the networks of gene expression regulation related to salt stress in peanut. A microarray study has been carried out in peanut roots under salt stress conditions, which revealed that metabolic pathway, biosynthesis of unsaturated fatty acids and plant-pathogen interaction were upregulated, while photosynthesis and phenylalanine metabolism were downregulated . TranscrTIP3 gene is significantly upregulated in response to salt stress. Furthermore, TIP3 overexpression in Arabidopsis resulted in enhanced seed germination under salt stress corroborating its important role in seed germination under salt stress.A comprehensive study of drought tolerance in cultivated peanut has been performed under salt stress environment and this concurrent stress application has detected several differentially expressed genes and transcription factors (TFs) such as MYB, WRKY, bHLH and AP2/ERF in response to salinity. Moreover, differentially expressed genes related to cell wall growth, antioxidant and peroxidase activity were significantly enriched while DEGs related to metabolic processes, oxidoreductase and catalytic activity were downregulated . AquaporPMP34 that encodes a peroxisomal nicotinamide adenine dinucleotide carrier, and Sodium/H+ antiporters (NHX7 and NHX8), and downregulated expression of proline dehydrogenase 2. This resulted in the accumulation of soluble sugars and proline to maintain the osmotic balance with an additional up-regulation of the aquaporin gene TIP2-1. Moreover, exogenous EBL application upregulated the expression of NHX7 and NHX8 to balance the ion concentrations across membranes with increased peroxidase activity to scavenge reactive oxygen species, and glutathione levels to improve salt tolerance in peanut.Brassinosteroids (BRs) are essential for plant growth and development, and play crucial roles in stress tolerance . HoweverLow temperature is a major environmental factor that limits plant growth, development and yield. Cold stress causes different degrees of damage to the peanut plant at the seedling, flowering, and all other growth stages. A transcriptome or differential gene expression analysis in response to cold or metal stress could provide a deeper insight into the transcriptional mechanism of plants and their protective role against damage. Differentially expressed peanut genes in response to different temperature regimes was carried out using suppression subtractive hybridization (SSH) for cultivated peanut seeds and this study identified genes that are involved in functional categories including metabolism, defense, stress response, signal transduction and transcriptional regulation .2H2, ERF, MYB, NAC and WRKY in response to cold stress, which could be crucial for peanut cold tolerance are non-coding small RNAs that play important roles in various abiotic stresses by modulating gene expression. However, there is no report on the role of miRNAs in cultivated peanuts during cold stress. Very recently, cold-responsive miRNAs and candidate target genes were identified in peanut cold tolerant and sensitive varieties during cold stress using a deep sequencing method. Their analysis revealed several specific cold responsive microRNAs, which appear to mediate cold response. And, several transcription factors including WDRL, GRF and ARF, and genes such as peanuts .EIL (EIN3-like), which reveals a link between ethylene signal transduction and Al resistance related genes in peanut (Aluminum (Al) is the most abundant metal element in the Earth\u2019s crust, and has toxic effects on plant growth in acidic soils . The tarn peanut . An ultrn peanut . The samn peanut .Arachis accessions under drought, salt, cold and metal stress conditions will provide a better understanding of the tolerance mechanism, and will further provide reference for improving abiotic tolerant peanut cultivar through genetic manipulation.Differential gene expression study of peanut plants in response to abiotic stresses, reported by the most of the studies Table\u00a03,Agrobacterium tumefaciens mediated genetic transformation. There are several reports on the characterization of differentially expressed genes in peanut and/or model plants to develop stress resistance plants. The list of transgenic plants deploying differentially expressed peanut genes is provided in Further characterization of differentially expressed genes during various abiotic stresses by genetic manipulation like transgenic approach would aid in developing stress tolerance peanut cultivars, which can help achieve increased crop productivity. Till today, different types of transgenic plants were generated by genetic engineering technique using AhERF019 in Arabidopsis resulted in enhanced tolerance to drought, heat, and salt stresses (LEA) gene was differentially expressed in wild peanut upon infection with late leaf spot pathogen and overexpression of AdLEA in tobacco resulted in enhanced tolerance of plants to dehydration, salinity and oxidative stress. Furthermore, AdLEA overexpressed tobacco plants maintained better photosynthetic efficiency under drought conditions implying that it could be a potential gene for genetic modification in crop plants gene and overexpression of AdGolS3 gene in Arabidopsis resulted in increased raffinose production and tolerance to drought, salt and osmotic stresses plays a significant role in regulating gene expression in plant responses to stresses and was identified from peanut EST sequences available in the NCBI database. Ectopic expression of stresses . Late Emp plants . In silistresses . A CBL-in plants .TIP3 was found differentially upregulated under salt stress condition in cultivated peanut. Furthermore, the ectopic expression of AhTIP3;1 contributed to improved seed germination under salt stress in Arabidopsis was found upregulated during plant-microbe interaction in peanut and further, the overexpression of AhCytb6 gene in tobacco resulted in enhanced seed germination under N2 deficit and salt stress conditions gene was observed to be upregulated was found to be differentially expressed in the wild peanut after late leaf spot infection stress in tobacco are important endogenous non-coding RNAs with an average size of 21 to 23-nt in length that regulate gene expression in plants and animals by regulating mRNA expression post-transcriptionally . RNA polAspergillus flavus under Al stress, root tips of Al-sensitive and Al-tolerant peanut cultivars were analyzed under Al stress condition. Further intergrated analysis of transcriptomics, sRNAs, and degradome data sets revealed differential expression of 89 miRNA-mRNA interactions that might be involved in PCD under Al stress . In respArachis species using differential expression analysis for stress tolerance. However, commercially cultivated transgenic plants were not developed in peanut so far using the identified genes. There could be several reasons for this. Since peanut is a crop of high commercial significance whose produce is of prime importance in human nutrition, it is not easy to get regulatory approvals from the respective Governmental authorities across the world for the deployment of transgenic plants for field- level cultivation. Probably, many major efforts were not made in peanut in this direction because of this reason. With the advent of genome editing technology for various plant systems, the future is very optimistic for developing genome edited crops including peanut for stress tolerance as genome-edited crops might get regulatory approvals more easily compared to transgenic plants.The biological stresses mainly comprise attack from pathogenic fungi, bacteria, viruses, nematode and insects, whereas the abiotic constraints include drought, salinity, cold, metal, waterlogging and temperature changes. To overcome these various stress environments, plants must be capable of tolerating these stress conditions by modulating their metabolism in the right direction. In this direction, the genetically modified crops are considered to be good candidates for sustainable food production. It is to be noted that there were several genes identified in Agrobacterium tumefaciens or Rhizobium rhizogenes mediated genetic transformation technique through either in vitro or in planta methods for improvement. Transgene expression is highly dependent on the promoter selection for gene expression followed by protein synthesis. Several promoters of various origins have been tested for transgene expression besides viral gene promoter CaMV35S in peanut. In the backdrop of this, no meaningful progress of gene editing technique that is gaining enormous attention recently has been made so far in peanut.Genome modifications allow improvements in stress and weed tolerance, plant breeding procedure, productivity, food quality and safety. However, introduction of genetically modified crops may adversely affect the environmental conditions exercising harmful effects on animals and humans and this has been the main concern of the environmentalists . There aThere are several powerful plant-targeted genome editing tools for functional and applied genetic manipulations that include engineered nucleases, such as Zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short palindromic repeats (CRISPR) systems .Recently developed prokaryotic immune system based CRISPR technology is a high-throughput genome editing tool that has been found to be very successful in a variety of plant species . The CRIBiotic stress tolerance where crop yield and quality are largely affected by biotic stresses like viral, fungal, bacterial and insects were improved by using CRISPSR/Cas9 system. For instance, wheat and rice have been made tolerant to their respective viral, bacterial and fungal diseases . Tomato,FAD2) gene in peanut. This gene codes for the desaturase that is responsible for the conversion of monounsaturated oleic acid into polyunsaturated linoleic acid. The knock out mutation in FAD2 resulted in high oleic acid content in peanut oil (AhNFR gene through hairy root transformation system and validated the function for nodule formation in peanut. Using the CRISPR/Cas9 system, AhFatB genes Arahy4E7QKU and ArahyL4EP3N were knocked out in peanut, and mutation at Arahy.4E7QKU displayed low palmitic acid and high oleic acid content significantly improving oil quality in peanut (Application of CRISPR/Cas9-based gene editing technique would provide genetic improvement in peanut cultivars against biotic and abiotic stresses. However, application of this breakthrough gene editing technology to peanut is still rare. Till date, there is limited report of CRISPAR/Cas9-based gene editing in peanut. This technique is used for knocking out fatty acid desaturase2 (anut oil . Shu et\u00a0n peanut . PotentiArachis divided into various Sections is a boon to the investigators undertaking differential expression studies using the previously popular techniques like cDNA-AFLP and the highly efficient RNA-Seq studies using the Next Generation Sequencing technologies that became available recently. The goal of these studies is to understand molecular mechanisms during stress conditions and identify the genes responsible for stress tolerance in peanut plants. Depending on the availability of financial resources, the choice of the technology can be made. The primary advantage with the NGS technologies is that they give faster results on gene expression at whole genome level compared to the earlier technologies. The wild Arachis germplasm offers excellent material for the differential expression studies because of the availability of genotypes that are both susceptible and highly resistant to corresponding trait, be it biotic or abiotic stress tolerance. The alloploid species belonging to the Section Rhizomataceae are very highly tolerant to abioic stresses like high temperature and water limited conditions. Hence, the germplasm can be used for identifying tolerance genes within the tolerant genotype itself by comparing sets with and without treatments. Otherwise, a more efficient option would be to compare the resistant and susceptible genotypes at the same ploidy level with and without suitable treatments. Information from such studies could lead to novel genes that would actually decide the trait under consideration. The genes identified can be used in other related legume crop plants. This is particularly because of the possible colinearity of different related genomes in legumes. Hence, the opportunities are enormous when the investigator uses the material judiciously.The wild germplasm belonging to the genus DK: Conceptualization, Writing \u2013 original draft. PBK: Conceptualization, Writing \u2013 review & editing."} {"text": "Liquid biopsy assays for minimal residual disease (MRD) are used to monitor and inform oncological treatment and predict the risk of relapse in cancer patients. To-date, most MRD assay development has focused on targeting somatic mutations. However, epigenetic changes are more frequent and universal than genetic alterations in cancer and circulating tumor DNA (ctDNA) retains much of these changes. Here, we review the epigenetic signals that can be used to detect MRD, including DNA methylation alterations and fragmentation patterns that differentiate ctDNA from noncancerous circulating cell-free DNA (ccfDNA). We then summarize the current state of MRD monitoring; highlight the advantages of epigenetics over genetics-based approaches; and discuss the emerging paradigm of assaying both genetic and epigenetic targets to monitor treatment response, detect disease recurrence, and inform adjuvant therapy. MRD does not cause clinical symptoms and is not detectable by traditional methods such as imaging or abnormal blood serum protein levels. MRD assays must be sensitive enough to detect as little as 1 cancerous cell in a background of 1 million noncancerous cells. This extreme sensitivity makes MRD assay development complex, but overcoming this barrier imbues MRD assays with the potential for much earlier detection of cancer recurrence than traditional methods, and thus earlier intervention with adjuvant chemotherapy or second and third-line treatments.Detection of MRD indicates the failure of treatment to eliminate all cancerous cells which implies greater probability of future disease recurrence. Monitoring MRD signals during the remission period allows early detection of disease progression . Assayin22.1DNA methylation is a covalent modification of the DNA strand that, in mammals, occurs almost exclusively within the sequence context of cytosine followed by guanosine (CpG) dinucleotides. The genomic acquisition of DNA methylation is an essential developmental process with diverse roles including repressive associations at gene promoters and mobile genetic elements or, conversely, increased transcriptional activity when found within gene bodies [reviewed in Greenberg & Bourc\u2019his ]. GenomeMost DNA methylation-based liquid biopsies target cancer-specific aberrations that separate cancer from its normal tissue counterpart. However, within healthy tissues DNA methylation exhibits highly cell type specific patterns across the genome . This un2.2The term \u201cfragmentomics\u201d describes the study of ccfDNA fragmentation patterns and the use of these patterns to decern biologically relevant information such as nucleosome positioning. Although few assays to-date utilize ccfDNA fragmentation patterns, numerous properties of ctDNA compared to healthy ccfDNA instill fragmentomics with the potential for use in oncological assays ; (ii) shAs for nucleosome positioning, ccfDNA fragmentation patterns downstream of transcription start sites have been shown to reflect differential nucleosome positioning between expressed and unexpressed genes . These cGoing forward, the most sensitive and universal MRD assays will likely combine these epigenomic approaches. Until recently, the combination of DNA methylation and fragmentomics in a single assay was not possible due DNA methylation detection relying on bisulfite conversion . Bisulfi3The marketplace for MRD liquid biopsy assays is new, but several MRD diagnostic tests have now received early regulatory approvals Table\u00a01.While there are only a few somatic mutation-based MRD panels in the marketplace, there are a host currently in development and undergoing clinic trials. For example, Strata Oncology are also exploring a two-staged tumor-informed panel design in their Sentinel trial for cancer recurrence . BurningNotably, genetic mutations are not broadly shared across cancers and the two-stage solutions to this shortcoming are limited by tumor heterogeneity and the volume of a tissue biopsy. That is, because only a subset of a tumor is sequenced there is still a high probability that mutations will be missed. However, a multi-omics approach can augment this shortcoming. The greater frequency and universality of epigenetic changes makes them more sensitive and universal markers for evidence of cancer after curative intent treatment, and somatic mutation testing highlights actionable variants that can inform subsequent treatment. This promise of MRD assays that incorporate epigenetics with somatic mutation testing is being realized. Guardant Health has combined somatic mutations, DNA methylation and fragmentomics into their LUNAR panel, which they have progressed into clinical trials for both primary detection and MRD of early-stage colorectal cancer .Multiple companies are also progressing purely epigenetic-based MRD panel approaches. MethylGene is undertaking a clinical trial on multiple myeloma patients that will utilize DNA methylation sequencing of ctDNA for MRD detection . While GWhile most product development for MRD is concentrated around sequencing large panels of markers, simple DNA methylation-based PCR tests can also be highly efficacious. Colvera, developed by Clinical Genomics, is available as an LDT in the USA and has Medicare coverage for MRD and recurrence monitoring of colorectal cancer. This methylated ctDNA test detected 66.0% of recurrence, significantly higher than the 31.9% sensitivity of carcinoembryonic antigen (CAE), the current standard of care , and alsInterestingly, a simple well-designed PCR test can have adequate diagnostic power when compared to a large NGS panel. This is illustrated when comparing the rates of primary detection of colorectal cancer across the GRAIL-sponsored circulating cell-free genome atlas (CCGA) study T (Trial i4Liquid biopsy is a powerful, multifaceted, and minimally invasive method for MRD detection and hence for monitoring therapeutic response, disease recurrence, or patient resistance to therapy. Although a relatively new field, liquid biopsy assays are showing promising results when compared to current standards of care. Two-staged somatic mutation approaches, where tumor sequencing informs MRD assay targets, allow clinicians to track actionable mutations and monitor for signs of treatment resistance. However, the time required to establish theses assays does not fit well with the patient journey, as clinicians need to know sooner than 5-6 weeks whether a patient is not responding to treatment. Therefore, epigenetic-based MRD assays are preferable at treatment onset, as epigenetic changes are typically more widespread and likely to be shared among a greater number of cancers than somatic mutations. With the recent advent of enzymatic methylation conversion, targeted sequencing approaches combining DNA methylation, fragmentomics and machine learning will likely come to predominate. However, DNA methylation-based PCR tests currently offer the most cost-effective solution within this niche. In fact, a compelling paradigm may be the combination of inexpensive serial testing with a DNA methylation-based assay, then following a positive MRD/recurrence result with a broad NGS-based somatic mutation panel to identify actionable mutations.AJ, JR, CM, KF, and WL wrote and revised this review. All authors contributed to the article and approved the submitted version."} {"text": "Editorial on the Research TopicRecent advances in hypospadiologyHypospadias is one of the most common genital anomalies in men and displays a wide range of complex phenotypes. Multiple studies have reported a marked global increase in hypospadias cases over the past three decades, although the underlying basis for this remains unclear , 2. WhilBaray et al., developed an automated deep learning-based method for accurate PC measurement using 2D images, which could significantly improve patient assessment by surgeons and researchers alike. The novel pipeline they propose includes three key consecutive steps: penile localization, shaft segmentation, and angle measurement considering only the proximal and distal parts of the penile shaft. This method may overcome current limitations encountered by conventional approaches to measuring arc-type PC.Penile curvature (PC) is a key anatomical component of many hypospadias phenotypes and can have long-lasting effects on patients\u2019 psychosexual health and quality of life. While several prior studies have attempted to establish criteria for evaluating PC, there is still no standardized method for doing so. Despite significant challenges with assessing PC in both clinical practice and research settings, numerous procedures are now being investigated that have potential to resolve longstanding issues. Zhou et al., one-stage correction of severe hypospadias was achieved using a free preputial tube graft in conjunction with urethral plate urethroplasty and a Buck's fascia integral covering (BFIC) to protect the neourethra and minimize fistula risk. Using an alternative approach, Li et al., report their experience with transverse preputial island flap urethroplasty (TPIFU) in a retrospective cohort study. In 136 patient who underwent single-stage TPIFU, re-operation to address postoperative complications was required in 39% of cases, the majority of which were due to urethrocutaneous fistulas .Among the wide spectrum of hypospadias anomalies, proximal cases include a subset of severe phenotypes that can significantly impact treatment protocols and post-operative results. In these instances, choice of surgical approach is heavily influenced by surgeon experience and personal preference in addition to patient anatomy . There is still considerable disagreement about the optimal method for treating proximal hypospadias, but surgeons are increasingly testing new approaches to achieve better patient outcomes. In a study by Tian et al., present the results of a retrospective cohort of 195 patients who underwent hypospadias repair and subsequently developed postoperative fistulas. Patients with recurrent fistulas after initial closure were compared with patients who achieved successful fistula closure, which revealed an association of catheter type used for drainage with local purulent discharge after surgery.Weidler et al., report their results from a multicenter collaboration evaluating the controversy surrounding optimal timing of surgery. In particular, their study focuses on decision making in individuals with differences in sexual development, as well as their caregivers and healthcare providers. Using a semi-structured interview, the authors evaluated potential determinants of successful outcomes in 110 participants. They identify several key themes including; (1) the nature/type of decision being made, (2) person involved in decision making, (3) timing of conversations about surgery, (4) barriers to decision-making surrounding surgery, (5) elements involved in these discussions, and (6) optimal approach to surgical decision-making. Priority was given to children and adolescents with disorders of sexual differentiation to ensure their involvement in all discussions. In summary, while many issues remain unresolved in the field of hypospadiology, novel approaches and improved understanding of surgical and patient-reported outcomes will be crucial to the continuing evolution of this challenging field."} {"text": "Iatrogenic ST elevation myocardial infarction (STEMI) after aortic valve surgery is a rare complication. Myocardial infarction (MI) due to mediastinal drain tube compression on the native coronary artery is also seen rarely. We present a case of ST elevation inferior myocardial infarction due to post-surgical drain tube placed after aortic valve replacement compressing on the right-sided posterior descending artery (rPDA).A 75-year-old female presented with exertional chest pain and was found to have severe aortic stenosis (AS). After a normal coronary angiogram and proper risk stratification, the patient underwent surgical aortic valve replacement (SAVR). One day after surgery in the post-operative area, the patient was complaining about central chest pain suggestive of anginal pain. Electrocardiogram (ECG) revealed that she has ST elevation myocardial infarction in the inferior wall. Immediately, she was taken to the cardiac catheterization laboratory, which revealed that she has occlusion of the posterior descending artery due to compression by a post-operative mediastinal chest tube. All features of myocardial infarction resolved after simple manipulation of the drain tube.The compression of the epicardial coronary artery after aortic valve surgery is very unusual. There are a few cases of other coronary artery compression due to mediastinal chest tube, but posterior descending artery compression causing ST elevation inferior myocardial compression is unique. Though rare, we need to be vigilant about mediastinal chest tube compression, which can cause ST elevation myocardial infarction after cardiac surgery. The iatrogenic compression of the native epicardial artery is a rare phenomenon. There are a few cases of bypass graft -4 or natA 74-year-old female with no past medical illness presented with exertional chest pain and was found to have severe aortic stenosis (AS). Electrocardiogram (ECG) shows features of left ventricular hypertrophy (LVH). On echocardiography, her mean pressure gradient across the aortic valve was\u00a047 mmHg. As she had symptomatic severe aortic stenosis (AS) without any other significant comorbidities, the plan was made to do surgical aortic valve replacement (SAVR). She underwent preoperative left heart catheterization, which shows normal epicardial coronary arteries.Eventually, the patient underwent a surgical replacement of the stenosed aortic valve with a bioprosthetic valve. The surgery was uneventful, and the patient was sent to the cardiac ICU for monitoring. A mediastinal drain tube was put in to prevent fluid accumulation after cardiac surgery. On post-operative day 1, the patient was complaining of central chest pain with radiation to the arm. ECG was done showing ST elevation in leads II, III, and arteriovenous fistula (aVF) with baseline LVH. It was puzzling as previously, she had no ECG changes suggestive of ischemic heart disease (IHD), and left heart catheterization was also normal. Bedside echocardiogram revealed wall motion abnormality in the middle and distal inferior wall with mildly reduced LV function. STEMI alert was activated, and the patient was taken to the catheterization laboratory emergently.A coronary angiogram revealed that the chest tube is intermittently compressing on the right-sided posterior descending artery (rPDA) limiting blood flow distal to the compression Figure . The draWe present a case of posterior descending artery compression by a mediastinal drain tube placed after SAVR, which is the first reported case. In the past, there were a few reports of native coronary artery or graft compression.Most complications of chest tube placement come from closed pleural chest tube placement, which could be benign to serious complications . There hComplications from open mediastinal tube placement after cardiac surgery are usually benign and underreported. Pneumothorax after removing such tubes or patients suffering from pain due to the tube placement is most encountered by cardiac surgeons . Yet, thAfter surgical aortic valve replacement (SAVR), myocardial ischemia or infarction could be due to supply-demand mismatch as a result of aortic cross-clamping causing ischemia in hypertrophied left ventricle (LV) . STEMI aBeing vigilant about post-surgical drain tubes that may cause compression in the coronary artery can be an easy fix and prevent dreaded complications. Mediastinal chest tubes causing the occlusion of the native coronary arteries are unexpected and easily overlooked."} {"text": "Objective. To evaluate the impact of setup uncertainty reduction (SUR) and adaptation to geometrical changes (AGC) on normal tissue complication probability (NTCP) when using online adaptive head and neck intensity modulated proton therapy (IMPT). Approach. A cohort of ten retrospective head and neck cancer patients with daily scatter corrected cone-beam CT (CBCT) was studied. For each patient, two IMPT treatment plans were created: one with a 3 mm setup uncertainty robustness setting and one with no explicit setup robustness. Both plans were recalculated on the daily CBCT considering three scenarios: the robust plan without adaptation, the non-robust plan without adaptation and the non-robust plan with daily online adaptation. Online-adaptation was simulated using an in-house developed workflow based on GPU-accelerated Monte Carlo dose calculation and partial spot-intensity re-optimization. Dose distributions associated with each scenario were accumulated on the planning CT, where NTCP models for six toxicities were applied. NTCP values from each scenario were intercompared to quantify the reduction in toxicity risk induced by SUR alone, AGC alone and SUR and AGC combined. Finally, a decision tree was implemented to assess the clinical significance of the toxicity reduction associated with each mechanism. Main results. For most patients, clinically meaningful NTCP reductions were only achieved when SUR and AGC were performed together. In these conditions, total reductions in NTCP of up to 30.48 pp were obtained, with noticeable NTCP reductions for aspiration, dysphagia and xerostomia . While SUR had a generally larger impact than AGC on NTCP reductions, SUR alone did not induce clinically meaningful toxicity reductions in any patient, compared to only one for AGC alone. Significance Online adaptive head and neck proton therapy can only yield clinically significant reductions in the risk of long-term side effects when combining the benefits of SUR and AGC. For this purpose, a retrospective cohort of ten head and neck squamous cell carcinoma patients with daily cone-beam CT (CBCT) was used to compare NTCP for six toxicities using three distinct scenarios. Differences in NTCP between each scenario was evaluated to assess the impact of SUR alone, AGC alone and SUR and AGC combined. Finally, the clinical significance of NTCP reductions associated with each mechanism was established using a decision tree inspired by a model-based patient selection algorithm.Our patient cohort consisted of ten head and neck squamous cell carcinoma patients treated at the Massachusetts General Hospital with volumetric modulated arc therapy, since CBCT imaging was not available for our proton therapy patients at the time of this study. Each patient dataset consisted of a planning CT acquired on a wide bore GE scanner as well as a series of daily CBCT obtained on an Elekta XVI system using a 100 kVp tube voltage and a 220-degree acquisition. The number of CBCTs available for each patient ranged between 30 and 35, for a total of 328 scans analyzed. No patient of this cohort had their treatment interrupted and no offline replanning was deemed necessary during the treatment courses.et alTwo clinical target volumes (CTV) were delineated on each planning CT by a trained radiation oncologist: a high-risk CTV including the primary tumor and high-risk lymph nodes, as well as a low-risk CTV, including bilateral lymph nodes considered at risk for subclinical disease. The constrictor muscles, larynx, oral cavity, spinal cord, brainstem, esophagus and both parotid glands were delineated on the planning CT. The esophagus, constrictor muscles and larynx were contoured following published guidelines for swallowing OARs . The first plan was robustly optimized to both CTVs using the minimax method and adaptation schemes (fast daily OA versus no adaptation). As done in similar studies, our data analysis was focussed on NTCP differences between each scenario rather than absolute NTCP values (Van De Water ar et al . Differeet alFocussing on AGC alone, our results indicate that online adaptive proton therapy can induce NTCP reductions that go beyond what is achieved when applying SUR only. Indeed, total NTCP reductions per patient for xerostomia, dysphagia, aspiration and oral mucositis reported in figure et alet alThe clinical significance of the reductions in NTCP induced by SUR and AGC was assessed using a decision tree inspired by the Dutch model-based selection system (Tambas et alet alet alet alThe fact that clinically meaningful toxicity reductions were observed in five out of ten patients also illustrates the heterogeneous effect of online adaptive proton therapy on toxicity reductions across our patient cohort. This is even more apparent in figure et alet alet alet alet alet alet alet alThis study had some limitations worth mentioning. First, uncertainties in image deformation, contour propagation and residual setup errors beyond treatment adaptation were neglected. NTCP reductions achieved in this work shall therefore be interpreted as the best-case scenario for AGC and might not be fully achievable in a clinical setting. However, it is also worth noting that several strategies have been suggested to mitigate the impact of these uncertainties in the context of online adaptive proton therapy: the integration of structure uncertainties in plan re-optimization (Nenoff et al (et alAnother limitation to consider is the fact that NTCP models were derived from photon patients. Blanchard et al showed tal et al. An evalIn conclusion, this study highlighted for the first time the impact of online adaptive proton therapy on toxicity risks. Combining effects from a reduction of the setup uncertainty setting by 3 mm and the AGC, online adaptive proton therapy based on a limited spot-intensity re-optimization workflow was shown to allow clinically meaningful toxicity reductions in 50% of our patient cohort, with total NTCP reductions up to 30.48 pp for the four main toxicities considered in this work."} {"text": "POT-PUFF sign has been introduced as a potential alternative for detecting malapposition during coronary bifurcation procedures. Here, we present two clinical cases from a developing country where the POT-PUFF sign was employed to assess the result of proximal optimization therapy after stent implantation. The POT-PUFF sign exhibits potential as an affordable and feasible approach for assessing stent malapposition in settings with limited resources.Acute stent malapposition poses a significant risk for adverse cardiac events following percutaneous coronary intervention. Detection of acute stent malapposition traditionally relies on intracoronary imaging techniques, such as intravascular ultrasound and optical coherence tomography, which may be limited in developing countries due to accessibility issues. A new angiographic sign called the Acute stent malapposition (ASM) refers to post-procedure lack of contact of stent struts with vessel walls. This condition can be detected using intracoronary imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Identifying and addressing malapposition is crucial as it can result in various complications, including impaired stent function, heightened risk of stent thrombosis, and potential adverse cardiac events . RecentlCase oneA 58-year-old man, hypertensive and a weaned smoker, had been suffering from exertional angina for several months. The electrocardiogram showed lateral biphasic T waves. Echocardiography revealed hypokinesia of the anterolateral wall with a moderately impaired ejection fraction of 45%. Coronary angiography revealed significant stenosis at the start of the main marginal artery Figure . After pCase twoOur second case was a 64-year-old hypertensive patient with dyslipidemia on statins. She was admitted for management of chronic coronary syndrome with New York Heart Association class 2 exertional dyspnea. The electrocardiogram was unremarkable. Echocardiography showed left ventricular hypertrophy without segmental contractility abnormalities and a preserved ejection fraction. Stress echocardiography showed ischemia in two segments of the right coronary artery territory. Coronary angiography revealed a long, significant stenosis in the middle segment of the right coronary artery Figure . After pAfter stent implantation, IVUS and OCT can identify remediable irregularities associated with both the stent and the underlying vessel wall. These irregularities include stent under-expansion, geographic plaque miss, strut malapposition, and stent edge dissection, and they have been linked to adverse percutaneous coronary intervention (PCI) outcomes . Strut mThe POT-PUFF sign presents a promising new angiographic indicator for detecting stent malapposition during POT after PCI. While further research is required to validate its effectiveness, the POT-PUFF sign shows great potential in enhancing stent apposition evaluation and improving PCI outcomes in resource-constrained settings."} {"text": "Glioblastoma (GBM) is an aggressive brain tumor with limited prognosis despite multimodal treatment approaches. Various immunotherapies have been investigated to address the need for novel therapeutic options in GBM with limited success. Recently, alterations in the metabolism of cancer cells which allow for tumor proliferation, but simultaneously alter immune populations leading to an immunosuppressive tumor microenvironment, have been investigated as contributory to therapeutic resistance. This review discusses metabolic alterations in GBM tumor cells which have been investigated as contributory to immunosuppression and resistance to immunotherapies.Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism. Glioblastoma (GBM) is the most common primary brain tumor with a limited prognosis and a median survival of 15 months despite an aggressive standard of care treatment consisting of maximal safe surgical resection followed by radiation and chemotherapy with temozolomide . DevelopOne novel emerging area of cancer therapeutics is immunotherapies, which target one of the hallmarks of cancer\u2014the ability to evade cellular immunity that would otherwise result in immunological targeting of tumor cells . While iThe tumor microenvironment is affected by unique cancer cell metabolism that not only promotes tumor cell growth but also alters the pH, oxygen, and metabolite contents that affect the survival and function of immune cells in the tumor microenvironment . MetabolGlycolysis is the most prominent metabolic pathway implicated in cancer metabolism as contributory to sustaining the energetic cost of growth and proliferation. During glycolysis, glucose is catabolized to pyruvate which is then converted to lactate to either be secreted or enter the TCA cycle generating ATP and NADH in the process. Glucose metabolism plays a significant role in the brain microenvironment given the high metabolic demand of the brain and lack of glycogen storage within the brain. High blood glucose levels and increased neuronal expression of glucose transporters have been linked to decreased survival in glioblastoma patients . HK2, PKFP, ALDOA, PGAM1, ENO1, ENO2, or PDK1 inhibits GBM tumor growth and prolongs survival in a mouse xenograft model . Gl. Gl13]. Glycolysis requires export of lactate from cells by transporters which co-transport lactate and protons (H+), leading to their accumulation in the tumor microenvironment and resulting in tumor acidosis which impacts the function of immune cells in the tumor microenvironment. Acidosis has been described in other cancers as contributory to immunosuppression . Lactic Strategies that free T cell glycolytic metabolism from the restrictions imposed on these cells by the tumor microenvironment have been evaluated in preclinical models. For example, genetic modification of tumor specific CD4 and CD8 T cells to overexpress phosphoenolpyruvate carboxykinase 1 (PCK1) increased the production of the glycolytic metabolite phosphoenolpyruvate, resulted in increased T cell glycolysis, increased T cell effector function, and restricted tumor growth and prolonged survival in a melanoma mouse model . FurtherLactic acid production has also been suggested to not only reduce anti-tumoral immune cell populations but also promote immunosuppressive populations. Notably, myeloid cells are resistant to lactic acid-induced apoptosis . In factGlycolytic alterations may also specifically impact neutrophils. While less is understood about the metabolic utilization of neutrophils in the tumor microenvironment than leukocytes, neutrophils are generally regarded as highly glycolytic. Neutrophil function has been described to highly depend on glucose availability with lack of glucose abrogating function . suggestInterestingly, the interplay between glycolytic tumor metabolism and immune cell function may be bidirectional with immune cells able to regulate metabolic pathways as well. Zhang et al. show that macrophages produce interleukin-6 which leads to downstream phosphorylation of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and facilitates a PGK1-catalyzed reaction towards glycolysis rather than gluconeogenesis through altered substate affinity . PGK1 phENO1, promoted M2 microglia polarization promoting immunosuppression and glioblastoma cell malignancy. Another recent study utilizing differentially expressed genes between high and low glycolytic activity to assign risk scores to classify high and low risk GBM patients found differential infiltration of immune cells and immune checkpoints, suggesting a relationship between glycolytic activity and immunosuppression in patients with GBM [Studies of glycolysis in glioblastoma have paralleled the findings in other cancer types of the significance of increased glycolysis in creating an immunosuppressive tumor microenvironment. The shift to increased aerobic glycolysis from oxidative phosphorylation in glioblastoma is associated with immunosuppression and tumor progression . In GBM,with GBM . Glutamine, an amino acid highly expressed in cancer cells, plays a critical role for cellular function and the generation of energy and metabolic precursors for macromolecule synthesis which help sustain anabolic growth. Glutamine is converted by glutaminase into glutamate which is then converted to \u03b1-ketoglutarate, a critical component of the TCA cycle and in the production of metabolic intermediates utilized in the production of lipids, nucleic acids, and proteins. Upregulated glutamine metabolism in cancer cells promotes tumor growth through supporting macromolecule biosynthesis, altered signaling pathways, and cancer cell proliferation and survival. The metabolism of glutamine provides carbons for the TCA cycle to sustain accelerated anabolism in cancer cells and promotes tumor growth ,40,41.Glutamine is amongst the most prevalent amino acids in the brain as a precursor to the excitatory neurotransmitter glutamate . GlutamaGlutamine metabolic pathways are also upregulated in glioblastoma. Glutamate dehydrogenase (GDH), an enzyme which catalyzes the conversion of L-glutamate into \u03b1-ketoglutarate as part of glutaminolysis, is upregulated in many human cancers and shown to promote tumor growth . An isoeGlutamine metabolism in cancer cells impacts the tumor microenvironment and the immune populations within it in ways similar to glucose metabolism . Cancer Increased uptake of glutamine by tumor cells may result in its depletion in the tumor microenvironment and affect the function of immune cells which utilize glutamine for their own metabolic programs. Activated T cells upregulate glutamine metabolism to generate \u03b1-ketoglutarate to enter the TCA cycle and generate ATP to fulfill the energetic demands of T cell proliferation . GlutamiTargeting glutamine metabolism in a mouse model of colon cancer through a glutamine antagonist 6-Diazo-5-oxo-L-norleucine, which broadly inhibits several glutamine-using enzymes, led to suppression of both oxidative phosphorylation and glycolytic metabolism in cancer cells and decreased tumor-related changes in the microenvironment with decreased hypoxia, acidosis, and nutrient depletion . In contAdditionally, glutamine metabolism by cancer cells leads to the enrichment of various immunosuppressive populations in cancer. Notably, \u03b1-ketoglutarate generated through glutaminolysis restricts anti-tumoral macrophage M1 activation . A separTargeting glutamine metabolism in cancers with known resistance to checkpoint blockade (triple negative breast cancer and lung carcinoma) with a small molecule inhibitor led to the marked inhibition of the generation and recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs) through apoptosis of these MDSCs . AdditioTargeting glutamine metabolism may enhance endogenous anti-tumor immunity through independent mechanisms promoting the metabolic programs of cytotoxic populations while inhibiting immunosuppressive populations. Given the success of combining targeting glutamine metabolism with checkpoint inhibitors in other immunotherapy resistant tumors, it may be worthwhile to explore this combination in GBM. Tryptophan is an essential amino acid utilized for protein biosynthesis and a biochemical precursor to physiologically important compounds such as serotonin and melatonin. The majority of tryptophan which is not incorporated into proteins is broken down into degradation products (kynurenines) via the kynurenine pathway . PhysiolTryptophan catabolism and alterations in kynurenine pathway has been implicated in poor prognosis in several cancer types, including in GBM . The corIDO1- and TDO2- mediated degradation of tryptophan by cancer cells is a driver of immune suppression in the tumor microenvironment through recruitment and activation of myeloid-derived suppressor cells (MDSCs) and induction of anergy of CD8+ T cells . DegradaTryptophan utilization by tumor cells leads to metabolic starvation of T cells which are unable to utilize tryptophan for their own functions and thus promotes immunosuppression in the tumor microenvironment. Inhibition of tryptophan degrading enzymes blocks enzymatic activity and restores cytotoxic T cell activity in vitro and in vivo . T cellsGiven the role of IDO through kynurenine synthesis in generating the tumor microenvironment allowing for immune escape in cancer, IDO inhibition has been explored as an attractive therapeutic option in multiple cancers. Inhibition of IDO was found to effectively normalize plasma kynurenine levels in patients with various tumor types . InteresKynurenine metabolites activate a ligand-activated transcription factor, aryl hydrocarbon receptor (AhR) which results in increased expression of IDO1 and IDO2 in a positive feedback loop. Targeting AhR in vitro led to decreased glioma cell viability . Opitz eTryptophan catabolism and its downstream metabolic pathways are known to contribute to the immunosuppressive tumor microenvironment and contribute to resistance to novel immunotherapies for malignant gliomas. Increased expression of IDO and TDO has been suggested as an acquired resistance mechanism to PD-1 and CTLA blockade in pre-clinical models of multiple cancers, including GBM ,74. The The combination of targeting tryptophan metabolism with immune checkpoint blockade has been also explored in glioblastoma. Combining 1-methyltryptophan, which inhibits IDO, with dual immune checkpoint blockade significantly improved survival in an orthotropic mouse GBM model correlating with increased T-cell survival and synergistic decrease of Treg infiltration . LikewisPotential limitations of IDO1 inhibition that led to failure in this phase 3 trial combining this approach with a PD-1 inhibitor include: insufficient inhibition of IDO1 at the doses being used; the ability of other enzymes involved in tryptophan metabolisms such as TDO2 or pathways downstream of IDO1 inhibition to compensate and still generate immunosuppressive tryptophan metabolites such as kynurenine and its derivatives when IDO1 is inhibited; and lack of patient selection based on IDO1 expression ,78. IDO1Targeting tryptophan metabolism may also have implications for vaccine related cancer therapies which rely on T cell mediated antitumoral responses. IDO expression correlated with lack of specific T cell enrichment at the tumor site and prevented the rejection of tumor cells in mice who have been preimmunized against tumor antigens with a vaccine . This efLipid metabolism physiologically functions to allow for cellular energy storage, synthesis of cellular membranes, and cellular signaling. In cancer, alterations in lipid metabolism help meet high bioenergetic demands by generating energy through beta-oxidation. Utilization of fatty acid oxidation in addition to increased glycolysis allows for bioenergetic flexibility in promoting aggressive tumor growth and metastasis . Glioma cells utilize lipid oxidation and upregulate transport of ketones generated from lipid metabolism to sustain growth . Lipid mAltered lipid metabolism in GBM impacts immune cell function, particularly that of T cells . T cellsWhile less is understood about the metabolic requirements of Treg cells, utilizing fatty acid oxidation over glycolysis may promote Treg survival over the survival of CD4 and CD8 T cells . Lipid sGBM cells are also able to evade the anti-tumor immune response due to altered lipid metabolism impacting the function of antigen presenting cells. Exogenous induction of lipid peroxidation and ferroptosis resulted in release of damage-associated molecular patterns from glioma cells that stimulate dendritic cell activation and maturation and can lead to activation of cytotoxic T lymphocytes by dendritic cells ,95. RecuWhile initially the central nervous system was thought to be an immune-privileged site, current thought points to the presence of immune surveillance in the brain following findings revealing the presence of dedicated lymphatic channels running parallel to dural venous sinuses and allowing for lymphocyte priming from antigen presenting cells in the brain ,100. DesThe most studied immunotherapeutic approaches for GBM are vaccines, immune checkpoint inhibitors, and biologic therapies . The mosImmune checkpoint inhibitors targeting PD-1/PD-L1 and/or CTLA-4 are also being investigated in phase 3 trials in GBM, with initial results suggesting no clinical benefit ,105. WhiBiologic therapies for GBM can be viral or cellular. Oncolytic viruses have overall met with limited success in GBM, and initial anti-tumor T cell immune responses generated by viral infiltration into tumor do not persist without serial treatment . MetabolMetabolic pathways implicated in maintaining immunosuppression in the GBM microenvironment have been well elucidated. However, the potential for targeting these metabolic pathways to condition the tumor microenvironment to become more responsive to immunotherapies remains underexplored in GBM. Preclinical data targeting metabolic pathways in conjunction with immunotherapies largely come from models of more immunogenic cancers. This presents an attractive avenue for further study in GBM, in which modifying a largely immunosuppressive environment may meaningfully alter immunotherapeutic response. While this review discusses the most studied metabolic pathways with respect to immunosuppression in GBM, several other metabolic pathway alterations occur to meet the energetic demands of GBM progression. Arginine metabolism reprogramming in GBM leads to increased intake and decreased degradation of arginine by tumor cells and has been linked to impaired T cell responses due to altered bioavailablity of arginine . TargetiWhile many immunotherapies are being investigated in GBM patients, none have resulted in major improvements in survival outcomes. Negative results from phase II and phase III clinical trials of vaccines and immune checkpoint inhibitors have challenged the potential of these approaches in GBM. Future directions for immune-based strategies for glioblastoma require treatment modalities that can convert a \u2018cold\u2019 tumor with significant local immunosuppression into a \u2018hot\u2019 tumor. The uniquely immunosuppressive environment generated by tumor cellular metabolism in GBM presents an opportunity for augmenting responses to immunotherapy. Combining immunotherapy with agents that target the metabolic alterations resulting in an immunosuppressive microenvironment may have greater success in generating an antitumor immune response. These combinations should be evaluated rigorously preclinically in order to ensure that the most biologically sound combination approaches addressing the antitumor immune response along with tumor metabolism are advanced to clinical trials."} {"text": "The United States FDA has approved daprodustat (DPD) as the first oral treatment option for anemia due to chronic kidney disease (CKD) in dialysis patients. Clinical trials have demonstrated DPD\u2019s efficacy and safety, showing non-inferiority to darbepoetin and suggesting reduced IV iron usage. DPD also holds potential for treating chronic kidney disease anemia in non-dialysis patients and may have benefits for patients with coexisting renal anemia and heart failure, pending further research and trials. The United States Food and Drug Administration (FDA) has approved daprodustat (DPD) for treating anemia due to chronic kidney disease (CKD) for patients undergoing dialysis for at least 4\u00a0months . This isAnother Randomized, Double-Blind, Phase 3 Study was carried out in Japanese hemodialysis patients with anemia to compare the effects of DPD and darbepoetin. With most participants obtaining and maintaining hemoglobin levels within the target range, the results showed DPD\u2019s non-inferiority to darbepoetin. Also, it was strongly advised to continuously check the hemoglobin response following the start of the DPD treatment. This study also suggested using less IV iron to regulate hemoglobin in individuals receiving DPD . AnotherDPD has not yet been approved for patients with CKD anemia without dialysis, but ASCEND-ND trial has demonstrated safety and efficacy of DPD in treating anemia due to CKD in patients not undergoing dialysis. . DPD wouData from the FDA\u2019s adverse event reporting system (FAERS) may indicate an elevated risk of GI bleeding when HIF-PHIs are used to treat renal anaemia. DPD treatment may also raise the risk of vascular calcification in CKD patients with hyperphosphatemia. Serum copper excess may also be noted in some patients in the treatment.Anemia in Heart Failure is a poor prognostic factor in both acute and chronic heart failure. Although anemia in heart failure is multifactorial, renal anaemia is one of the major causes. Coexisting renal and heart failure is reported to be associated with increased mortality . The StuProvenance and peer review: Not Commissioned, externally peer-reviewed."} {"text": "Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer related-death in the worldDespite reported benefits, colonoscopy outcomes may differ depending on quality of the endoscopist performing the procedure. Among others, this relates to differences in ability of endoscopists to accurately assess polyp characteristics such as locationOver the last decade, artificial intelligence (AI) in biomedical science has received growing attention. AI can be defined as the simulation of human intelligence by computer systemsWhile evidence is currently scattered, we aimed to write a narrative review to provide a broad overview of current developments within the field of AI and computer science for computer-aided assessment of colorectal polyps. This includes assessment of polyp location, size, morphology and histology, including degree of dysplasia (low grade dysplasia [LGD] versus high grade dysplasia [HGD]) and, in case of suspected malignancy, invasion depth. Since computer-aided polyp detection concerns an already more thoroughly studied and evaluated topicthof July 2022. Key search terms used were \u201ccolorectal,\u201d \u201cpolyp,\u201d \u201cartificial intelligence,\u201d \u201csize,\u201d \u201clocation,\u201d \u201cmorphology,\u201d \u201chistology,\u201d \u201cdysplasia\u201d and \u201cinvasion depth.\u201d Only studies published in English were screened. Reference lists of retrieved studies were manually screened to identify other relevant publications.A comprehensive literature search was performed in the MEDLINE/PubMed, Embase and Cochrane Libraries from the inception of the databases up to and including the 17Accurate determination of polyp location is important to facilitate identification of a polyp or polypectomy site during consecutive colonoscopies and/or surgical procedures. In addition, polyp location can aid in polyp histology predictionTo determine the location of the endoscope tip during colonoscopy procedures, and hence the location of observed polyps, endoscopists often rely on identification of various endoscopic anatomical landmarks and differences in colonic caliber, color tones and vasculature of different colon segmentsSeveral deep learning approaches for orientation in the colon based on analysis ofendoscopic videos and images have been proposed 45464Proposed systems could possibly aid endoscopists in orientation within the colon. However, current studies still concern feasibility studies and accuracy is mostly still limited. Besides, usage of a segment classification that assumes that all colons and segments are of similar length currently limits feasibility of the proposed motion-based localization systemToward the future, the issue of a lack of a solid reference standard could possibly be addressed by using magnetic endoscopic imaging (MEI) devices. These devices can improve accuracy of determination of location within the colon during colonoscopyPolyp size has been shown to be associated with the risk that a polyp harbors advancedhistological featuresIn daily practice, polyp size is based on visual estimation by the endoscopist. However, this strategy is prone to interobserver variabilityWhile most studies showed promising results, some issues should be addressed. Most importantly, similar to polyp location, a robust reference standard is not available for polyp size. This is illustrated by the fact that different reference standards were used in the different studies, limiting robustness and comparison of performance of the different systems. Additionally, several studies used binary polyp size classificationsNext steps for the development of more robust computerized polyp size measurement methods should include prospective evaluation of proposed systems in real-time clinical settings. Simultaneously, the problem concerning the lack of a solid reference standard might possibly be addressed through usage of recently developed endoscope-integrated or -attached polyp measurement toolsPolyp morphology is an important feature for polyp malignancy risk-assessmentColorectal polyps can generally be subdivided into neoplastic and non-neoplastic.Neoplastic lesions concerns both lesions yielding malignant potential and malignant lesions,while non-neoplastic lesions do not yield malignant potential. Hence, removal and analysisof non-neoplastic lesions is often unnecessaryA wide variety of studies describing computer systems trained to differentiateneoplastic and non-neoplastic lesions based on polyp phenotype has been published. For thisreview, we will highlight available prospective clinical trials evaluating the performanceof such systems in real-time clinical settings and using either white light, (magnified)narrow band imaging (NBI) or blue light imaging (BLI) imaging modalities 77787To facilitate implementation of optical diagnosis strategies in daily practice, the Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) initiativeFrom clinical perspective, the fact that different studies managed sessile serrated lesions (SSLs) in different ways should also be addressed. While SSLs are estimated to make up 15\u201330% of CRC casesDespite remaining limitations and need for further optimization of system performances to reach PIVI and SODA thresholds, most CADx systems for differentiation of neoplastic and non-neoplastic lesions showed to be able to meet expert endoscopist performance in real-time clinical settings. In addition, a significant optical diagnosis learning curve for \u2018non-expert\u2019 endoscopists was illustratedTable S1)Several studies assessing the feasibility of deep learning approaches for differentiation of polyps with different degrees of dysplasia (LGD versus HGD) are available innovations in upcoming years will likely aid in improving accuracy of existing CADx systems, while there are also still numerous purposes for which possibilities of computer-aided diagnosis is yet to be explored. In example, besides computer systems that could aid endoscopists in assessment of polyp morphology, systems for purposes such as suggestion of appropriate polyp resection method or assessment of completeness of resection might yield significant clinical potential.The strength of this review is that, to the best of our knowledge, this is the first review to provide such a broad overview of available studies on computer-aided diagnosis of all polyp characteristics essential for clinical decision making. However, in the context of the extensive scope of the aim of this review, we decided to comply to a narrative rather than a systematic review approach. While this might have resulted in accidental miss of relevant publications, this can be considered a limitation.To conclude, with recent breakthroughs in the field of AI and computer science, a major increase in research on the topic of computer-aided colorectal polyp assessment is seen. With commercial availability of CADx systems for differentiation between neoplastic and non-neoplastic polyps, first steps toward improved endoscopy quality with use of CADx systems in daily practice might be ahead. However, optimization of performance is still required to ensure that these CADx systems meet all performance thresholds. Besides, toward the future, further innovation, exploration and clinical validation of computer-aided diagnosis approaches for diagnosis of other polyp characteristics is required for realization of complete computer-aided polyp assessment."} {"text": "Pleural infection, or pleural empyema, is a severe medical condition associated with high morbidity and mortality rates. Timely and accurate prognostication is crucial for optimizing patient outcomes and resource allocation. Rapid scoring systems have emerged as promising tools in pleural infection prognostication, integrating various clinical and laboratory parameters to assess disease severity and quantitatively predict short-term and long-term outcomes. This review article critically evaluates existing rapid scoring systems, including CURB-65 , A-DROP , dehydration, respiratory failure, orientation disturbance, and low blood pressure), and APACHE II , assessing their predictive accuracy and limitations. Our analysis highlights the potential clinical implications of rapid scoring, including risk stratification, treatment tailoring, and follow-up planning. We discuss practical considerations and challenges in implementing rapid scoring such as data accessibility and potential sources of bias. Furthermore, we emphasize the importance of validation, transparency, and multidisciplinary collaboration to refine and enhance the clinical applicability of these scoring systems. The prospects for rapid scoring in pleural infection management are promising, with ongoing research and data science advances offering improvement opportunities. Ultimately, the successful integration of rapid scoring into clinical practice can potentially improve patient care and outcomes in pleural infection management. Pleural infection, commonly known as pleural empyema, is a serious medical condition characterized by the accumulation of infected fluid in the pleural space, the thin, fluid-filled cavity surrounding the lungs. It can arise as a complication of various respiratory infections, such as pneumonia, and may result from both bacterial and, less frequently, fungal pathogens. Pleural infection poses a significant health burden worldwide, with high morbidity and mortality rates, especially in vulnerable populations such as the elderly, immunocompromised individuals, and those with pre-existing lung diseases -4. ManagPrognostication is pivotal in determining the most appropriate therapeutic approach and predicting patient outcomes in pleural infection. Identifying patients with severe diseases and poor prognoses can aid clinicians in tailoring treatment plans and allocating resources more efficiently. Traditional prognostic indicators such as clinical signs, laboratory parameters, and radiological findings are valuable but may lack the desired accuracy to predict disease progression reliably -10. The Rapid scoring systems have emerged as promising tools in the prognostication of pleural infection. These scoring systems leverage clinical, radiological, and laboratory parameters to generate a quantifiable score, enabling clinicians to quickly evaluate the severity of the disease and predict the likelihood of specific outcomes, such as mortality, treatment response, and length of hospital stay ,15. By sThis review aims to comprehensively evaluate the predictive potential of rapid scoring systems in pleural infection. By critically analyzing the existing literature and summarizing the findings from various studies, we aim to provide an in-depth understanding of the utility and limitations of these scoring systems in clinical practice. We will compare their performance in predicting short-term and long-term outcomes. Additionally, we will explore the factors that may influence the accuracy of these scoring systems, such as patient demographics, microbiological and radiological findings, and the presence of comorbidities.Overview of existing rapid scoring systems for pleural infectionsIn recent years, significant advancements have been made in developing and validating rapid scoring systems tailored for pleural infection prognostication. These scoring systems represent a crucial step toward enhancing clinical decision-making and optimizing patient care in the management of this complex condition. By providing a swift and reliable method to assess disease severity and predict outcomes, these rapid scoring systems offer a valuable tool for healthcare providers . Three pThe CURB-65 ScoreOriginally devised for predicting outcomes in community-acquired pneumonia, the CURB-65 score has been adapted and validated for use in pleural infection scenarios. It is based on five readily available clinical variables: confusion, urea level, respiratory rate, blood pressure, and age \u226565 years. By incorporating these parameters, the scoring system offers a simple yet effective approach to risk stratification and prognostication in pleural infection cases .The A-DROP ScoreOriginally designed for predicting severe pneumonia, the A-DROP score has found relevance in the context of pleural infection prognostication. This scoring system comprises five essential parameters: age, dehydration, respiratory failure, orientation disturbance, and low blood pressure. By encompassing these key variables, the A-DROP score assists in identifying patients at higher risk of adverse outcomes, and guiding appropriate interventions .The APACHE II ScoreWidely employed in intensive care units, the APACHE II score is a comprehensive scoring system that incorporates various physiological parameters to assess disease severity and predict outcomes in critically ill patients, including those with pleural infection. While the APACHE II score may involve more extensive laboratory measurements and clinical evaluations, it offers a more detailed and nuanced assessment of patient status, aiding in precise prognostication .These rapid scoring systems serve as valuable tools for healthcare providers, enabling them to assess disease severity and anticipate patient outcomes rapidly. These scoring systems offer a standardized and objective approach to pleural infection prognostication by integrating key clinical and laboratory parameters. By promptly identifying patients at higher risk of adverse outcomes, clinicians can optimize treatment plans, allocate resources effectively, and potentially improve patient outcomes .Despite their effectiveness, it is essential to recognize that these scoring systems are adjunctive tools and should not replace clinical judgment. The context of each patient's presentation, comorbidities, and response to therapy remains crucial in the overall management of pleural infection. Continued research, validation, and refinement of these rapid scoring systems are vital for maximizing their clinical utility and further improving patient care in pleural infection management. With ongoing efforts and multidisciplinary collaboration, rapid scoring systems promise to positively impact pleural infection management in the future .Comparison of different scoring systemsScoring Criteria and ComponentsScoring criteria and components form the foundation of rapid scoring systems in pleural infection prognostication, as they determine the variables used to generate a numerical score reflecting disease severity. These variables' selection varies among scoring systems based on their intended scope and underlying concepts .Some rapid scoring systems like CURB-65 and A-DROP utilize more straightforward and easily accessible clinical parameters to calculate the score. These criteria typically include age, respiratory rate, blood pressure, and mental status. These variables can be quickly assessed at the bedside and are commonly available in most healthcare settings. By focusing on straightforward clinical indicators, these scoring systems offer a convenient and time-efficient approach to prognostication, particularly in resource-limited environments .On the other hand, the APACHE II score takes a more comprehensive approach by integrating a wide range of physiological and laboratory measurements. These variables encompass arterial pH, oxygenation, serum creatinine levels, and hematocrit. The APACHE II score was originally designed for assessing the severity of critically ill patients in intensive care units and has been adapted for use in various clinical settings, including pleural infection. Including a broader array of physiological parameters enhances the APACHE II score's discriminative ability, allowing for a more detailed evaluation of disease status and patient outcomes .The choice between simpler clinical variables and more complex physiological measurements depends on the scoring system's intended use and clinical context. While rapid scoring systems like CURB-65 and A-DROP offer practicality and ease of use, the APACHE II score provides a more nuanced assessment, especially for critically ill patients. When selecting the most appropriate rapid scoring approach for pleural infection prognostication, healthcare providers must consider the scoring system's applicability to their specific patient population and available resources. These scoring criteria and components are essential for risk stratification and clinical decision-making, contributing to improved patient care and outcomes .Pros and Cons of Each Scoring SystemThe CURB-65 and A-DROP scores offer practical benefits due to their straightforwardness and ease of calculation. These scores utilize easily obtainable clinical parameters, including age, respiratory rate, blood pressure, and mental status, which can be swiftly evaluated at the patient's bedside. Their limited reliance on extensive laboratory tests makes them particularly suitable for settings with limited resources, where access to advanced medical facilities might be constrained. Furthermore, their uncomplicated nature allows for rapid risk assessment, enabling timely interventions in patients with pleural infection. However, the simplicity of the CURB-65 and A-DROP scores might result in some degree of oversimplification in disease evaluation. The sensitivity, specificity, positive predictive value, and negative predictive value of CURB-65 were 71%, 69%, 35%, and 91%, respectively. The best-performing version of the systemic inflammatory response syndrome (SIRS) criteria showed rates of 62%, 73%, 35%, and 89%, respectively, while the standardized early warning scoring system (SEWS) exhibited rates of 52%, 67%, 27%, and 86%, respectively. By concentrating on a restricted set of criteria, these scoring systems may not fully encompass the intricacies and variations present in cases of pleural infection. This limitation could potentially impact their accuracy in predicting outcomes .On the contrary, the APACHE II score provides a more advanced and comprehensive evaluation of a patient's condition, which holds particular significance for those critically ill with pleural infections. The APACHE-II score demonstrated a sensitivity of 89.9% and a specificity of 97.6%. By amalgamating various physiological measurements and laboratory results, the APACHE II score delivers a thorough assessment of the severity of the disease and the dysfunction of organs. This renders it especially pertinent within intensive care units (ICUs) confines. Its capacity to consider multiple variables enables a more subtle and precise classification of risk, thereby assisting healthcare practitioners in customizing treatment strategies for critically ill patients. Nevertheless, the reliance on the APACHE II score on multiple intricate laboratory measurements and complex computations could impede its immediate application within standard clinical practice, particularly in non-ICU environments. In scenarios with limited time and resources, the extensive data collection demanded by the APACHE II score might not always be feasible or pragmatic. Consequently, this could diminish its practicality and clinical influence .Current Challenges in Prognostication Using Rapid ScoringWhile rapid scoring systems hold promise in aiding prognostication for pleural infection, several challenges must be addressed to maximize their clinical utility. Firstly, these scoring systems' validation and external applicability pose significant concerns. Many of these systems are developed and validated in specific patient populations, which may limit their generalizability to diverse cohorts or healthcare settings. To ensure their reliability across various contexts, it is crucial to conduct rigorous validation studies in different patient populations representative of real-world scenarios .Secondly, successfully integrating rapid scoring systems into routine clinical practice requires overcoming practical hurdles. Healthcare providers must receive adequate training and awareness regarding the use and interpretation of scoring results. Seamless incorporation into existing clinical workflows and overcoming potential resistance to change are essential steps in maximizing the impact of these scoring systems on patient care .Another critical challenge is centered around predicting long-term outcomes. While rapid scoring systems often concentrate on short-term outcomes like hospital mortality or length of stay, complexity arises when predicting long-term outcomes, including factors like recurrence rates and functional recovery. These aspects demand a more extensive follow-up period and meticulous data collection. The development of scoring models that can reliably forecast these long-term outcomes holds significant importance, as it can greatly enhance patient management strategies and the support provided post-infection .Addressing these challenges requires continued research and collaboration among healthcare institutions and researchers. External validation across diverse patient populations, transparent reporting of findings, and prospective studies can enhance the reliability and credibility of rapid scoring systems. Additionally, advances in data science and integrating novel biomarkers may offer opportunities to refine these scoring approaches, leading to more accurate and personalized prognostication for pleural infection .By overcoming these challenges and refining existing rapid scoring systems, clinicians can make more informed decisions, tailor treatments, and allocate resources effectively, ultimately leading to improved patient outcomes and enhanced management of pleural infection. With ongoing efforts and future advancements, rapid scoring systems have the potential to revolutionize the way pleural infection is managed, providing valuable tools for healthcare providers and better care for patients .Prognostic value of rapid scoring in pleural infectionEvaluating the Predictive Accuracy of Rapid Scoring SystemsSensitivity and specificity analysis: Sensitivity measures the proportion of true positive cases correctly identified by the scoring system, i.e., the ability to classify patients with adverse outcomes correctly. Specificity, on the other hand, measures the proportion of true negative cases correctly identified, i.e., the ability to classify patients with favorable outcomes correctly. A comprehensive analysis of sensitivity and specificity provides valuable insights into the scoring system's ability to discriminate between patients with different outcomes. High sensitivity and specificity indicate a scoring system's ability to accurately identify positive and negative cases, thereby increasing its reliability in distinguishing patients with better or worse prognoses .Receiver operating characteristic (ROC) curves: ROC curves graphically illustrate the trade-off between sensitivity and specificity at various score thresholds. By plotting sensitivity against (1 - specificity) for different threshold values, the ROC curve visually represents the scoring system's performance in distinguishing between patients with different outcomes. The area under the ROC curve (AUC) quantifies the overall discriminative ability of the scoring system. An AUC value close to 1 indicates excellent discriminative power, meaning the scoring system can effectively differentiate between patients with favorable and adverse outcomes. Conversely, an AUC value close to 0.5 suggests poor discrimination, equivalent to random chance, rendering the scoring system less effective in predicting patient outcomes . ResearcPredictive Potential for Short-Term OutcomesMortality prediction: Mortality prediction is a critical aspect of managing pleural infection, as identifying patients at higher risk of death enables healthcare providers to initiate timely interventions and allocate resources effectively. By integrating clinical and laboratory parameters, rapid scoring systems aim to quantify the mortality risk in infected patients. The scores generated by these systems can serve as an early warning system, alerting clinicians to patients with a higher likelihood of adverse outcomes. Studies that analyze the association between rapid scoring system scores and actual mortality rates are of paramount importance. Evaluating the accuracy and reliability of these scoring systems in predicting mortality is essential for their successful implementation in clinical practice. Validated scoring systems can support evidence-based clinical decision-making, guiding aggressive treatment approaches for high-risk patients and potentially improving overall survival rates in pleural infection cases .Treatment response: Assessing the predictive potential of rapid scoring systems on treatment response is equally significant. Identifying patients less likely to respond to standard therapies is crucial for early intervention and alternative treatment strategies. Rapid scoring systems can assist in predicting treatment response by considering factors such as disease severity, pathogen characteristics, and patient-specific variables. By flagging non-responsive or slow-responding cases, clinicians can promptly modify treatment regimens, thereby preventing disease progression and minimizing complications. This proactive approach to treatment tailoring may improve therapeutic efficacy and enhance patient outcomes. Furthermore, predicting treatment response can aid in the judicious use of healthcare resources, optimize medication utilization, and reduce unnecessary interventions .Length of hospital stay: Prolonged hospital stays in pleural infection cases impact patient well-being and impose a substantial economic burden on healthcare systems. Rapid scoring systems that accurately predict the length of hospitalization can provide valuable insights for resource management and discharge planning. By estimating the expected duration of hospital stay, healthcare providers can allocate resources more efficiently, including hospital beds, staff, and medications. This allows for smoother patient flow and reduces overcrowding in medical facilities. Additionally, accurate predictions of hospital stay duration enable healthcare teams to engage in proactive discharge planning, ensuring that patients receive appropriate care and support after discharge. By minimizing unnecessary hospitalization, rapid scoring systems can contribute to optimizing healthcare resources and improve overall patient care in the context of pleural infection management ,37.Predictive Potential for Long-Term OutcomesRecurrence rates: Pleural infection recurrence is a vexing issue that poses challenges in patient management. Identifying individuals at higher risk of recurrence is crucial for implementing appropriate surveillance and follow-up strategies. Rapid scoring systems, with their ability to provide a quantitative assessment of disease severity, may offer valuable insights into the likelihood of recurrence. Clinicians can tailor long-term treatment planning and preventive measures for high-risk patients by analyzing the correlation between scoring system scores and recurrence rates. A scoring system capable of predicting recurrence can prompt intensified monitoring, early interventions, or targeted therapies to reduce the burden of recurrent pleural infections and improve patient outcomes ,39.Functional outcomes and quality of Life: Beyond short-term outcomes such as mortality and recurrence rates, the impact of pleural infection on functional outcomes and quality of life is paramount. Many survivors of pleural infection experience impaired lung function, reduced exercise capacity, and diminished overall quality of life. Scoring systems that can predict long-term functional outcomes may prove instrumental in optimizing rehabilitation efforts and post-infection support. By identifying patients at risk of poor functional recovery, clinicians can initiate timely interventions such as pulmonary rehabilitation, physical therapy, and psychological support to enhance the patient's overall well-being and quality of life ,41.Understanding the predictive value of rapid scoring systems for both short-term and long-term outcomes is essential for their effective clinical application. The analysis of various studies investigating these aspects provides a comprehensive overview of the potential benefits and limitations of using rapid scoring systems in pleural infection management. Integrating rapid scoring into clinical practice can facilitate risk stratification, personalized treatment planning, and informed decision-making. However, it is crucial to recognize these scoring systems' limitations and potential biases and address them through rigorous validation and future research. By refining and enhancing the accuracy and utility of rapid scoring systems, healthcare providers can optimize patient care and improve outcomes in pleural infection management. Ultimately, the successful integration of rapid scoring into routine clinical practice can positively impact patient well-being and healthcare resource allocation, bringing us closer to more effective and patient-centered pleural infection management strategies ,21.Factors affecting the prognostic accuracy of rapid scoringAccurate prognostication is a critical aspect of managing pleural infection effectively. Rapid scoring systems offer a quantifiable and standardized approach to assessing disease severity and predicting patient outcomes. However, to ensure their reliability and usefulness in clinical practice, it is essential to consider various patient-specific factors that can influence the predictive accuracy of these scoring systems . One sucMicrobiological and radiological findings are another crucial aspect of pleural infection management. The causative microorganisms, their antibiotic sensitivity, and the extent of lung involvement and pleural effusion on imaging can significantly affect disease severity and treatment response. Rapid scoring systems incorporating these findings into their algorithms may offer more accurate prognostic predictions . ComorbiMoreover, interpreting scoring results in the context of the severity of pleural infection is crucial. In mild or moderate cases, scoring systems may have limited discriminatory ability due to the relatively uniform nature of the patient population. However, scoring systems can offer more accurate prognostic insights in severe or complicated infections, guiding clinicians towards more aggressive interventions and monitoring strategies .Impact of Patient DemographicsPatient demographics, specifically age and sex, influence disease progression and outcomes in pleural infection. Age-related factors can significantly impact the clinical course of the infection. As patients age, changes in immune function and physiological reserves may increase infection vulnerability, making elderly individuals more susceptible to severe pleural infection. Additionally, comorbidities commonly accompanying aging can complicate disease management and influence treatment response. Therefore, considering age-related variations in prognostic scoring systems is essential to accurately predict disease severity and outcomes in different age groups .Furthermore, gender-related differences in pleural infection outcomes have been observed in some studies. While the underlying reasons for these disparities are not yet fully understood, it is believed that hormonal and immunological differences between males and females may contribute to varying disease outcomes. For instance, estrogen is known to have immunomodulatory effects that might influence the body's response to infection. Some studies have suggested that female patients with pleural infection may experience milder disease courses and have better treatment responses than males. By incorporating gender as a parameter in prognostic scoring systems, it is possible to account for these gender-specific differences and improve the accuracy of predicting outcomes for both male and female patients .Addressing patient demographics in rapid scoring systems is essential for personalized medicine and individualized patient care. Tailoring treatment strategies based on age and gender considerations can help clinicians optimize therapeutic interventions and improve patient outcomes. However, it is crucial to ensure that any consideration of demographics in scoring systems is evidence-based and supported by rigorous research. Understanding the impact of age and gender on pleural infection outcomes is an ongoing area of investigation, and continued research in this domain will further enhance the accuracy and utility of rapid scoring systems in pleural infection prognostication .Role of Microbiological and Radiological FindingsMicrobiological and radiological findings are integral components in diagnosing and managing pleural infection. Identifying causative microorganisms and their susceptibility to antibiotics is crucial for guiding appropriate antimicrobial therapy, significantly impacting treatment response and overall patient outcomes. Rapid scoring systems that consider microbiological data have the potential to enhance predictive accuracy, particularly in cases where tailored antibiotic treatment is necessary .Microbiological data can reveal valuable information about the type of pathogen causing the infection, its virulence, and its antibiotic resistance. Scoring systems that incorporate microbiological findings can aid clinicians in identifying high-risk patients who may require prompt escalation to targeted and more aggressive therapies. This enables timely adjustments to treatment regimens, potentially preventing treatment failure and the development of complications .Conversely, evaluating disease severity and tissue involvement heavily relies on radiological characteristics. Essential insights regarding pleural effusion, lung parenchymal engagement, and necrosis are provided through imaging techniques like chest X-rays and computed tomography (CT) scans. These radiological attributes mirror both the local and systemic effects of the disease, thereby enhancing clinicians' comprehension of the disease's status and possible complications .Scoring systems integrating radiological parameters offer a more comprehensive and nuanced disease evaluation. Such assessments can assist in risk stratification, allowing healthcare providers to identify patients with more severe infections who may require more intensive management, such as drainage procedures or surgical interventions . By consInfluence of Comorbidities on Scoring SystemsComorbidities significantly shape the clinical course of pleural infection, influencing disease progression, treatment response, and patient outcomes. Conditions such as diabetes, chronic kidney disease, heart failure, and immunosuppressive states can weaken the immune system, impair lung function, and increase the risk of complications. Consequently, patients with comorbidities are often at higher risk of adverse outcomes, including prolonged hospital stays, treatment failure, and increased mortality .Incorporating comorbidities into rapid scoring systems can enhance their prognostic accuracy by providing a more comprehensive assessment of the patient's overall health status. Scoring models considering these additional risk factors can better identify high-risk patients requiring more aggressive interventions or closer monitoring. Tailored treatment plans based on accurate risk stratification can improve clinical outcomes and resource utilization, ensuring that the most vulnerable patients receive the necessary care . HoweverAdditionally, choosing which comorbidities to include in the scoring systems must be carefully considered. Not all comorbidities may impact pleural infection outcomes equally, and some may be more relevant in specific patient populations. Thus, the selection of comorbidities should be based on their clinical significance and the availability of data . MoreoveInterpreting Scoring Results in the Context of Pleural Infection SeverityThe interpretation of scoring results in the context of pleural infection is critical when utilizing rapid scoring systems. It is important to recognize that these scoring systems' accuracy and predictive power may vary depending on the overall severity of the pleural infection in a given patient population . The disDespite their potential usefulness, clinicians need to understand that rapid scoring systems are adjunctive tools and not definitive predictors of outcomes. These systems are designed to aid in risk stratification and decision-making but should not be solely relied upon to make critical clinical decisions. Instead, they should be used with clinical judgment and other diagnostic assessments, such as radiological findings, microbiological data, and the patient's overall clinical status . By inteClinical implications and application of rapid scoringRole of Rapid Scoring in Clinical Decision-MakingRapid scoring systems in pleural infection management have the potential to significantly impact clinical decision-making by providing a quantitative and standardized assessment of disease severity and prognostication. These scoring systems offer valuable information to healthcare providers, aiding in risk stratification, treatment tailoring, and follow-up planning .Risk stratification: Rapid scoring systems excel in identifying patients at higher risk of adverse outcomes, such as mortality or treatment failure. These systems can efficiently classify patients into risk categories by analyzing clinical and laboratory parameters. This enables clinicians to prioritize interventions and allocate resources effectively, especially in resource-constrained settings where optimal utilization of healthcare resources is paramount .Treatment tailoring: One of the key challenges in pleural infection management is selecting the most appropriate treatment strategies for individual patients. Rapid scoring systems play a pivotal role by providing insights into disease severity and potential response to treatment. The scoring results can guide clinicians in choosing the most suitable antimicrobial therapy and drainage procedures and tailoring treatment plans based on the predicted disease severity. This personalized approach enhances therapeutic efficacy, minimizes the risk of treatment failure, and reduces the likelihood of complications .Follow-up planning: Beyond short-term prognostication, rapid scoring systems offer valuable information for long-term follow-up planning. By predicting disease trajectory and long-term outcomes, such as recurrence rates, these systems can inform healthcare providers about the need for post-discharge care and surveillance. Timely detection of potential complications and recurrent infections allows for proactive intervention, leading to better disease management and patient outcomes .Integrating rapid scoring systems into clinical practice empowers healthcare providers with evidence-based decision-making tools, aiding in more informed and precise patient care. The ability to quickly assess disease severity, predict outcomes, and tailor treatments based on individual patient characteristics enhances the overall management of pleural infection, ultimately leading to improved patient outcomes and enhanced healthcare resource utilization. However, ongoing research and validation are essential to continually refine and optimize these scoring systems, ensuring their effectiveness and reliability in real-world clinical settings. By harnessing the full potential of rapid scoring systems, healthcare providers can revolutionize pleural infection management and elevate the standard of care for patients affected by this challenging condition .Integration of Rapid Scoring into Current Management GuidelinesValidation and adaptation: Thorough validation is essential before implementing rapid scoring systems. This involves evaluating the performance of the scoring system in diverse patient populations to ensure its generalizability across different contexts. Validation studies should encompass various demographic profiles, disease severities, and geographic locations. In some cases, adaptation of the scoring system to specific local contexts may be necessary to account for variations in patient characteristics and healthcare practices .Education and training: Effective education and training programs are crucial to familiarize healthcare providers with the rapid scoring system's use and interpretation. Clinicians need to understand the rationale behind the scoring criteria, the significance of specific variables, and how to calculate the scores accurately. Additionally, emphasizing that the scoring system is an adjunctive tool to support clinical judgment can help mitigate any concerns of over-reliance on the scoring results .Standardized documentation: Consistent and standardized documentation of scoring system parameters in patient records is vital for continuity of care. Healthcare providers should diligently record the data used to calculate the score, the actual score itself, and any updates during treatment. Standardized documentation enables clinicians to track disease progression over time and aids in assessing the effectiveness of treatment strategies based on changes in the scoring results .Interdisciplinary collaboration: Pleural infection management involves the collaboration of various medical specialists, each contributing their expertise to patient care. Effective interdisciplinary collaboration is essential for integrating rapid scoring systems seamlessly into the overall management approach. Collaborating with pulmonologists, infectious disease specialists, radiologists, and other relevant disciplines like cardiothoracic\u00a0ensures that all aspects of patient care are considered, and the scoring system's results are interpreted comprehensively .Practical Considerations and Challenges in Implementing Rapid ScoringAccessibility of data: The availability of necessary clinical and laboratory data required for rapid scoring may vary across different healthcare settings. In some facilities, electronic health records (EHRs) might be well-established, allowing easy access to relevant patient data. However, in resource-limited or smaller healthcare facilities, the absence of comprehensive EHR systems could hinder data accessibility. Efforts should be made to streamline data collection and ensure the completeness of data inputs for accurate scoring. This may involve improving data capture and recording practices, and fostering interoperability between healthcare information systems .Scoring system selection: Choosing the most appropriate rapid scoring system for a specific clinical setting requires careful consideration of various factors. Different scoring systems may have been developed and validated in diverse patient populations or healthcare contexts. As such, it is essential to evaluate the applicability and accuracy of each scoring system in the specific patient cohort and resource constraints of the healthcare facility. Factors such as patient demographics, available resources, and the overall clinical context should be considered during the selection process to ensure that the chosen scoring system aligns with the needs and capabilities of the healthcare setting .Time constraints: Rapid scoring systems are designed to provide quick and efficient disease severity and prognosis assessments. However, the practicality of their implementation can be impacted by time constraints, particularly in busy clinical settings where healthcare professionals have limited time to dedicate to scoring calculations. The scoring process should be user-friendly, intuitive, and time-efficient to integrate rapid scoring into routine clinical practice seamlessly. Implementing user-friendly electronic scoring tools or incorporating scoring algorithms into electronic medical record systems can help minimize the time investment required for scoring calculation .Future Directions and Potential Improvements in Rapid Scoring SystemsComprehensive scoring models: To enhance the accuracy of prognostication, future scoring systems could be developed as more comprehensive models. By incorporating additional variables, such as molecular biomarkers or novel radiological parameters, these systems can provide a more nuanced and detailed assessment of disease severity and progression. Integrating biomarkers reflecting the host's immune response or pathogen virulence may offer valuable insights into disease outcomes and treatment responses .Artificial intelligence (AI) integration: Leveraging AI algorithms could revolutionize rapid scoring systems by analyzing vast datasets and identifying patterns that might not be apparent through conventional methods. AI integration can significantly improve the predictive power of these systems. Machine learning algorithms can adapt and refine scoring models based on real-world data, ensuring continuous improvement and adaptability to evolving clinical scenarios .External validation and standardization: It is essential to rigorously validate and standardize rapid scoring systems across diverse patient populations and healthcare settings for widespread clinical adoption. Continued research and collaboration among healthcare institutions and research centers can facilitate the validation process, ensuring the reliability and generalizability of these scoring approaches .Longitudinal predictions: Advancements in scoring methodologies may enable dynamic and longitudinal predictions, offering real-time updates on patient outcomes throughout treatment. Longitudinal assessments can provide insights into disease progression, response to therapies, and potential complications, allowing clinicians to adjust treatment strategies proactively .Top of form critique and limitations of rapid scoring systemsCriticism of Current Scoring ApproachesWhile rapid scoring systems have demonstrated their potential in aiding prognostication for pleural infection, they are not exempt from criticism. Several key criticisms of current scoring approaches warrant consideration:Oversimplification: One significant critique of some rapid scoring systems is their tendency to oversimplify the complexity of pleural infection. By focusing on a limited set of parameters, these scoring systems may not fully capture the multifaceted nature of the disease. The oversimplification could lead to inadequate prognostic accuracy, particularly in cases with diverse clinical presentations and variable disease trajectories .Generalizability: Many rapid scoring systems have been developed and validated in specific patient populations, often based on data from single institutions or regions. Consequently, there may be concerns regarding the applicability of these scoring approaches to more diverse patient cohorts. The lack of external validation across different healthcare settings and populations hinders their generalizability and raises questions about their reliability in real-world clinical scenarios .Lack of longitudinal assessment: Rapid scoring systems typically provide static assessments of disease severity at a particular time point. The absence of dynamic or longitudinal assessments limits their ability to predict changes in disease trajectory over time. In pleural infection, disease progression and response to treatment may evolve over days or weeks, and a single snapshot may not capture the full clinical picture .Limited predictive value for long-term outcomes: While rapid scoring systems have shown promise in predicting short-term outcomes, such as mortality and treatment response, their ability to predict long-term outcomes remains a challenge reliably. Variables influencing long-term recovery, recurrence rates, and functional outcomes are complex and multifactorial, making their inclusion in scoring systems more complex .Limitations of Available Studies and DataSmall sample sizes: Many studies evaluating rapid scoring systems may have limited sample sizes due to the rarity of severe pleural infections or other logistical constraints. Small sample sizes can reduce statistical power, making it challenging to draw definitive conclusions. Moreover, findings from such studies may lack generalizability to larger, more diverse patient populations, potentially limiting the external validity of the scoring systems .Heterogeneity of studies: Studies evaluating rapid scoring systems often utilize varying patient populations, methodologies, and outcome measures. This heterogeneity can complicate direct comparisons between different scoring approaches, hindering the establishment of a consensus on the most effective scoring system for pleural infection prognostication. A standardized approach to study design and outcome measurements would facilitate meaningful comparisons and enhance the reliability of the findings .Retrospective nature: Many studies assessing rapid scoring systems in pleural infection rely on retrospective data, which can introduce inherent biases and limitations. Retrospective data collection may be subject to selection bias, as patient data may not have been originally collected for scoring system evaluation. Additionally, retrospective data might lack completeness, leading to missing or incomplete information that could impact the accuracy and reliability of prognostic evaluations .Missing data and follow-up: Incomplete data and loss to follow-up present significant challenges in prognostic evaluations using rapid scoring systems. Missing data can result from various factors, including patients' refusal to participate in follow-up assessments or incomplete medical records. This missing data can lead to underestimation or overestimation of prognostic accuracy and potentially introduce bias into the results. Ensuring complete and accurate data collection, as well as adequate follow-up, is essential to minimize these potential biases and enhance the validity of prognostic assessments .Addressing Potential Sources of BiasLarge, prospective multicenter studies: Conducting well-designed prospective studies with large and diverse patient populations is essential. By collecting data from multiple healthcare centers, these studies can improve the generalizability of the findings and ensure that the results represent the broader patient population. Prospective studies also allow for standardized data collection, minimizing the risk of data inconsistencies and enhancing the statistical robustness of the scoring system .External validation: External validation of rapid scoring systems is critical to establishing their predictive accuracy in different clinical settings and patient cohorts. Validating the scoring systems in settings beyond their original development ensures that they perform consistently and reliably across diverse healthcare contexts. Such validation strengthens the evidence base supporting the use of these scoring systems and increases confidence in their clinical applicability .Longitudinal assessment: Incorporating longitudinal assessments into rapid scoring systems can provide more accurate predictions of disease trajectories over time. By tracking changes in patient status and outcomes throughout treatment and follow-up, longitudinal assessments can offer insights into the dynamic nature of pleural infection and its response to interventions. This temporal dimension can further enhance the predictive value of the scoring systems, guiding clinicians in making more informed decisions throughout the patient's healthcare journey .Transparent reporting: Transparent reporting of study methods, data collection, and potential sources of bias is crucial for ensuring the credibility and reproducibility of research findings. Comprehensive and clear reporting allows other researchers and healthcare professionals to understand and evaluate the study's methodology and potential limitations. It fosters an environment of scientific rigor and encourages transparency in research, which is vital for building trust in the validity and applicability of rapid scoring systems in pleural infection prognostication .This review article has comprehensively assessed the predictive potential of rapid scoring systems in pleural infection prognostication. Pleural infection is a significant health concern, demanding accurate prognostic tools for effective management. Our analysis of existing scoring systems such as CURB-65, A-DROP, and APACHE II revealed their strengths and limitations in predicting short-term and long-term outcomes. While rapid scoring systems show promise in aiding clinical decision-making and risk stratification, they are not without drawbacks and face challenges related to data limitations and potential biases. However, their integration into clinical practice can potentially improve patient outcomes and optimize resource allocation. Moving forward, rigorous validation, reporting transparency, and data science advances offer promising avenues for refining rapid scoring systems. Multidisciplinary collaboration and prospective studies are critical to unlocking the full potential of rapid scoring in pleural infection management, ultimately contributing to better patient care and outcomes."} {"text": "Extracellular RNAs are an emerging research topic in fungal-plant interactions. Fungal plant pathogens and symbionts release small RNAs that enter host cells to manipulate plant physiology and immunity. This communication via extracellular RNAs between fungi and plants is bidirectional. On the one hand, plants release RNAs encapsulated inside extracellular vesicles as a defense response as well as for intercellular and inter-organismal communication. On the other hand, recent reports suggest that also full-length mRNAs are transported within fungal EVs into plants, and these fungal mRNAs might get translated inside host cells. In this review article, we summarize the current views and fundamental concepts of extracellular RNAs released by plant-associated fungi, and we discuss new strategies to apply extracellular RNAs in crop protection against fungal pathogens.Extracellular RNAs are an emerging topic in plant-fungal communication.\u2022 Fungi utilize RNAs to manipulate host plants for colonization.\u2022 Extracellular RNAs can be engineered to protect plants against fungal pathogens.\u2022 Fungal-plant interactions can have beneficial, detrimental, or neutral effects on plant hosts. Pathogenic fungi pose serious threats to agronomic yield and ecosystems that is largely conserved between fungi and plants. Key factors of RNAi, namely RNA-dependent RNA polymerase (RDR), Dicer-like (DCL), and Argonaute (AGO) proteins, are highly conserved in both plants and fungi . EVs are nanoparticles encasing cytoplasmic molecules including proteins and RNAs in a lipid bilayer, which are secreted into the extracellular space into the root cortex of its host plant Eucalyptus grandis. Treatment of roots with synthetic Pisolithus milRNAs mimicked regulation of Eucalyptus target genes and strengthened formation of deep Hartig net during root colonization roots in order to establish root nodule symbiosis into the soybean AGO1b to induce cross-kingdom RNAi of nodule-repressive plant genes. Interestingly, both cases of cross-kingdom RNAi help to establish distinct forms of root symbiosis, in which microbial small RNAs seem to act as early stage interaction signals, because RNA delivery into plant cells occurs before the formation of fungal Hartig net and bacterial nodules.The fungal vascular pathogen Zymoseptoria tritici 11 and RH37, which all specifically bind to the EV small RNAs, as well as the two non-specific RBPs annexins (ANN)1 and ANN2 and mRNAs with cognate motifs for targeting them to sites of EV biogenesis. In mammalian systems, multiple RBPs have been implicated in RNA loading into EVs siRNAs into infecting B. cinerea. These A. thaliana small RNAs are suggested to be transported via plant EVs RNAs was found in the plant extracellular fraction . Accordingly, essential field trials in the USA are proceeding to pave the way for final approval. Such development of successful SIGS application keeps high hopes that RNA spray also becomes conceivable for plant protection against fungal pathogens in the near future.Since the discovery of cross-kingdom RNAi and its technological implementation into HIGS application, RNAs have been engineered to confer resistance in plants against diverse pathogenic organisms with significant success and DCLs (RNAi pathway) on cotton (Jain et al. B. cinerea infection in tomato and chickpea under controlled conditions (Nino-Sanchez et al. B. cinerea infection (Qiao et al. Since extracellular RNA stability and delivery have been identified as the major challenges to bring SIGS into a success story against fungal pathogens (Hernandez-Soto and Chacon-Cerdas The SIGS approach stands for a more eco-friendly plant protection strategy that is already in transition into potential field application in first trails (Rank and Koch"} {"text": "Pancreatic cancer is currently the fourth most common cause of cancer-related deaths and is predicted to be the second leading cause of cancer-related mortality by the year 2030. Most of the malignant neoplasms of the pancreas are ductal adenocarcinomas (PDAC). For several reasons, the prognosis of PDAC is exceedingly poor. Surgical resection is the only curative treatment option, but only about 10\u201320% of patients present with resectable tumors at the time of diagnosis. Moreover, most pancreatic carcinomas are resistant to conventional (radio)chemotherapy. Current clinical standard treatment regimens comprise either mFOLFIRINOX or gemcitabine (with nab-paclitaxel). The selection of either of these regimens is currently based on the patient performance status and comorbidities, while the underlying individual tumor biology is commonly not considered. Although multiple studies aimed at establishing molecular profiles and identification of actionable molecular targets of PDACs, targeted therapies for PDAC patients have not (yet) become an integral part of clinical routine practice. In addition to treatment prediction based on molecular profiling, e.g., in the context of a molecular tumorboard, preclinical culture models that reflect the complex interactions of tumor cells with their microenvironment are promising tools to understand molecular mechanisms of PDAC and to test individual treatment responses. These patient-derived models comprise adherently growing primary cell lines, organoid cultures, organotypic slice cultures and patient-derived xenografts.Garcia et al. recently published a comprehensive review on two-dimensional (2D) cell cultures, 3D organoid cultures, and genetically engineered mouse models (GEMMs) with a special focus on patient derived xenograft (PDX) models . AdherenIn light of the limitations of PDXs as a preclinical model for individual therapy response prediction in personalized medicine, 3D organoid cultures are a highly promising tool. Frappart and Hofmann comprehensively reviewed the methodology and potential use of organoid cultures to improve clinical management of PDAC . EfficieAs mentioned above, most preclinical culture models lack the immune cell compartment. However, multiple suppressive immune cell types including macrophages, myeloid-derived suppressor cells (MDSCs) and regulatory T cells are found in early pancreatic lesions and persist through cancer progression. Holokai et al. described an elegantautologous pancreatic cancer organoid-immune cell co-culture model that may be able to predict the efficacy of targeted therapies . Based oAnother model system that should be mentioned in this context are organotypic slice cultures (OTSCs). We recently established this ex vivo model in our laboratory to explore its potential use for ex vivo response prediction . OTSCs aIn summary, we conclude that to date there is no optimal model system for preclinical response prediction of individual PDAC patients to therapy. Each model system discussed here has its benefits and weaknesses and does not fully reflect the individual patient\u2019s tumor biology in vivo. However, since they complement each other, they may be used in combination rather than singly for reliable response prediction. All of these preclinical patient-derived culture models are certainly highly promising tools in personalized treatment of PDAC; their clinical implementation, though, requires further evaluation and fine tuning."} {"text": "The clinical use of cellular immunotherapies is gaining momentum and the number of approved indications is steadily increasing. One class of cellular therapies\u2014chimeric antigen receptor (CAR)-modified T cells\u2014has achieved impressive results in distinct blood cancer indications. These existing cellular therapies treating blood cancers face significant relapse rates, and their application beyond hematology has been underwhelming, especially in solid oncology. Major reasons for resistance source largely in the tumor microenvironment (TME). The TME in fact functionally suppresses, restricts, and excludes adoptive immune cells, which limits the efficacy of cellular immunotherapies from the onset. Many promising efforts are ongoing to adapt cellular immunotherapies to address these obstacles, with the aim of reshaping the tumor microenvironment to ameliorate function and to achieve superior efficacy against both hematological and solid malignancies. Cellular immunotherapies, encompassing the use of modified autologous or allogeneic immune cells as treatment against disease, have recently advanced to become part of the standard of care in a few types of relapsed and refractory hematological malignancies. Recent evidence suggests that they might even progress to earlier lines of treatment at least in some indications, highlighting the untapped potential of these approaches.Overall, cellular immunotherapies have so far employed dendritic cell (DC), T cells, or natural killer cells (NK) into patients for treatment of disease. DC vaccines, which utilize mature dendritic cells or monocyte-derived dendritic cells derived from patient blood, harness the natural role of the dendritic cell in antigen presentation and T cell licensing to target cancer. Dendritic cells are pulsed with tumor-associated antigens and neoantigens that would then be presented to T cells in lymph nodes to induce cytotoxic lymphocyte priming and polarization to mount a specific immune response. Various DC vaccines have shown promising safety and efficacy in clinical trials against pediatric solid tumors and other forms of solid tumors \u20133. TheseMeanwhile, TCRs and CARs are receptors genetically engineered into T cells isolated from patient blood and reintroduced into the patient to target cancers. TCRs used are derived from natural sequences that bind the desired antigen and behave similarly to normal TCRs . In contThe tumor microenvironment\u2014comprises malignant cells together with their immediate environment consisting of immune cells, fibroblasts, extracellular matrix (ECM), blood vessels, and secreted factors. The TME can support the survival and proliferation of tumor cells and tumor-associated cell populations and thus contributes a major share to cancer hallmarks Fig.\u00a0. Crucial. Along these lines, the TME profoundly regulates and suppresses immune responses and appears as the aspect to beat to enable cell therapy efficacy.Chemokines released by tumor cells recruit and retain other populations of immunosuppressive cells into the tumor microenvironment Fig.\u00a0. T-regulMany insights have already been gained into improving existing cellular therapy. For instance, application via intratumoral injection leads to increased efficacy of adoptive CAR-T cells in certain tumor indications by physically circumventing the issue of TME exclusion and adoptive cell infiltration , 43. To Chemokines are mediators signaling for directed migration towards the source they originate from . Chemokines orchestrate the localization of cells within the body and accordingly play a crucial role in the trafficking of immunosuppressive cells to the TME , 50. HowChemokine engineering into therapeutic immune cells has been incorporated into cellular therapies with the goal of increasing the migration of both endogenous inflammatory cells and also adoptively transferred cells into the tumor Fig.\u00a0. The cheAnother related strategy to increase immune infiltration is endogenous activation and proliferation, ultimately leading to higher anti-tumor effector cell numbers at the tumor site. In this sense, T cells can be genetically engineered to express immune checkpoint inhibitors, with anti-PD-1 or anti-PD-L1 antibodies being the most utilized avenue \u201361. AntiThe TME is typically rich in cytokines such as IL-1, favoring expansion and polarization of immune suppressive cell populations of myeloid and lymphoid origin . In contThe aforementioned strategies remodeling the cytokine environment in the TME indirectly affect TAMs, MDSCs, and T-regs by antagonizing their suppressiveness or reversing their suppression program. However, other cellular therapy approaches aim to directly target these immunosuppressive populations for elimination or remodeling Fig.\u00a0. For exaSignificant obstacles of cellular immunotherapy in solid tumors do not only arise from immunosuppressive cell populations and a lack of immune cell activation within the TME but are additionally characterized by the establishment of CAF-mediated tumor stroma as a physical barrier, diminishing cellular therapy effectiveness. Along these lines, therapy can be enhanced if either the cellular components creating stroma are depleted or acellular stromal components are digested Fig.\u00a0. FibroblA different strategy to surmount the desmoplastic stroma of the TME and enable superior immune cell infiltration is the direct targeting of fibrous proteins, glycosaminoglycans, and proteoglycans composing the ECM via matrix-degrading components. Heparanase (HPSE) is an enzyme that decomposes heparan sulfate proteoglycans and has been found to be insufficiently expressed in CAR-T cells, thereby limiting their capacity to infiltrate stroma-rich tumors . EquippiVarious strategies have also been developed to address the secondary issue of physical tumor-exclusion\u2014aberrant and dysfunctional vasculature that leads to poor T cell infiltration Fig.\u00a0. One strRecent efforts to remodel the tumor microenvironment with cellular therapies have advanced with the advent of engineering CARs or CAR-like receptors on myeloid lineage cells, notably on macrophages and in some instances dendritic cells Fig.\u00a0. TraditiWhile cellular therapies have come a long way to become an established method of cancer treatment, their future potential for increased efficacy in hematological malignancies and even meaningful efficacy in solid tumor indications largely relies on their ability to address the obstacles posed by the TME. This review highlights the current considerable efforts that have been made to improve various aspects of cellular therapies to reshape the TME to become more permissible for treatment: novel concepts that target immunosuppressive cell populations, inflame an immune-restricted tumor, and address chemotactic signaling and physical barriers excluding immune infiltration. The improvements made on these therapies have been shown to lead to superior anti-tumor efficacy compared to more standard cellular therapies. Moreover, many cellular therapies covered here that target the TME as an entity have been combined with other treatments that primarily target the tumor, forming a dual-pronged targeting approach that in many cases shows synergistic efficacy. Additionally, concepts incorporating combinatorial improvements that address multiple TME obstructions show further enhanced function, demonstrating additionally the promising and synergistic nature of reshaping the tumor microenvironment, and hints at robust effects for combinatorial treatments with existing therapies such as ICB. Promising pre-clinical and clinical results of many of the therapies listed bode well for the application of cellular immunotherapies for the treatment of both hematological and solid tumors in the future."} {"text": "Introduction: Chediak-Higashi syndrome (CHS) is rare autosomal recessive disorder caused by bi-allelic variants in the Lysosomal Trafficking Regulator (LYST) gene. Diagnosis is established by the detection of pathogenic variants in LYST in combination with clinical evidence of disease. Conventional molecular genetic testing of LYST by genomic DNA (gDNA) Sanger sequencing detects the majority of pathogenic variants, but some remain undetected for several individuals clinically diagnosed with CHS. In this study, cDNA Sanger sequencing was pursued as a complementary method to identify variant alleles that are undetected by gDNA Sanger sequencing and to increase molecular diagnostic yield.Methods: Six unrelated individuals with CHS were clinically evaluated and included in this study. gDNA Sanger sequencing and cDNA Sanger sequencing were performed to identify pathogenic LYST variants.Results: Ten novel LYST alleles were identified, including eight nonsense or frameshift variants and two in-frame deletions. Six of these were identified by conventional gDNA Sanger sequencing; cDNA Sanger sequencing was required to identify the remaining variant alleles.Conclusion: By utilizing cDNA sequencing as a complementary technique to identify LYST variants, a complete molecular diagnosis was obtained for all six CHS patients. In this small CHS cohort, the molecular diagnostic yield was increased, and canonical splice site variants identified from gDNA Sanger sequencing were validated by cDNA sequencing. The identification of novel LYST alleles will aid in diagnosing patients and these molecular diagnoses will also lead to genetic counseling, access to services and treatments and clinical trials in the future. Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by partial oculocutaneous albinism, bleeding diathesis, recurrent infections, an increased risk of developing the hyperinflammatory condition called hemophagocytic lymphohistiocytosis (HLH), and neurologic impairment . The preCHS has significant clinical overlap with several other genetic disorders, emphasizing the importance of a molecular diagnosis. Other disorders that include gray or silvery hair as observed in CHS include Griscelli syndrome , Elejalde neuroectodermal melanolysosomal syndrome (MIM 256710), and oculocerebral syndrome with hypopigmentation (MIM 257800) . There aLYST) gene is the only known molecular cause of CHS and bi-allelic pathogenic variants in LYST establish a molecular diagnosis detects the majority of pathogenic variants, but for some individuals clinically diagnosed with CHS, pathogenic variants remain undetected, likely due to large-scale indels and deep intronic variants or synonymous exonic variants that lead to aberrant splicing. Uniparental disomy leading to the inheritance of two copies of a pathogenic LYST variant from one parent has also been reported as a molecular mechanism for CHS or the Diagnosis and Treatment of Patients with Inborn Errors of Metabolism or Other Genetic Disorders protocol 76-HG-0238 approved by the National Human Genome Research Institute\u2019s Institutional Review Board. Written informed consent was obtained prior to the study. Clinical evaluation included collecting the medical and family history, physical examination, complete blood count (CBC) blood test. Peripheral blood smear analysis and microscopic hair examination were used to assess the presence of giant inclusions in leukocytes and pigment clumping in hair shafts, pathognomonic features of CHS.Six patients clinically diagnosed with classical or atypical CHS were included in this study. These patients were enrolled over the course of 10\u201320\u00a0years in the Investigation of Chediak-Higashi Syndrome and Related Disorders protocol 00-HG-0153 . Quantitative PCR was performed using TaqMan gene expression assays according to the manufacturer\u2019s specifications. Further details are presented in the Supplementary Data.Total RNA was extracted from cultured primary dermal fibroblasts or melanocytes using the RNeasy Mini Kit (Qiagen). Genomic DNA was removed by on-column DNase I digestion (Qiagen) during total RNA extraction. Reverse transcription was performed using the Omniscript Reverse Transcription Kit (Qiagen) and Oligo (dT)LYST (NM_000081.3) coding sequence (exons 3\u201353), including intron-exon boundaries, were amplified by PCR using the primers listed in Genomic DNA (gDNA) was extracted from peripheral blood or cultured primary dermal fibroblasts using standard procedures. gDNA from cultured primary fibroblasts was used if the gDNA from peripheral blood was no longer available. Regions of the LYST coding sequence (exons 3\u201353) were amplified by PCR using the primers listed in Total RNA was extracted from cultured primary dermal fibroblasts or melanocytes using the RNeasy Mini Kit (Qiagen). cDNA was synthesized by reverse transcription with the High-Capacity RNA-to-cDNA Kit (Applied Biosystems). Regions of the PCR products were cloned into the pCR4-TOPO TA vector using the TOPO TA Cloning Kit (Invitrogen). Single clones were Sanger sequenced to individually analyze the cDNA alleles for which chromatograms obtained from the initial cDNA Sanger sequencing were difficult to interpret.Variant pathogenicity classification was performed according to the standards and guidelines presented by the ACMG-AMP and the ACGS . Furtherp-value of less than 0.05 was considered statistically significant.Statistics were performed using GraphPad Prism 8 version 8.4.3 . A two-tailed Mann-Whitney test was performed for experiments comparing two sets of data. A CHD3 presented with silvery hair, pale skin, and ocular albinism as well as a history of recurrent respiratory and skin infections and nose bleeds. He was clinically diagnosed with classical CHS at the age of 7\u00a0years. Abnormal pigment clumping was observed in his hair shafts . He receStaphylococcus aureus (MRSA). She also had learning difficulties and a mood disorder. Pathognomonic giant inclusions were observed in her leukocytes and abnormal pigment clumping in her hair shafts . These cellular findings substantiate prior cellular findings reported in human CHS and in the beige mouse model (Pathogenic variants have been identified throughout the ication) . Eight oication) ; Table 1ication) . AlthougLYST-expressing cell types, including dermal fibroblasts, melanocytes, NK cells, and lymphoblastoid cell lines, for the preparation of total RNA. Archiving cells from each parent and all available family members would also be useful for variant phasing and segregation studies.cDNA Sanger sequencing in combination with conventional gDNA Sanger sequencing offers several advantages. First, cDNA Sanger sequencing can detect variant alleles that are not readily detectable by conventional gDNA Sanger sequencing. While establishing a clinical diagnosis is valuable, the confirmation of a molecular diagnosis is critical for optimal patient care, genetic counseling for the individual and their family members, and eligibility in future clinical trials. Second, cDNA Sanger sequencing is relatively easy to incorporate into the molecular genetic testing workflow, requiring only routine cell culture and total RNA extraction techniques. An important consideration is patient sample archiving of LYST. Furthermore, only cDNA from each of the six patients was analyzed in this study due to sample availability. While we were unable to assess cDNA from cells derived from family members due to sample availability, cDNA Sanger sequencing could be performed to segregate LYST alleles in a family even if the variant at the level of gDNA is unknown.A key limitation of this study was that we were unable to identify the cause of the full or partial exon skipping at the gDNA level for some alleles. While efforts were made to sequence nearby intronic regions and identify exonic synonymous variants that might lead to the aberrant splicing, proving the consequence of such variants requires further functional validation. With the decreasing costs of genome sequencing and targeted next-generation sequencing, these are becoming viable options for the identification of deep intronic variants leading to splicing changes in LYST gene in CHS. Because of the increasing access to next-generation sequencing and its rapid turnaround time, we recommend the utilization of clinical genome sequencing to include copy number variant analysis for patients in which CHS is suspected. When available, RNA sequencing using lymphoblastoid cell lines and melanocytes could help delineate the resulting splice site abnormalities from intronic variants. For standard clinical practice using exome sequencing and when clinical genome sequencing is not available, targeted gDNA Sanger sequencing and copy number detection is recommended for patients highly suspected to have clinical CHS, followed by RNA sequencing (as above) or cDNA Sanger sequencing if only one or no variants are detected by gDNA Sanger sequencing. It will also be interesting to pursue efforts on long-read sequencing technologies to identify deletions in these large genes and to phase variants in the absence of parental samples in the future. Overall, the identification of disease-causing variants will aid in the future diagnosis and care of individuals with CHS.In this study, the integration of thorough clinical phenotyping and conventional gDNA Sanger sequencing in combination with cDNA Sanger sequencing increased the mutational spectrum of CHS. Based on our experience from this study, we provide the following recommendations for molecular genetic testing of the"} {"text": "Inhaled medications, including beta-agonists, muscarinic antagonists, and corticosteroids, are the backbone of chronic obstructive pulmonary disease (COPD) treatment, and pharmacotherapy plans are frequently optimized during and following hospitalization. Clinical practice guidelines acknowledge that patients living with COPD may experience medication errors from inadequate inhaler technique or device faults, but inhaled medication errors within COPD pharmacotherapy plans remain unreported. This literature review aimed to collect and present studies describing medication errors occurring with inhaled medications in patients living with COPD during and following hospitalization. The databases searched included Ovid MEDLINE, Embase, and International Pharmaceutical Abstracts. One hundred forty-five unique studies were collected, and 10 studies were included. The rate of inhaled medication errors reported across the 10 studies ranged between 2.5% and 66% of patients living with COPD and who were hospitalized or discharged. The incidence and types of medication errors reported across the studies varied significantly. Standardization in categorizing and reporting inhaled medication errors is necessary for future studies to determine the true incidence of inhaled medication errors occurring in patients living with COPD who are hospitalized or discharged. Patients living with chronic obstructive pulmonary disease (COPD) may take medications to palliate symptoms, improve health status, tolerate exercise, and reduce the risk and severity of exacerbations of COPD (ECOPD) . InhaledHowever, the comprehensive formulary of inhaled medications may be overwhelming for both patients and prescribers and thus there is potential for medication errors. Hospitalization is a critical time wherein inhaled medication errors may occur and between 7% and 33% of patients living with COPD will experience at least one COPD-related hospitalization annually . PatientThe purpose of this review is to collect and present literature describing medication errors occurring with inhaled medications in patients living with COPD during and following hospitalization.Review methodsThis was a literature review utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol . The resAn electronic literature search was performed using Ovid MEDLINE, Embase, and International Pharmaceutical Abstracts on February 14, 2023. Search strings for each database are included in Appendix A and adhered to the PRISMA-S extension for literature search reporting . Study rResults from each database search were exported as a Research Information Systems file and then imported into Covidence . During the initial file upload, Covidence automatically de-duplicated identical records retrieved across databases. Abstracts were independently screened by two authors (KH and MG) and screening conflicts were resolved by a third author (PB). Full texts were independently screened by two authors (KH and MG) and screening conflicts were resolved by a third author (PB). Data abstraction was independently performed by two authors (KH and MG). To minimize heterogeneity across the articles and among authors, extraction was performed using a template in Covidence. Data collected included study location, study design, characteristics of the cohort , characteristics of patients living with COPD , and medication errors. There are many frameworks for reporting medication errors, medication error research, and outcomes attributable to medication errors . BecauseFigure Ten studies were ultimately included and are charted in Table Medication-related problemsIn a pilot study conducted at an academic medical center, pharmacists performing admission and discharge medication reconciliation discovered a medication-related problem (MRP) in 96% of patients during admission and discharge transitions of care, with an average of six MRPs encountered per patient . These MOne Veterans Affairs health care center conducted a pre-post study and found an absolute decrease of greater than 10% in prescribing errors upon discharge in each of the categories of SABA, LABA/LAMA, and ICS upon implementing an order set for ECOPD . DecreasPrescribing errors and omissionsOne retrospective cohort study of older adults hospitalized in Palestine leveraged the Screening Tool of Older Persons\u2019 Prescriptions and Screening Tool to Alert to Right Treatment (STOPP/START) to determine potentially inappropriate prescribing via inappropriate medications and omissions . The autIn one multisite retrospective cohort study conducted in Australia, 93.2% of hospitalized COPD patients received nebulized ipratropium, with 48% of these patients deemed as having received inappropriate nebulized ipratropium because they were ordered (duplicative) inhaled ipratropium concomitantly . At discDiscussionThe rate of inhaled medication errors was heterogeneous across the 10 studies in this review -16. BrowThis literature review is not without limitations. Although the authors utilized a systematic approach to searching, assessing, and presenting the included studies, this literature review did not meet the technical standards of either a systematic or scoping review. Future systematic reviews on the themes and topics raised within this literature review are necessary to answer patient-specific questions. The authors did not perform a bias assessment of each article and doing so would have qualified the methodologic rigor of the included studies; although six studies were retrospective designs ,13,14,16As few as 2.5% or as many as 66% of patients living with COPD who are hospitalized may experience an error in their inhaled medication pharmacotherapy plan. Pharmacologic classes with reported errors include short- and long-acting beta-agonists, muscarinic antagonists, and inhaled corticosteroids. Standardization in categorizing and reporting inhaled medication errors is necessary in subsequent studies; the Pharmacy Quality Alliance Frameworks or Medication Error Reporting and Prevention Index are validated and widely used instruments that may be considered in future studies. Future research should aim to clearly compare and contrast findings across clinical settings and investigations and determine the true incidence of inhaled medication errors."} {"text": "Maiato and Silva discuss the origin and fate of chromosome segregation errors that satisfy the spindle assembly checkpoint, focusing on anaphase surveillance/correction mechanisms and post-mitotic clearance pathways. Enduring chromosome segregation errors represent potential threats to genomic stability due to eventual chromosome copy number alterations (aneuploidy) and formation of micronuclei\u2014key intermediates of a rapid mutational process known as chromothripsis that is found in cancer and congenital disorders. The spindle assembly checkpoint (SAC) has been viewed as the sole surveillance mechanism that prevents chromosome segregation errors during mitosis and meiosis. However, different types of chromosome segregation errors stemming from incorrect kinetochore\u2013microtubule attachments satisfy the SAC and are more frequent than previously anticipated. Remarkably, recent works have unveiled that most of these errors are corrected during anaphase and only rarely result in aneuploidy or formation of micronuclei. Here, we discuss recent progress in our understanding of the origin and fate of chromosome segregation errors that satisfy the SAC and shed light on the surveillance, correction, and clearance mechanisms that prevent their transmission, to preserve genomic stability. Saccharomyces cerevisiae [300 billion cell divisions must take place every day in the human body to ensure tissue homeostasis and function . In vitrrevisiae ), these Somatic cell aneuploidy is implicated in tumorigenesis, genomic instability, tumor evolution, metastasis, drug resistance, and reduced cancer patient survival, whereas germline aneuploidy directly accounts for infertility, pregnancy loss, and developmental disorders . HoweverCell cycle checkpoints are constitutive feedback control mechanisms that delay cell cycle progression until completion of a critical event, providing time for the correction of potential errors . EliminaRecent high-resolution live-cell studies tracking kinetochore or chromosome behavior through metaphase and anaphase in human somatic cells in culture have revealed that many more chromosomes tend to lag behind in anaphase than previously anticipated . This beThe role of anaphase spindle mechanics was first established through the observation that merotelic kinetochores with uneven microtubules facing the poles experience a significant stretch and elongate under tension, eventually favoring segregation to the correct daughter cell. Only a small fraction (<10%) of the merotelic kinetochores that persist through anaphase show an even microtubule ratio facing the poles and result in long-lasting lagging chromosomes that missegregate . Live imMore recently, it was demonstrated that spindle elongation is directly required for anaphase error correction . The acuAurora B kinase activity at centromeres plays a key role in error correction during early mitosis . HoweverTwo possible models have been proposed to explain how a midzone-based Aurora B activity gradient mediates error correction during anaphase . One is An alternative model favors the idea that midzone Aurora B activity mediates anaphase error correction of merotelic kinetochores by assisting the mechanical transmission of spindle forces to a stable kinetochore\u2013microtubule interface on lagging chromosomes . Live-ceDirect measurements of kinetochore\u2013microtubule half-life during anaphase revealed a low kinetochore\u2013microtubule turnover , which wThe finding of a distinct phosphorylation state on Aurora B substrates at kinetochores of anaphase lagging chromosomes suggestsBut why is the spatiotemporal control of NER important? On one hand, preventing premature NER on incompletely separated chromosomes during normal anaphase protects against polyploidy. Whole-genome duplication is a common evolutionary event that is also frequent in >30% of human tumors early in tumorigenesis and is thought to promote chromosomal instability and metastasis by providing a selective advantage in certain contexts . On the One may argue that a delay of just a few minutes in a process that is normally completed within 5\u201310 min in human somatic cells cannot be explained by a robust checkpoint mediated by Aurora B at the spindle midzone. Instead, midzone microtubules may act independently of Aurora B activity by forming a physical barrier that selectively prevents the recruitment of non-core nuclear envelope proteins , includIn an attempt to separate the role of microtubules from that of Aurora B at the spindle midzone in the spatiotemporal control of NER, high-resolution live-cell microscopy was used to simultaneously monitor Aurora B activity on chromosomes, the recruitment of NPC proteins, and the distribution of spindle midzone microtubules throughout anaphase, upon manipulation of Aurora B midzone localization . These eQuantitative microscopy analyses further revealed that even just a small but significant delay in the completion of NER relative to the main segregating chromosome masses allows most anaphase lagging chromosomes in human cells to gradually correct and move away from the spindle midzone. Moreover, this delay depended on the establishment of a midzone-based Aurora B phosphorylation gradient that prevented formation of micronuclei . TherefoConcerning potential targets involved in the spatiotemporal regulation of NER, Aurora B may regulate Condensin I removal and/or recruitment of HP1 and LBR as chromosomes separate during anaphase or may mAnaphase lagging chromosomes that escape surveillance and correction mechanisms operating in anaphase rarely missegregate to give rise to aneuploidy, but they may lead to the formation of micronuclei . ImportaMicronuclei derived from chromosome segregation errors have four possible outcomes upon mitotic exit: (1) persistence as independent structures; (2) reincorporation into the main nucleus; (3) degradation; or (4) extrusion sensor that mounts a type-I IFN innate immune response through its adaptor protein STING, referred to as the cGAS-STING pathway . The actGiven the possible role of p53 in limiting the proliferation of aneuploid and micronucleated cells, an outstanding question is whether the cGAS-STING pathway somehow crosstalks with p53. Recently, a mutant form of p53 was shown to suppress innate immune signaling through the cGAS-STING pathway, resulting in immune evasion and tumor progression . In thisWhile a lot remains to be known regarding the mechanisms underlying cGAS-STING\u2013mediated immunosurveillance of mitotic errors and their respective implications for tumor evolution, defective micronuclei are now well established as potential hubs for chromothripsis . ChromotWhile the high rates of aneuploidy during female meiosis have been linked to a weakened SAC and intrinsically unstable kinetochore\u2013microtubule attachments , aneuploIn addition to direct missegregation from misaligned chromosomes, late-aligning chromosomes associated with peripheral nuclear positioning during interphase are also more prone to lag behind in anaphase and missegregate at higher frequencies . LikewisOverall, these recent findings instigate future studies to determine the underlying mechanisms that normally prevent aneuploidy during mitosis and meiosis, while continuing to evaluate the contribution of aneuploidy-inducing events of different origin and how cells deal with them in health and disease contexts."} {"text": "Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult Caucasian women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Disease rarity and wide geographic patient distribution has previously limited substantive mechanistic investigation into iSGS pathogenesis.By harnessing pathogenic mucosa from an international iSGS patient cohort and single-cell RNA sequencing, we unbiasedly characterize the cell subsets in the proximal airway scar and detail their molecular phenotypes. Results show that the airway epithelium in iSGS patients is depleted of basal progenitor cells, and the residual epithelial cells acquire a mesenchymal phenotype. Observed displacement of bacteria beneath the lamina propria provides functional support for the molecular evidence of epithelial dysfunction. Matched tissue microbiomes support displacement of the native microbiome into the lamina propria of iSGS patients rather than disrupted bacterial community structure. However, animal models confirm that bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity. Human samples from iSGS airway scar demonstrate adaptive immune activation in response to the proximal airway microbiome of both matched iSGS patients and healthy controls. Clinical outcome data from iSGS patients suggests surgical extirpation of airway scar and reconstitution with unaffected tracheal mucosa halts the progressive fibrosis.Our data support an iSGS disease model where epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. These results refine our understanding of iSGS and implicate shared pathogenic mechanisms with distal airway fibrotic diseases. Idiopathic subglottic stenosis (iSGS) is a rare but devaHistologically, iSGS cases show pronounced fibrosis restricted to the proximal airway mucosa . DiverseIn iSGS the functional alterations underlying airway remodeling remain poorly understood. In this study, we harnessed tissue samples from an international iSGS patient cohort and cutting-edge molecular tools to define the molecular phenotype of the proximal airway mucosa at single-cell resolution. Our results provide an unbiased assessment of the cell types within the normal human subglottis and illuminate the changes accompanying iSGS. The results suggest epithelial barrier dysfunction and immune infiltration are key components of iSGS pathogenesis. Matched superficial and deep tissue microbiomes support displacement of the native microbiome into the lamina propria of iSGS patients rather than disruption of bacterial community structure. However, animal models confirm that bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity in remodeling after mucosal injury. Clinical data support the role of epithelial dysfunction in treatment response. Our data suggests that in iSGS the native microbiome is displaced across a dysfunctional epithelial barrier leading to an adaptive immune response which drives obstructive airway fibrosis. These novel results reshape our understanding of iSGS, implicate shared pathogenic mechanisms with distal airway fibrotic diseases, and open new avenues for therapy.Supplemental Table T1) and performed scRNAseq using the 10x Genomics Chromium platform . The samples were collected and processed at two different sites ; however, both sites collected cases and controls. To maximize our ability to identify rare cell populations, we jointly analyzed data from all samples. We defined inclusion criteria for cells based on observations from the entire dataset, removed low-quality cells accordingly, applied normalization and variance stabilization of the 25,974 recovered cells using Seurat. Initially one small CD8 effector T cell population was grouped together with a larger CD8 T effector population due to observations that cell cycle activity was driving distinct cluster identity. All cell types were identified both in airway scar and healthy mucosa. Notably, we did not observe overt batch effects driven by processing site or sequencing batch in our dimensionality reduction and visualization . Cell types/states were also manually grouped into 4 broad tissue classes based on their identity . Quantification of cell types demonstrated significant differences between iSGS airway scar and matched healthy mucosa controls. Airway scar showed significantly more Immune cells and significantly fewer epithelial cells . When grouping cells into their tissue layer, the epithelium demonstrated significantly more DEG than immune cells . In addi< 0.001) (DEG: P = 0.007) . The dif= 0.007) .Supplemental Figure S4). Gene ontology (GO) pathway analysis supported the Hallmark geneset EMT findings; iSGS airway scar showed enrichment for mitochondrial matrix genes . In parallel, proliferating epithelial cells in iSGS airway scar showed down-regulated glycosylation and junctional protein complexes . Both aerobic respiration and loss of cell-cell adhesion are consistent with EMT.Molecular and functional evidence of epithelial dysfunction in iSGS scar. We further analyzed the epithelial clusters and idenTo provide functional evidence of epithelial barrier dysfunction, we investigated if native bacterial displacement into the deeper lamina propria was a unique feature of iSGS. Employing fluorescence in situ hybridization (FISH) with the pan-bacterial probe, Eub338, we investigated if mucosal biopsies from iSGS and healthy controls evidenced bacteria in the deep layers of the proximal airway mucosa. Representative FISH stains show iSGS mucosa possessed signal for bacteria in the deeper lamina propria while healthy control did not . In a seCharacterization of the mucosal microbiome in iSGS. Given the observed bacterial displacement into the lamina propria of the airway mucosa, we investigated if alterations in microbiome community structure were also observed in iSGS. We first quantified the number of 16S rRNA gene copies in deep tissue biopsies via qPCR . We deteSupplemental Figure S6). The majority of bacterial species present in healthy subglottis were consistent with the established healthy lung microbiome composed of supraglottic predominant taxa . Using ptococcus).Supplemental Fig. 7A) nor between disease severity and alpha diversity or richness .Additional microbial community structure testing using established diversity and richness indices confirmed no detectable differences between iSGS, iLTS and healthy controls. ANOVA testing of alpha diversity and richness .Anatomic location of bacterial species in iSGS mucosal scar. To validate our findings and explore if superficial and deep tissue sampling methods produced unique bacterial communities, we next compared published 16S rRNA sequencing data of superficial swabs of iSGS scar (n = 5) with ourSupplemental Fig. 8). As expected, wild-type mice developed mucosal inflammation and significant thickening of the lamina propria 14 days after injury . Interestingly however, no significant thickening of the lamina propria was observed when using either germ-free mice , or severe combined immunodeficient mice (SCID) lacking ce (SCID) & B.eff cells in scar , along with more CD4 + Treg and more NK cluster 2 cells . In contrast, the NK cluster 1 population was significantly reduced in scar .The native proximal airway microbiome generates an antigen-specific immune response in infiltrating CD4 + and CD8 + T cells. In order to probe the function of the observed immune infiltrate, tissue biopsies acquired during the operative endoscopy of 5 unique iSGS patients were used to create fresh single-cell suspensions as described. Suspensions were rested for 6 hours, then cultured in the presence of a matched iSGS airway microbiome, the microbiome from an unrelated healthy subject, or left untreated.After 24 hours of stimulation, cells were washed and stained for markers of T cell activation (CD154) and analyzed via flow cytometry . For CD4Clinical data suggest that restoring epithelial barrier function is associated with a more durable treatment response. Treatment outcomes of iSGS patients in an ongoing cohort study demonstrIdiopathic subglottic stenosis (iSGS) is a debilitating localized fibrosis of the proximal airway. Affected patients possess tightly conserved clinical demographics, histopathology, and physiologic impairment . Our humThe pseudostratified epithelium lining the human airway comprises several distinct populations of cells with specialized effector functions. Airway epithelium and the overlying mucociliary layer maintain a physical barrier against environmental insults . Many primary respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, and idiopathic pulmonary fibrosis (IPF), display substantial pathological alterations in the airway epithelium. Evidence suggests that impairment of the epithelial barrier allows bacteria to penetrate the overlying mucociliary layer, intercalate within the epithelium, and activate host immunity. When sustained inappropriately, this inflammation can culminate in fibrotic tissue remodeling and physiologic impairment.in vitro human data and genetic evidence suggest that the airway epithelium plays a central role in disease susceptibility of the residual epithelial cells showed a mechanistic target of rapamycin (mTORC1) pathway activation and enhanced aerobic metabolism. mTOR is a master sensor that integrates environmental factors to regulate cell growth. In general, activation of mTOR stimulates proliferation, mitochondrial biogenesis, and oxidative phosphorylation . The GESAlthough an often-overlooked anatomic subsite, the subglottis is uniquely enriched in antigen-presenting dendritic cells and T lymphocytes . AdditioPrior small case series examining environmental factors contributing to iSGS have implicated disruption of the proximal airway microbiome, one using pathogen-specific molecular approaches, and anoHowever, the displaced microbiome may not be the sole target of the adaptive immune response observed in iSGS mucosal scar. A feed-forward inflammatory loop may become established when peptides from microbial proteins share suffi cient structural similarity with self-peptides and activate autoreactive T cells, termed \u201cmolecular mimicry\u201d. InflammAlthough we acknowledge the limited ability to assign causality in pathologic studies involving human tissue, single-cell transcriptional profiling provides an unbiased assessment of the cell types within the human subglottis and illuminates the epithelial and immune alterations accompanying disease. Histologic localization of pathogens deep in the lamina propria and bacterial community profiling support the functional impact of the observed epithelial dysfunction rather than suggest microbiome disruption is a primary driver of disease. Animal models confirm the importance of both bacteria and host immunity in the pathogenesis of airway fibrosis after epithelial injury and robust clinical data suggests restoring the epithelial barrier with healthy mucosa minimizes disease recurrence.Despite the inherent limits involved in rare disease research, our findings dramatically shift our concept of iSGS disease pathogenesis . UnbiaseDetailed experimental methods are included in the Supplemental Material."} {"text": "Integrating robotics into orthopedic healthcare represents a transformative paradigm shift driven by technological advancements. This editorial explores the profound impact of robotics on the diagnosis, treatment, and rehabilitation of musculoskeletal conditions. Robotics redefines precision in orthopedic surgery through advanced imaging and real-time feedback, resulting in minimized disruption to tissues and faster recovery. Personalized treatment plans leverage robotics' capabilities to tailor procedures to individual anatomical characteristics, enhancing outcomes and reducing complications. Minimally invasive procedures, facilitated by robotics, mitigate trauma and expedite patient recovery. This collaboration between surgeons and robotic systems enhances precision without supplanting human expertise. Moreover, robotics extends to postoperative rehabilitation, utilizing exoskeletons and motion-capture systems to optimize mobility and strength recovery. While challenges of cost and training exist, proactive collaborations are shaping the future of robotics in orthopedic care. Ethical considerations underline the importance of balancing human intervention with robotic assistance. As robotics evolves, orthopedic healthcare embraces a future where technology and human expertise synergize, ultimately conquering musculoskeletal conditions. In recent years, the realm of healthcare has been undergoing a transformative journey fueled by remarkable technological advancements. Among the most impactful areas experiencing this revolution is orthopedic healthcare, where robotics catalyzes a paradigm shift in approaching the diagnosis, treatment, and rehabilitation of musculoskeletal conditions. As the symbiotic relationship between robotics and orthopedic care continues to evolve, a future brimming with the potential for enhanced precision, swifter recovery times, and overall improved outcomes comes into view.Orthopedic conditions, an extensive array of musculoskeletal disorders, have long posed challenges due to the intricate complexity of human anatomy and the delicate nature of bone and joint structures. Robotics' assimilation into orthopedic care has introduced a new dimension, addressing these challenges with unprecedented precision and efficacy.Robotic systems revolutionizing orthopedicsSeveral robotic systems have emerged as game-changers in orthopedic surgery, each offering unique features and benefits.MAKO Surgical SystemThe MAKO system is renowned for its application in joint replacement surgeries. Advanced imaging and real-time feedback assist surgeons in precise bone preparation and implant positioning, resulting in improved alignment and joint function. Its haptic feedback mechanism aids in accurate bone resection. MAKO utilizes computed tomography (CT) scans to create patient-specific 3D models. Surgeons plan implant placement virtually, ensuring optimal alignment. The robotic arm is guided by the surgical plan in the operating room and provides haptic feedback to prevent excessive bone resection. Surgeons retain control while benefiting from enhanced accuracy.ROSA ROSA is widely utilized in neurosurgery and spine procedures. Its features include real-time intraoperative data, image guidance, and robotic arms for enhanced surgical precision. ROSA facilitates minimally invasive surgeries and assists in complex spinal deformity corrections. ROSA integrates with various imaging modalities\u00a0like CT and X-ray, to create a comprehensive surgical plan. It assists in cranial and spinal surgeries by providing real-time data, enabling precise targeting and trajectory planning. The system's robotic arms are guided by the surgeon's commands, enhancing procedural accuracy.NAVIO Surgical SystemNAVIO offers robotics-assisted procedures in orthopedics, focusing on knee surgeries. It employs intraoperative planning and a handheld robotic-assisted tool for precise bone resurfacing. NAVIO's image-free registration enhances accuracy and outcomes in knee arthroplasty. NAVIO operates without preoperative imaging, utilizing a computer-assisted tool for intraoperative planning. Surgeons use tactile guidance to create a patient-specific plan and execute bone resurfacing accurately. This system enhances implant alignment, potentially improving implant longevity and patient satisfaction.Stryker Mako Total Hip Arthroplasty SystemThe Stryker Mako total hip arthroplasty system (Stryker) is tailored specifically for total hip arthroplasty. It provides a combination of 3D preoperative planning and robotic arm assistance during surgery. Surgeons benefit from real-time feedback, facilitating accurate acetabular cup positioning and leg length restoration. This system combines preoperative planning with intraoperative robotic assistance. Surgeons use a handheld robotic arm to prepare the acetabulum and place the cup precisely. Real-time feedback ensures accurate leg length restoration and hip offset, minimizing complications.RAS (Robotic Arm System) in Spine SurgeryRAS systems are designed to enhance the accuracy of pedicle screw placement in spine surgeries. They utilize advanced imaging and robotic arms to guide surgeons in complex procedures, reducing the risk of nerve injury and revision surgeries. RAS employs advanced imaging and navigation to guide robotic arms for pedicle screw placement. Surgeons create a preoperative plan, and the robotic arm assists in accurate trajectory execution. This reduces radiation exposure, enhances accuracy, and potentially reduces revision surgeries.TM Robotic Guidance SystemMAZOR X Stealth EditionThe MAZOR X Stealth\u2122 Edition robotic guidance system offers both preoperative and intraoperative planning capabilities. With features like customizable implant options, optimal trajectories for implants, and advanced 3D analytics, this planning functionality empowers surgeons to enhance construct optimization and achieve a more predictable surgical procedure. The foundation of robotic precision lies in cutting-edge registration and mechanical stability. The MAZOR X\u2122 platform establishes a closed-loop connection between the robotic arm mounted on the operating table, the securely positioned patient, and a rigid link between the robot and the patient's skeletal structure. This robotic system is table-mounted, optimizing the operating room space while ensuring unparalleled precision. The Stealth\u2122 Navigation technology provides real-time visualization of implant placement within the patient's anatomy, aligning with the pre-operative plan. By seamlessly integrating two guidance technologies into a comprehensive platform, surgeons can confidently execute procedures during surgery, effectively bridging the gap between planning and execution. The navigation feature offers the visibility required to complete the surgical plan. With an accuracy rate of up to 100%, the MAZOR X Stealth\u2122 Edition ensures precise screw placement.Precision redefinedAmong the most compelling contributions of robotics to orthopedics is its capacity to elevate surgical precision. Conventional surgical techniques often hinge on the surgeon's manual dexterity, leaving room for inadvertent errors. Robotic systems, fortified with advanced imaging and real-time feedback mechanisms, empower surgeons to meticulously plan and execute procedures with a degree of accuracy measured in sub-millimeters . This lePersonalized treatment plansIntroducing robotics in orthopedic surgery marks a revolutionary phase in tailored treatment plans. Robotic systems enable surgeons to intricately strategize procedures that cater to each patient's unique anatomical characteristics . This hiMinimally invasive proceduresRobotics has been instrumental in fostering the proliferation of minimally invasive procedures within orthopedics . ConventAdvantages of robotic systems in orthopedicsThe following are the advantages of\u00a0robotic systems in orthopedics.Enhanced precision: Robotic systems offer unmatched precision and accuracy in executing surgical tasks, leading to improved implant alignment and surgical outcomes.Personalized treatment: Robotic platforms allow for the customization of surgical procedures based on each patient's unique anatomy, potentially reducing complications and improving long-term outcomes.Minimized tissue trauma: Robotic-assisted procedures often require smaller incisions and result in less disruption to surrounding tissues, leading to reduced postoperative pain and faster recovery times.Improved implant placement: Robotic systems enable precise implant positioning, potentially increasing implant longevity and patient satisfaction.Real-time feedback: Many robotic platforms provide real-time feedback to surgeons during procedures, allowing for adjustments and ensuring optimal outcomes.Complex maneuvers: Robotic arms can execute complex maneuvers that might be challenging for a human hand, enhancing the surgeon's capabilities.Reduced radiation exposure: In procedures such as spine surgery, robotics can reduce the need for fluoroscopy, leading to lower radiation exposure for both patients and surgical staff.Disadvantages of robotic systems in orthopedicsThe following are the disadvantages of\u00a0robotic systems in orthopedics.High initial costs: Robotic systems require substantial investments in terms of equipment and training, potentially increasing the overall cost of procedures.Learning curve: Surgeons need to undergo specialized training to operate robotic systems effectively, and the learning curve can initially extend procedure times.Limited flexibility: Robotic systems follow preplanned trajectories, which might limit the surgeon's ability to make spontaneous adjustments during the procedure.Dependency on technology: Technical malfunctions or software glitches could interrupt surgeries or lead to suboptimal outcomes, highlighting the system's reliance on technology.Time-consuming setup: Setting up the robotic system and registering patient data can add time to the overall surgical process, especially during the learning phase.Complexity of integration: Integrating robotic systems into existing surgical workflows might be challenging and require adjustments in hospital processes.Ongoing maintenance and costs: Beyond the initial investment, robotic systems require maintenance, software updates, and potential hardware upgrades, leading to ongoing costs.Surgeon-support collaborationA fundamental tenet of understanding robotics in orthopedics is that it augments, rather than supplants, the role of surgeons. Robotic systems are invaluable tools, furnishing real-time insights, haptic feedback, and unparalleled visualization during procedures. Surgeons retain complete control while benefiting from the precision and data-driven guidance offered by the robotic platform . This coPostoperative rehabilitationThe impact of robotics resonates beyond the confines of the operating room, extending to the rehabilitation phase. Robotics-assisted rehabilitation devices, including exoskeletons and motion-capture systems, are revolutionizing how patients regain mobility and strength after orthopedic procedures . These dChallenges and ethical considerationsWhile integrating robotics into orthopedic healthcare holds great promise, it concurrently presents challenges and ethical considerations. The initial expenses associated with procuring and implementing robotic systems can be substantial, engendering concerns about accessibility and healthcare inequities. Furthermore, specialized training to proficiently operate these systems necessitates ongoing education and skill development investments. Ethical dilemmas arise in cases where the equilibrium between human expertise and robotic assistance is at issue. Striking the right balance between surgeon intervention and robotic autonomy necessitates meticulous deliberation. The focus should invariably remain on safeguarding patients\u2019 well-being and ensuring that the benefits of automated technologies outweigh any potential risks.The path aheadAs the realm of robotics in orthopedic healthcare continues its expansion, a proactive and visionary approach is indispensable. Collaborative endeavors involving engineers, medical practitioners, and regulatory authorities are pivotal in refining existing technologies and conceiving novel solutions that cater to the evolving needs of patients. Investments in research and development will be instrumental in fostering innovation, thereby propelling the creation of even more sophisticated robotic systems capable of redefining the boundaries of orthopedic care.Integrating robotics into orthopedic healthcare marks a watershed moment in the medical arena. Its precision, personalization, and minimally invasive approach reshape the landscape of orthopedic procedures, offering patients renewed hope and an enhanced quality of life. As the medical community, policymakers, and technology innovators navigate the challenges and ethical considerations, the collective responsibility lies in shaping a future where robotics and human expertise harmoniously converge, redefining the horizons of orthopedic healthcare. With each surgical procedure and rehabilitation session, robotics propels us closer to a world where musculoskeletal conditions are not merely treated but unequivocally conquered."} {"text": "To describe clinical features and the course of a case of non-necrotizing herpetic retinitis secondary to Varicella zoster virus (VZV).A single case report documented with multimodal imaging.A 52-year-old female patient with a past medical history of diabetes mellitus who presented with painful red right eye (OD). Ophthalmic examination showed perilimbal conjunctival nodule, granulomatous anterior uveitis, sectoral iris atrophy and increased intraocular pressure. Fundus examination in OD revealed posterior multifocal retinitis. Left eye examination was unremarkable. Polymerase chain reaction (PCR) of aqueous humor sample confirmed the presence of VZV DNA. Systemic antiviral therapy allowed the improvement of intraocular inflammation and disappearance of the retinal non necrotizing retinitis after one year of regular follow-up.Non-necrotizing retinitis is an underdiagnosed form of VZV ocular infection. Herpesviridae are common worldwide. Among the spectrum of viral retinitis, acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), and Cytomegalovirus (CMV) retinitis are the most severe and sight threatening viral infections [Viral infections due to fections . Besidesfections . The purA 52-year-old female with a past medical history of diabetes mellitus, presented with progressive pain, redness and vision loss of the right eye (OD). Her best corrected visual acuity (BCVA) in OD was 20/200 and 20/20 in the left eye (OS). Anterior segment examination of OD showed a perilimbal nodular conjunctival lesion, granulomatous anterior uveitis with sectoral iris atrophy Fig.\u00a0. IntraocCase reports of NNHR have been described in five patients with positive test results for HSV or VZV in AH who had non-necrotizing retinitis consisting mainly of vasculitis, papillitis, or vitritis . Other cPCR was shown to be a powerful technique that allows detection of small quantities of DNA and RNA in ocular fluids. Various infectious agents can be detected with high specificity and sensitivity, including viruses. Results of PCR analysis of ocular fluids, being available within 24 to 48\u00a0h, have greatly improved the diagnosis of ocular viral infections, particularly those caused by human herpesviruses. AH analysis was contributory in 86.4% of patients with necrotizing viral retinopathies . BodaghiThe viral retinitis described in our patient is different from most cases of atypical viral retinitis reported in the literature, but resembles the cases reported by Hazirolan et al., with retinal lesions that are smaller and focally situated at the posterior pole without progression with antiviral treatment .The underlying reason for the variable clinical manifestations and severity of herpetic posterior uveitis is unknown but could be, in addition to pathogen-related factors, influenced by the variation in patients\u2019 immune capacity. Bodaghi et al. hypothesized that necrotizing herpetic retinitis were due to an intracellular presence of the virus with subsequent cytopathic damage, whereas the NNHR were assumed to be associated with tissue damage based on immunological processes . WensingHazirolan et al. suggested that viral retinopathies might constitute a continuous spectrum of diseases, which clinical presentations depend on the patient\u2019s immune status. Our patient, as well as theirs, with focal posterior non-necrotizing viral retinitis may be located at the starting point of the spectrum of herpetic retinopathies and constitute the mildest form of the disease . HoweverA remission was obtained in all cases after reaching the proper etiological diagnosis and initiating antiviral treatment. Oral acyclovir is mostly used for 6\u00a0weeks , but thiAlbert et al. reported several recurrences after arrest of antiviral treatment, it was the first case of anterior uveitis recurrence after NNHR described in the literature . Long-stFuture studies including a larger number of NNHR patients could reveal characteristics we were unable to identify here. The differential diagnosis of atypical viral retinitis is difficult clinically as it can mimic various other retinal conditions. In agreement with the previous studies, we propose viral analysis of ocular fluids in patients with retinitis, even in the absence of retinal necrosis, before initiation of immunomodulatory therapy and/or in those patients whose symptoms worsen while undergoing immunomodulatory treatments.Varicella zoster virus can cause a wide spectrum of clinical manifestations ranging from severe ARN to slow-progressing necrotizing and non-necrotizing types of inflammation. Non-necrotizing herpetic retinitis are currently underdiagnosed. PCR analysis of ocular fluids along with multimodal imaging could contribute to the confirmation and thus an earlier recognition of the diagnosis and the initiation of appropriate therapy."} {"text": "A review exploring biological, chemical, and physiological processes that occur between aboveground plant components and belowground (rhizosphere) networks that may be altered due to waterlogged conditions. Above- and belowground linkages are responsible for some of the most important ecosystem processes in unmanaged terrestrial systems including net primary production, decomposition, and carbon sequestration. Global change biology is currently altering above- and belowground interactions, reducing ecosystem services provided by natural systems. Less is known regarding how above- and belowground linkages impact climate resilience, especially in intentionally managed cropping systems. Waterlogged or flooded conditions will continue to increase across the Midwestern USA due to climate change. The objective of this paper is to explore what is currently known regarding above- and belowground linkages and how they impact biological, biochemical, and physiological processes in systems experiencing waterlogged conditions. We also identify key above- and belowground processes that are critical for climate resilience in Midwestern cropping systems by exploring various interactions that occur within unmanaged landscapes. Above- and belowground interactions that support plant growth and development, foster multi-trophic-level interactions, and stimulate balanced nutrient cycling are critical for crops experiencing waterlogged conditions. Moreover, incorporating ecological principles such as increasing plant diversity by incorporating crop rotations and adaptive management via delayed planting dates and adjustments in nutrient management will be critical for fostering climate resilience in row-crop agriculture moving forward. Above- and belowground linkages have long been identified as critical for numerous ecological processes in both natural and managed systems . The mosGlobal change biology influences above- and belowground interactions, altering chemical, biological, and physiological processes and overall plant survival in natural landscapes. Climate stress can drastically alter biogeochemical cycles due to shifts in biomass allocation, whereby plants often allocate more resources belowground . From a 2 of land globally had a greater rate of mycorrhizal colonization, greater alkaline phosphomonoesterase-producing bacteria, and greater overall abundance of bacterivorous nematodes relative to the native species in a mixed polyculture community. This demonstrates that invasives are able to exploit available nutrients by fostering bacteria\u2013nematode interactions more efficiently than their counterpart native species. As climatic extremes such as flooding and drought increase, exploitation of resources and alteration of chemical and biological processes by invasive species will only continue , though the degree of the flooding effect was greater for some taxa than others suggesting variability in their tolerance levels . Successful weed control in corn was determined to need 5\u201310 cm precipitation within 15 d of application to effectively incorporate herbicides and facilitate \u00aduptake by weeds or winter barley (Hordeum vulgare) should be considered. These crops will all be in the ground with living roots during the winter months prior to any extreme precipitation that might impact the growing season. Small-seeded brassica species such as camelina, carinata, and most recently oilseed pennycress may also have utility as a winter annual option. Inclusion of these species into rotations with altered growth habits, nutritional content, and low C:N components may further influence above- and belowground cycling dynamics. Extending crop rotations and including three or more species often enhances soil C accumulation has been developed and marketed as Perennial Kernza\u00ae. Kernza has been shown to drastically reduce nitrate leaching and improve soil health . The goal of perennial grain production is to develop a crop that can compete with annual crops but delivers ecosystem services like perennials found in nature due to deep and extensive root systems. For example, intermediate wheatgrass , though it is unclear ultimately how or when these webs will begin to stabilize and what the ultimate influence will be on the ecosystem. Species shifts in weed populations are anticipated, and existing methods for control may be less effective under extreme weather conditions. Adaptive management in row-crop agriculture, including increased biodiversity and perenniality that bolsters trophic interactions and nutrient balance, will be critical within flooded agroecosystems to mitigate the level of destabilization that is anticipated. Furthermore, we have demonstrated major areas in research especially in regard to rhizosphere processes, including plant\u2013microbe interactions that may foster climate resilience within cropping systems. More research addressing both above- and belowground responses to flooded conditions and how these influences crop productivity and ecosystem function within agroecosystems is needed. Lastly, breeders should consider above- and belowground linkages when identifying key traits for flood-tolerant cultivars."} {"text": "Nature depicted the genomic differences between late-stage treated metastatic cancers and early-stage untreated primary cancers via a pan-cancer whole-genome sequencing (WGS) analysis.1 This study characterizes unique features of metastatic solid tumors and provides a valuable resource for further investigating tumor evolution and treatment resistance.Recently, a study by Edwin Cuppen\u2019s group published in 2 about 90% of cancer-related death can be attributed to advanced metastatic diseases, and unfortunately, most are incurable by aggressive treatment regimes.3 Therefore, it is important to identify genome differences between metastatic and primary tumors and evaluate their influence on treatment resistance. This may help in understanding and leveraging therapeutic interventions, thus to create more effective therapeutic regimens. The study by Edwin Cuppen and colleagues established a harmonized WGS dataset of 7108 tumor samples from 71 cancer types, including more than 4700 metastatic cancer samples from Hartwig Medical Foundation (Hartwig) dataset and more than 2300 untreated primary cancer samples from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , including single-base substitutions (SBSs), double-base substitutions (DBSs) and indels (IDs). This result indicates that TMB does not inevitably reflect the status of cancer progression, and the entire mutation spectrums are formed before or during primary cancer progression. Further comparison of mutational process activity revealed the existence of exogenous (such as exposure to platinum or radiation-based treatments) and endogenous (such as increase in APOBEC and SBS1 mutation burden) mutational processes that generate TMB differences. By investigating the divergence of SBS1 mutation burden in detail, the authors revealed a highly cancer type-specific SBS1 mutation burden per age. The majority of tumor types showed a prominent enrichment of SBS1 mutations along with age in both primary and metastatic lesions, however, 4 cancer types only displayed increased SBS1 mutation burdens in metastatic cohorts in an age-independent manner.Compared with TMB, an elevated frequency of structural variants (SVs) was noticed in most tumor types included in metastatic cohorts. The underlying genomic instability signatures linked to this phenomenon are TP53 alterations and genome ploidy, which exhibited significant pan-tumor correlations with duplications and deletions, thus likely to play an essential role in SV increase in metastatic cancers. In addition, the researchers found a modest overall increase of driver gene alterations in patients with metastatic cancers. The majority of genetic drivers enriched by cancer metastasis were tumor-type specific, including some well-known driver genes related to resistance to anticancer treatments, whereas 3 genetic drivers exhibited significant enrichment in metastatic cohorts across various cancer types, suggesting that changes in such genes may promote invasiveness via interfering with tumorigenesis hallmarks of pan-cancer. When comparing therapeutically actionable variants for each type of cancer, the authors found that the metastatic cohort had an overall higher proportion of patients with such variants, although the distribution was highly cancer type specific.The presence of treatment-resistant genetic drivers in advanced cancers led the authors to identify therapeutically enriched drivers (TEDs) that were either treatment enriched or exclusively found in a treatment-specific and cancer type-specific manner. Ultimately, 61 TEDs related to 33 therapeutic groups were identified, and most top hits were well-established resistant drivers to anticancer treatments. Notably, TP53 alterations were found to be frequently relevant with multiple treatment resistances, indicating such variants are potential predictive markers for augmented cancer plasticity and aggressiveness instead of the resistance mechanism for a specific tumor type. Overall, TEDs could be found in 53% of patients in metastatic cohort. After excluding TEDs, the raw difference between primary and metastatic tumors will be reduced by 36% in the number of drivers per sample, suggesting that a significant portion of the metastatic-enriched drivers are very likely linked to anticancer treatment resistance.5 Despite the aforementioned contributions, this study was also limited by the usage of distinct laboratory workups and sequencing procedures for the tumor samples from different datasets and the finite sample sizes of some cancer cohorts. Therefore, it is important to enlarge cancer cohorts and further uniform sample collation and sequencing processes to facilitate and validate the present understanding of cancer development. Moreover, genomic alterations are unable to fully elucidate cancer metastasis and resistance, and using the information from tumor microenvironment and additional cancer omics will also be essential for further anatomizing and better understanding the underlying mechanisms.Taken together, this study confirmed previous findings observed in certain cancer types and provided novel biological insights into the unique characteristics of metastatic cancers and their genomic differences with primary tumors, such as low intratumor heterogeneity, high genomic instability and elevated SVs. Nevertheless, the extent of genetic differences between metastatic and primary cancers varied significantly across cancer types and was affected by anticancer treatment exposure. Among the 23 tumor types, breast, clear cell renal cell, thyroid, prostate and pancreatic neuroendocrine cancers showed strong transformation in genomic landscape in advanced stages. In addition, this study provides a valuable resource for further investigating other aspects of cancer progression, such as the study on genetic immune escape alterations between metastatic and primary cancers conducted also by Edwin Cuppen\u2019s group recently."} {"text": "Biomaterials offer numerous opportunities to preserve spheroid function and guide spheroid behavior by tailoring the local microenvironment.Spheroids are three-dimensional cell aggregates that mimic fundamental aspects of the native tissue microenvironment better than single cells, making them a promising platform for the study of tissue development and therapeutics. Spheroids have been investigated for decades as models in cancer research, yet we have only just scratched the surface of their potential clinical utility in cell-based therapies. Like many cells, spheroids commonly exhibit a loss of key attributes upon implantation, motivating the need for strategies to regulate their function Systemic or localized injection of cells results in poor survival and inconsistent behavior due to the lack of instructional cues or aberrant signaling from the diseased microenvironment. As an alternative to monodisperse cells, spheroids are three-dimensional cell aggregates that retain key aspects of the cellular microenvironment including cell-cell interactions, engagement with an endogenous cell-secreted extracellular matrix (ECM), and gradients in signaling that result in heterogeneous nutrient distribution that better recapitulate native tissues. Furthermore, spheroids secrete substantially more endogenous trophic factors that promote neovascularization and influence the inflammatory microenvironment Biomaterials have an essential role in the development and application of spheroid-based technologies. Beyond materials-based approaches for spheroid formation, entrapment of spheroids in tunable biomaterials has emerged as a promising strategy to instruct spheroid function and differentiation and regulate cell migration from the spheroid into the surrounding tissues. The synergistic effects of biomaterial properties and spheroid signaling, although not fully understood, directly influence cytokine production, cell spreading and migration, viability, and differentiation. Thus, intelligent selection of a biomaterial is required and should be taken into consideration to instruct spheroid behavior and achieve the desired therapeutic effect.2Our group has predominantly studied spheroids formed of mesenchymal stromal cells (MSCs) to potentiate their secretion of regenerative trophic factors and guide their direct contributions to tissue formation. Spheroids of other cell types are under investigation, and key factors such as cell type and spheroid diameter are intrinsically related to their desired application. Nonetheless, the interplay of additional environmental cues can affect spheroid function and instruct behavior for specific applications. Spheroid function is regulated by the biophysical properties of the spheroid carrier material or entrapment of other components within the spheroid to guide cell function and differentiation.Spheroid function has been widely controlled by encapsulation in engineered hydrogels and controlling biophysical properties such as adhesivity, stiffness, and viscoelasticity. Alginate hydrogels covalently modified with cell-adhesive RGD (Arg-Gly-Asp) peptides are widely used as model systems and vehicles for cell transplantation. RGD-modification regulated cell adhesion, outgrowth, and tissue formation using MSC spheroids e.g., Yes-associated protein, YAP). These findings demonstrate the potential of cell-based materials to increase biomineralization without the need for exogenous osteoinductive cues or growth factors. Recent advances in macromolecular crowding approaches may open the door to improve growth factor retention and influence other relevant ECM properties such as protein content or fiber alignment Instructive materials can also be incorporated within the spheroid itself to guide cell function. As spheroids initially lack an endogenous ECM, our group formed spheroids with an engineered, MSC-secreted ECM to activate integrin signaling In many applications, it may be necessary to leverage biomaterials that provide structure or regulate spatial patterning to achieve desired tissue formation using spheroids. For example, silicon nanowires were applied to promote differentiation of human induced pluripotent stem cell spheroids (hiPSC) into hiPSC-derived cardiomyocytes for cardiac repair 32) that promote angiogenesis, modulate the inflammatory microenvironment, and stimulate wound repair, and MSC spheroids secrete more trophic factors than monodisperse MSCs. MSC spheroids entrapped in fibrin hydrogels with higher elastic moduli (\u223c45\u00a0kPa) secreted significantly more VEGF, while PGE2 secretion was greater for spheroids in softer gels (\u223c5\u00a0kPa) The MSC secretome is a potent collection of bioactive factors that stimulates host cell migration and tissue repair. MSCs secrete endogenous factors such as vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE4Spheroids have enormous promise for use as building blocks for tissue regeneration. Although initial applications injected spheroids into diseased tissues without supportive biomaterials, substantial evidence confirms the capacity for material-driven approaches to potentiate spheroid function. However, we have yet to create materials that accurately model the complex characteristics and behavior exhibited by many human tissues. The use of biomaterials that mimic the biophysical properties of native tissues will increase the therapeutic potential of spheroids in clinical applications.via ultrasound, light, or delivery of fast-reacting small molecules that rapidly stiffen or weaken the biomaterial. Just as spheroids better recapitulate native tissues by increasing complexity from conventional 2D culture systems, we must embrace the same logic of increased complexity and multilayer design when developing biomaterials. This is made more challenging by the need to maintain biocompatibility. Nonetheless, new materials will propel the effective instruction of cell spheroids and establish them as a powerful tool for regenerative medicine, drug discovery, and disease modeling (The development of biomaterials possessing gradients in stiffness, composition, and soluble cues that imitate the heterogeneity of native tissues is a step in the right direction. These attributes can be enabled by chemistries that facilitate non-invasive tunability modeling .Fig. 1BiThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests:J. Kent Leach reports financial support was provided by UC Davis Health System. David H. Ramos Rodriguez reports financial support was provided by UC Davis Health System."} {"text": "Neuroinflammation is a key secondary event after spinal cord injury (SCI) and can increase barriers to regeneration, leading to various neurological disorders. Infiltrated hematogenous innate immune cells into the injured site are considered the main effector cells of the inflammatory responses after SCI. Glucocorticoids were the standard of care for spinal cord trauma for years due to their anti-inflammatory properties yet were also associated with unwanted side effects. While the administration of glucocorticoids is controversial, immunomodulatory strategies that limit inflammatory responses provide the potential therapeutic approaches to promote functional regeneration following SCI. Herein, we will discuss emerging therapeutic strategies to modulate inflammatory responses to enhance nerve recovery after spinal cord trauma. Traumatic Spinal Cord Injury (SCI) results in an initial primary injury, followed by secondary events including ischemia, anoxia, and excitotoxicity for the first minutes, hours, and days after injury \u20134. As a Various gene therapy-based approaches have been introduced in the last twenty years and continue to be utilized as a powerful therapeutic approach to alter or correct defective genes for the treatment of multiple diseases ,13. WhilNanomedicine employing polymeric nanoparticle (NP) has received significant attention due to its inherent therapeutic potential to modulate immune responses to cure inflammatory responses-mediated disorders including SCI \u201322. PrevStem cells can proliferate and differentiate into any cell type present in the body. Considering their therapeutic potential and abilities of self-renewal and differentiation, stem cells are widely used following SCI ,32. In aImmunotherapeutic approaches for the treatment of SCI have the capacity to indirectly and/or directly enhance functional recovery. Although many preclinical studies have demonstrated therapeutic effects of immunomodulatory factors on SCI, the introduction of these strategies in the clinic faces various limitations for SCI victims. Further investigations will be required to assess how each of the immunomodulatory factors can be employed synergistically to reprogram the immune system to promote functional recovery after SCI while limiting life-threatening side effects."} {"text": "Background: Overall, ~12% of outpatient visits result in an antibiotic prescription, and 30% of those prescriptions are inappropriate. Behavioral nudges help influence practitioner behavior. We hypothesized that peer comparison combined with a behavioral nudge would influence prescribers to reduce antibiotic prescriptions and improve antimicrobial stewardship in the outpatient setting. We pilot-tested this intervention in outpatient primary care clinics associated with a large Veterans Affairs (VA) medical center. Methods: We conducted a clustered randomized controlled trial of 12 community-based outpatient clinics. All practitioners in the intervention arm received quarterly comparative feedback reports and, when indicated, quarterly patient alert letters. Comparative feedback reports gave personalized feedback about antibiotic prescriptions for upper respiratory tract infections, comparing the recipient\u2019s antibiotic prescriptions to the average for all practitioners at the primary care clinics included in our study. Patient alert letters notified practitioners to patients in their panel with recently detected Clostridioides difficile or resistant organism and their antibiotic exposures. We assessed outpatient visits during the preintervention period (April\u2013September 2020), the intervention period (October 2020\u2013September 2021), and the postintervention period (October 2021\u2013September 2022). A mixed-effects logistic regression model predicting antibiotic prescriptions compared the arms across these periods. Results: The outpatient populations observed in the intervention and control arms were similar during each phase of the study. Prior to the intervention, the average proportion of visits with an antibiotic prescription was lower among clinics in the intervention arm . This difference broadened slightly during the intervention period and the postintervention period . Throughout the study, clinics in the intervention arm typically used more doxycycline and azithromycin and less amoxicillin-clavulanate and sulfamethoxazole-trimethoprim compared to clinics in the control arm. . In the 6-month preintervention period, which coincided with the early phase of the COVID-19 pandemic, antibiotic prescriptions in the intervention compared to control clinics were similar. During the intervention and postintervention periods, the proportion of visits with an antibiotic prescription remained steady for clinics in the intervention arm and increased for those in the control arm. These results suggest that this pilot study using a low-intensity intervention consisting of comparative feedback reports and patient alert letters was successful in influencing the antibiotic prescribing behavior of primary care clinicians practicing in community-based outpatient clinics affiliated with a VA medical center.Financial support: This study was funded by Merck.Disclosures: None"} {"text": "Cervical cancer is the fourth-leading cause of cancer incidence and death among females according to Global Cancer Statistics 2018.This video demonstrates the fertility-sparing surgery procedure containing radical trachelectomy and pelvic lymphadenectomy with bilateral ascending branches of uterine arteries preservation. The patient was a 34-year-old woman diagnosed with International Federation of Gynecology and Obstetrics stage IB1 moderately differentiated squamous cervical cancer who expressed a strong desire for reproduction. After sufficient consultation, she decided to receive a fertility-sparing treatment protocol. This video highlights the feasibility of sufficiently dissecting paracervical structures and exposing uterine artery branches with complex procedures and no assistance via TU-LESS. We adopted a simplified uterine manipulator, which minimized the squeezing and injury to the cervix, to assist exposure of the surgical field. Resection of the cervix was accomplished transvaginally with a cold knife to ensure sufficient margin. Pathology examination of surgical margin, lymph node specimens, and lymphovascular invasion were negative. The umbilical incision was closed by Zheng\u2019s anchor suturing technique to prevent incisional complications and improve cosmetics.Minimally invasive surgery is safe and effective for fertility-sparing without compromising oncologic outcomes, especially in patients with a tumor size <2\u2009cm."} {"text": "Bipolar patients (BP) frequently have cognitive deficits, that impact on prognosis and quality of life. Finding biomarkers for this condition is essential to improve patients\u2019 healthcare. Given the association between cognitive dysfunctions and structural brain abnormalities, we used a machine learning approach to identify patients with cognitive deficits.The aim of this study was to assess if structural neuroimaging data could identify patients with cognitive impairments in several domains using a machine learning framework.Diffusion tensor imaging and T1-weighted images of 150 BP were acquired and both grey matter voxel-based morphometry (VBM) and tract-based white matter fractional anisotropy (FA) measures were extracted. Support vector machine (SVM) models were trained through a 10-fold nested cross-validation with subsampling. VBM and FA maps were entered separately and in combination as input features to discriminate BP with and without deficits in six cognitive domains, assessed through the Brief Assessment of Cognition in Schizophrenia.The best classification performance for each cognitive domain is illustrated in Table 1. FA was the most relevant neuroimaging modality for the prediction of verbal memory, verbal fluency, and executive functions deficits, whereas VBM was more predictive for working memory and motor speed domains.Overall, the tested SVM models showed a good predictive performance. Although only partially, our results suggest that different structural neuroimaging data can predict cognitive deficits in BP with accuracy higher than chance level. Unexpectedly, only for the attention and processing speed domain the best model was obtained combining the structural features. Future research may promote data fusion methods to develop better predictive models.None Declared"} {"text": "Sickle cell disease (SCD) is a prevalent inherited hemoglobin disorder encompassing a cluster of congenital hemolytic anemias, each distinguished by the prevalence of sickle hemoglobin (HbS) . Anemia,Numerous novel agents are currently undergoing clinical development or have been introduced into clinical practice. In addition, the attempts to reduce long-term complications and enhance quality of life continue. This Special Issue aims to delineate both our current understanding and future options in SCD. All articles submitted to this Special Issue underwent a meticulous peer review process. Ultimately, two articles, two brief reports and one review were published. These five manuscripts are discussed below.(i)Forte and colleagues provided important data on the timely issue of COVID-19 and SCD, updating outcomes after two years of the pandemic .(ii)Tsitsikas and colleagues presented the rate of dental extractions in SCD, providing up-to-date knowledge on an understudied complication .(iii)Biswas and colleagues reviewed the role of mitochondria as an emerging consequential in SCD, highlighting pathophysiological and therapeutic challenges .(iv)Kuo and colleagues reported that thromboprophylaxis reduced venous thromboembolism in SCD patients with central venous access devices, studying a large retrospective cohort .(v)Gavriilaki and colleagues studied the immune response of adult SCD patients after their vaccination against COVID-19, providing the experience of a Greek center.Considering the multi-faceted challenges of SCD, we hope that this Special Issue will inspire researchers and clinicians to continue their explorations into novel advances in this field ."} {"text": "Artificial intelligence (AI) algorithms have been applied in abundant medical tasks with high accuracy and efficiency. Physicians can improve their diagnostic efficiency with the assistance of AI techniques for improving the subsequent personalized treatment and surveillance. AI algorithms fundamentally capture data, identify underlying patterns, achieve preset endpoints, and provide decisions and predictions about real-world events with working principles of machine learning and deep learning. AI algorithms with sufficient graphic processing unit power have been demonstrated to provide timely diagnostic references based on preliminary training of large amounts of clinical and imaging data. The sample size issue is an inevitable challenge for pediatric oncology considering its low morbidity and individual heterogeneity. However, this problem may be solved in the near future considering the exponential advancements of AI algorithms technically to decrease the dependence of AI operation on the amount of data sets and the efficiency of computing power. For instance, it could be a feasible solution by shifting convolutional neural networks (CNNs) from adults and sharing CNN algorithms across multiple institutions besides original data. The present review provides important insights into emerging AI applications for the diagnosis of pediatric oncology by systematically overviewing of up-to-date literature. The exponentially growing knowledge and techniques have explored innovative perspectives for multi-layered diagnoses in pediatric oncology that the expectation of patients and their families have been developed for their specific situation to receive optimized care instantly and comprehensively. Artificial intelligence (AI) strategies can tackle enormous amounts of original data in a short time to solve complex tasks with high accuracy , 2. PhysAI has developed into various computer-assisted theories and is mainly implemented with working principles of machine learning (ML) and deep learning (DL). AI algorithms fundamentally capture data, identify underlying patterns, achieve preset endpoints, and provide decisions and predictions about real-world events. ML, as a main subset of AI, indicates a different flowchart compared with traditional hard-coded software programs which apply algorithms to construct predictive models dynamically by training large amounts of historical data. DL, as a growing aspect of AI, represents benefits in learnable weights and high efficiency with minimal pre-processing based on the structure of convolutional neural networks (CNNs) with multiple inter-connected layers. DL-CNNs composed of multiple stacked CNN layers have advantages in accurate, faster, vendor-independent processing compared with ML algorithms applied previously . NotablyThe application of AI not only makes full use of the various aspects of clinical diversity but also helps to address the current lack of objectivity and universality in expert systems . The appDespite the current AI advancements, the sustainable development of health AI tools relies on the availability of large datasets with strict quality control . SeveralThe prosperous development of AI techniques promotes numerous potential applications in pediatric oncology with two main bottlenecks for successful utilities, including the need for large data entry and a strong graphic processing unit (GPU) with appropriate computer and memory power. AI algorithms provide timely references based on large amounts of clinical and imaging data and sufficient GPU power . MeanwhiClinicians make clinical diagnoses depending on their professional knowledge and clinical experience through signs, symptoms, laboratory, and imaging examinations. It seems hard to guarantee diagnostic accuracy and consistency by dealing with abundant and multidimensional data from the human brain. The AI algorithms have advantages in learning and training vast amounts of data and integrating it into a certain outcome in a very short time, which allows efficiency and effectiveness of computer-aided diagnosis (CAD) in clinical practices. DL algorithms have recently made significant progress in extracting and processing information from medical images, which have been applied in various medical tasks extensively not only in radiology and pathology with satisfactory performance comparable to or even superior to that of human experts. Notably, DL algorithms could identify underlying information from medical images associated with tumor diagnosis . The AI A performance comparison of diagnosis in pediatric hematological malignancies using AI strategies is shown in A performance comparison of diagnosis in pediatric intracranial tumors using AI strategies is shown in versus non-tumor/hemorrhagic and classify subtypes of brain tumors.Attallah , 43 propversus benign diseases [AI techniques have been applied in the diagnosis of pediatric extracranial tumors, mainly including soft-tissue and bone tumors . For bondiseases , 54. TheZhang et al. and FranAI-based principles have been used for the detection and segmentation of pediatric malignant tumors. For example, Wu et al. used a rH3 K27M amplification status in children with midline glioma with significantly greater accuracy ranging from 0.788 to 0.867 than prediction by chance. Giwa et al. [The AI algorithms have represented strengths in detecting tumor patterns by identifying underlying genetic and molecular characteristics associated with specific macroscopic tumor features based on medical images and/or high-throughput data. Zhao et al. reporteda et al. applied The application of AI technology faces some important challenges that must be resolved to ensure its use in pediatric cancer diagnosis . For exaAI techniques have revolutionized the diagnostic field of oncology. Although AI approaches have been widely implemented in adult tumors, specialized applications of AI algorithms in childhood cancer are still limited probably attributed to the insufficient amounts of available data sets. There are limited opportunities to transfer well-trained CNN architectures built on adults into pediatric oncology few CNNs are directly generalizable from adults to children. Therefore, it\u2019s warranted urgently to develop dedicated AI algorithms applied in pediatric oncology. Although the data sets of pediatric oncology are not large enough to perform standardized DL analysis in medical imaging , the int"} {"text": "The purpose of this report is to provide a comprehensive account of an exceptional case involving the presentation of congenital rubella syndrome (CRS) in a newborn. Furthermore, it aims to document the successful regression of CRS through medical treatment alone. We present the case of a five-day-old infant who was referred to our facility as a CRS case. The patient presented with bilateral white corneal opacity, which was observed shortly after birth. The mother was diagnosed as rubella-positive during pregnancy. Upon the initial examination under anesthesia, both eyes exhibited central white corneal opacity accompanied by large intrastromal cysts. Although a few breaks in Descemet's membrane were observed in both eyes, there were no signs of vascularization or the presence of iridocorneal or lenticular-corneal adhesions. After undergoing medical treatment consisting of topical sodium chloride and steroids, the cysts in both eyes completely regressed. Subsequently, the patient underwent penetrating keratoplasty to further address the dense scar. This case enhances our comprehension of ophthalmological complications associated with CRS and provides valuable insights into alternative therapeutic approaches for corneal stromal cysts. Congenital rubella syndrome (CRS) is a prevalent congenital infection known for its wide range of severe ophthalmic and systemic complications . It typiA five-day-old male infant with a confirmed diagnosis of CRS was referred to our facility for examination due to the presence of white corneal opacification in both eyes. The patient's mother also had a confirmed diagnosis of reactive rubella during pregnancy. Upon the initial examination under anesthesia, both eyes exhibited central white corneal opacity along with large intrastromal cysts. Although a few breaks in the Descemet membrane were identified in both eyes, no signs of neovascularization or iridocorneal or lenticular-corneal adhesions were observed Figure . UltrasoCRS is a prevalent congenital infection characterized by various clinical manifestations, including heart defects, hearing impairments, and ophthalmological abnormalities . The mosIn conclusion, this case study brings attention to the infrequent presentation of corneal stromal cysts in a newborn with CRS, emphasizing the importance of identifying uncommon ophthalmological manifestations associated with CRS. The effective nonsurgical management of corneal stromal cysts demonstrates a noninvasive treatment option. This case contributes to a broader understanding of ophthalmological complications and provides valuable insights into alternative therapeutic approaches for corneal stromal cysts."} {"text": "The objective was to study clinical cases and understand the link betweencesarean section scar defect with hydrometra and secondary infertility. Aretrospective case series from an assisted reproductive center and infertilitytreatment clinic in the United Arab Emirates. We had five patients withsecondary infertility diagnosed with cesarean section scar defect withpersistent hydrometra based on high resolution transvaginal ultrasoundassessment. The patients underwent surgical repair for the cesarean section scardefect followed by infertility treatment. Transvaginal ultrasound examinationshowed a normal endometrial cavity with triple lining endometrium and absence ofhydrometra; and clinical pregnancy was the main outcome measure. Surgicalcorrection of cesarean section scar defect was successfully performed in thecases presented. The patients had their fertility restored. Clinical studiesrevealed that cesarean section scar defect may lead to abnormal uterinebleeding, dysmenorrhea, pre-/post-menstrual spotting, heavy or prolonged menses,pelvic pain and secondary infertility. Theoretically, an inflammatory response,such as a wound healing process in the uterus due to hydrometra associated withscar defect may impair embryo implantation. The clinical case studies presentedhere are based on the correct diagnosis of the cesarean section scar defect withhydrometra and its successful surgical repair. The patients in our study hadtheir symptoms resolved and attained clinical pregnancy. The number of cesarean sections (C-section) performed is steadily increasing acrossthe world .C-section scar defect can be visualized using transvaginal ultrasound andhysteroscopy . ThisfiThere are only a few studies on the clinical association between secondaryinfertility and C-section scar defect .Repair of C-section scar defect is done by using a minimally invasive surgical methodsuch as hysteroscopy or/and laparoscopy and vaginal procedures ; presented to Al Ain Fertility Centerbetween January 2016 and December 2020. Exclusion criteria:Infertility cases presented with C-section scar defect without hydrometra.Clinical characteristics of patients: all the patients were agedbetween 28 to 41 years who underwent surgical management for cesarean sectionscar defect with hydrometra to treat secondary infertility.Diagnosis: Symptoms related to cesarean section scar defect were reported. Clinical diagnoses were confirmed by transvaginalultrasound imaging. Surgical Treatment: All the surgicalprocedures were performed by hysteroscopy and laparoscopy as per explainedbelow: - Hysteroscopic resection: The uterine cavity isdistended using NaCl solution. Positive pressure is ensured with an automaticpressure infuser. The inferior and superior edges of the defect are resectedusing a cutting loop and coagulation is performed on the thinnest part of thescar approval was obtainedbefore the beginning of the study. The data presented are with completeanonymity of published information and the images used are undernon-identifiable category (ultrasound). In addition, careful case-by-caseassessment was made to ensure that content is fully anonymous and presents norisk to confidentiality of the study participants.invitro fertilization (IVF) treatment under standard antagonistprotocol with preimplantation genetic testing , fluid-filled pouch at the scar site due to impaired woundhealing and thinning of the anterior uterine wall , dysmenorrhea, pelvic pain, postmenstrual spotting, adenomyosis,endometriosis, abscess formation, cesarean scar ectopic pregnancy, and infertility demonstrated that 80% of thepatients diagnosed with a C-section scar defect that had surgical treatments(hysteroscopic and laparoscopic isthmoplasty) became pregnant within 24 months anddelivered before 36 months of treatment. In cases of infertility treatment, thereproductive performance after the scar defect correction surgery shows theeffectiveness of the accurate diagnosis and treatment of patients using efficienttechniques , and when no normalendometrial lining can be visualized. Studies postulated various mechanisms by whichscar defect hydrometra may interfere with embryo implantation ("} {"text": "As previous studies have shown, indications of drugs adjudicated by these RCTs often get expanded m ensues .A combination of patient-specific factors very often acting wholly significant impact on ability to both adhere to and deal with consequences of rising medication counts in patients with CKD. These often take form of sub-optimal medication adherence, worsening cognitive impairment. The latter is both a factor of declining kidney function itself as well as incident on it due to overall frailty. These factors generally makes it challenging to manage medications in CKD patients.Potentially inappropriate medications maintain a bidirectional relationship with polypharmacy, and both share similar unwanted downstream consequences. Restricting the definitional threshold of polypharmacy in chronic kidney disease patients regardless of underlying primary etiology to only Kidney specific medications is key to reliably identifying patient cohorts for directed interventions. To compliment this, and additionally optimize the management of PIMs and polypharmacy in CKD patients, utility of established structural therapeutic frameworks such as pharmacotherapy optimization and or medication therapy management (MTM) may also prove invaluable long term."} {"text": "Scher,3 This additional risk is not only due to the association of perinatal inflammation with cerebral haemorrhage and white matter injury,4 but also to the neuronal toxicity of supra-physiological serum concentrations of interleukin-1 beta observed in this situation.5 Even in preterm children without severe neonatal brain injury, perinatal inflammation remains independently associated with decreased motor and social abilities at 30 months of corrected age.3Perinatal inflammation exposure represents an additional risk factor for impaired developmental trajectory in preterm infants.6 This identification is crucial to provide individualised early developmental intervention programmes for these infants. Such programmes have been shown to improve motor and cognitive outcomes in preterm children.7EEG is the primary tool for functional evaluation of brain activity in preterm infants hospitalised within the neonatal unit. Serial longitudinal EEG recordings before term age can accurately assess brain maturation in preterm infants, and identify infants with an unfavourable early developmental trajectory.8 Beyond the estimation of discontinuity and amplitude offered by aEEG evaluation, conventional multi-channel EEG provides key information about other network-based brain activity, such as synchrony, frequency, and reactivity.9 It also delivers crucial information on the dynamics of transient endogenous generators occurring through the complex process of brain maturation.9 The two studies included in our systematic review were limited to aEEG analysis and reported inconsistent findings associated with perinatal inflammation exposure.2 Nevertheless, perinatal inflammation led to a modification of EEG frequencies in most of the preclinical studies assessing its effect on foetal sheep EEG, underlying the importance of the quantitative analysis of conventional EEG in the assessment of early brain maturation.2We agree that amplitude-integrated EEG (aEEG) is currently a useful tool to supervise the brain activity of critically ill preterm infants hospitalised in neonatal units that do not have 24/7 access to conventional EEG. However, aEEG provides a limited assessment compared to conventional EEG, particularly in very preterm neonates who do not demonstrate distinguishable sleep-wake cycling before 29 weeks of gestational age.10Conventional multi-channel EEG is essential to assess brain maturation in preterm infants, especially in those exposed to additional developmental risk factors such as perinatal inflammation. The need for a specialist to apply and interpret conventional multi-channel EEG has often been seen as an impediment to its widespread use within the neonatal unit. However, rather than simplifying the process by utilising fewer channels with less information, we believe that modern engineering solutions will allow the widespread introduction of conventional multi-channel EEG in neonatal units. There have been tremendous recent advances in the development of quantitative analysis and machine learning to develop automated algorithms for conventional multi-channel EEG analysis; such automatisation will soon assist in the further introduction of conventional multi-channel EEG beyond specialist centres."} {"text": "Aim/ObjectiveWithin the dynamic healthcare technology landscape, this research aims to explore patient inquiries within outpatient clinics, elucidating the interplay between technology and healthcare intricacies. Building upon the initial intelligent guidance robot implementation shortcomings, this investigation seeks to enhance informatic robots with voice recognition technology. The objective is to analyze users' vocal patterns, discern age-associated vocal attributes, and facilitate age differentiation through subtle vocal nuances to enhance the efficacy of human-robot communication within outpatient clinical settings.MethodsThis investigation employs a multi-faceted approach. It leverages voice recognition technology to analyze users' vocal patterns. A diverse dataset of voice samples from various age groups was collected. Acoustic features encompassing pitch, formant frequencies, spectral characteristics, and vocal tract length are extracted from the audio samples. The Mel Filterbank and Mel-Frequency Cepstral Coefficients (MFCCs) are employed for speech and audio processing tasks alongside machine learning algorithms to assess and match vocal patterns to age-related traits.ResultsThe research reveals compelling outcomes. The incorporation of voice recognition technology contributes to a significant improvement in human-robot communication within outpatient clinical settings. Through accurate analysis of vocal patterns and age-related traits, informatic robots can differentiate age through nuanced verbal cues. This augmentation leads to enhanced contextual understanding and tailored responses, significantly advancing the efficiency of patient interactions with the robots.ConclusionIntegrating voice recognition technology into informatic robots presents a noteworthy advancement in outpatient clinic settings. By enabling age differentiation through vocal nuances, this augmentation enhances the precision and relevance of responses. The study contributes to the ongoing discourse on the dynamic evolution of healthcare technology, underscoring the complex synergy between technological progression and the intricate realities within healthcare infrastructure. As healthcare continues to metamorphose, the seamless integration of voice recognition technology marks a pivotal stride in optimizing human-robot communication and elevating patient care within outpatient settings. In recent years, the healthcare sector has witnessed significant advancements in technology integration, exemplified by the deployment of informatic robots across various medical settings. Notably, incorporating mobile intelligent guidance robots (IGRs) within outpatient clinics has emerged as a catalyst for enhancing operational efficiency, optimizing processes, and elevating patient experiences . These aIn 2021, we published a comprehensive assessment in Cureus, critically examining the initial implementation of IGRs within an outpatient clinic setting [To address inefficiencies such as frivolous inquiries and childlike interactions, this study involves augmenting the IGR with voice recognition technology. The primary objective of this augmentation is to analyze users' vocal patterns and discern age-related vocal characteristics, thereby enabling the differentiation of age through subtle vocal nuances. This process entails utilizing advanced voice analysis techniques and machine learning algorithms . This apVoice recognition operates on algorithms that evaluate vocal cadences and establish correlations with age-associated vocal attributes. It's crucial to acknowledge that while voice recognition technology possesses inherent limitations that may affect absolute accuracy, it grants the capability to approximate users' ages. By leveraging the IGR's proficiency in comprehending and analyzing conversational context, the robot can glean generational references and contextual cues, thereby facilitating an estimative boundary of the user's age range.Subsequently, in November 2022, an enhanced IGR equipped with voice recognition technology was deployed at the central lobby of an outpatient setting for 20 days, mirroring the temporal framework of the previous 2019 study. Following data accrual, the collected dataset underwent meticulous analysis, focusing on content accuracy and the frequency of successful human-robot interactions. This investigation relied on quantitative and comparative methodologies, comprehensively assessing user inquiries and data efficiencies post-upgrade. The research attempts to pinpoint areas amenable to refinement and offers strategic insights to guide future enhancements.In this study, 101,672 outpatient visits were documented throughout the designated study duration, resulting in 30,301 human-robot interactions transpiring within 20 days. Notably, within this extensive corpus, 22,423 interactions were classified as successful interactions, a criterion defined by the robot's provision of a relevant response to the inquiry presented. Acknowledging that the IGR could not respond to languages other than Mandarin Chinese and English due to inherent programming constraints is imperative. Furthermore, notable categories such as numerically focused queries, inquiries unrelated to the hospital context, childlike interactions, and nuisance inquiries were substantially minimized or systematically omitted from the recorded dataset.Quantitative data comparing the two distinct study periods is presented in Table Characterized by the continuous enhancement of system applications, Figure Compellingly, health triage-related inquiries and appointment issues emerge as the second and third most frequent themes within the top 10 questions. This observation carries implications that resonate with the existing healthcare framework within China. It mirrors the contemporary state of the healthcare landscape wherein the primary health system remains in a formative phase, accompanied by a noteworthy lack of coordination within the broader healthcare infrastructure. Simultaneously, appointment-related concerns underscore the challenges within the appointment scheduling process, potentially reflecting disparities in resource allocation and logistical intricacies.Drawing a comparative lens to the antecedent year 2019, Figure Nevertheless, amid this trajectory of advancement, latent challenges persist. Foremost among these challenges is the constraint of language selection. In a global healthcare landscape where linguistic diversity prevails, the current scope of our informatic robots remains predominantly confined to Mandarin Chinese and English. The necessity for an expanded linguistic horizon aligns with the multifaceted nature of patient demographics and the imperative of inclusivity within healthcare automation.The incorporation of voice recognition technology marks a significant milestone in the domain of informatic robots deployed in outpatient clinics. This innovative augmentation has yielded notable successes, particularly in improving patient-robot interactions. The capacity of voice recognition technology to analyze users' vocal patterns and identify age-related voice characteristics has effectively addressed a crucial communication challenge, facilitating a more tailored and efficient exchange of information between patients and robots . MoreoveOutpatient clinics consistently serve as crucial windows for patients seeking medical care. However, the introduction of informatic robots, while enhancing efficiency, potentially erodes the essential trust inherent in healthcare interactions . PatientMitigating these apprehensions necessitates comprehensive patient education initiatives . Such inBy equipping patients with relevant knowledge, the significance of the interaction is reinforced, reducing the likelihood of frivolous or childlike interactions . Design Future advancements include the integration of machine learning algorithms, which will support continuous learning from patient interactions, thereby refining responses and adapting to evolving patient needs . CarefulInformatic robots possess the potential to catalyze a transformative shift in outpatient clinics, optimizing efficiency and elevating patient care. However, the intricacies associated with their use require careful consideration . A harmoThe successful integration of voice recognition technology into informatic robots has delivered substantial benefits for patient-robot interactions within outpatient clinics. This technology is a promising step toward optimizing healthcare automation by enabling more accurate age differentiation, fostering personalized engagements, and contributing to a growing knowledge base. As the healthcare landscape evolves, voice recognition technology emerges as a cornerstone in the ongoing quest to refine patient care and enrich the human-robot interaction paradigm.In summary, the narrative surrounding the integration of informatic robots within outpatient clinics embarks on an evolutionary trajectory characterized by dynamic refinement. This narrative underscores the intricate nexus of technology and healthcare services, resonating with repercussions transcending societal and clinical paradigms. As progress is championed, the pursuit of enhancing the precision of patient inquiries resonates with overarching themes of technological amalgamation. Simultaneously, a steadfast commitment to embracing linguistic diversity epitomizes the ethos of inclusivity intrinsically linked to healthcare. Each advancement is an echelon of progress within this narrative, propelling unwavering dedication toward shaping a more nuanced and responsive healthcare future."} {"text": "Long-acting injectable antipsychotics (LAIAs) are currently the most effective alternative for patients with schizophrenia who exhibit poor adherence. LAIAs can lead the course of treatment with the potential to increase adherence in schizophrenia treatment.Present the results of a network metaanalysis on the comparative efficacy of LAIs in schizophrenia.Included trials of adults with schizophrenia compared the efficacy of LAI vs LAI or placebo through the Positive and Negative Syndrome Scale (PANSS). Efficacy was evaluated through the standarized mean differences (SMD) from baseline to endpoint in the PANSS total scores.Results from 15 studies reported usable results for PANSS score (five antipsychotics compared) are shown in Figure 1. In hierarchical order, haloperidol, aripiprazole, risperidone, and paliperidone reduced the PANSS score significantly more than other drugs.Image:Most LAIAs are equally efficient at reducing overall symptoms, and differences between individual LAIAs are non-significant.None Declared"} {"text": "New-generation vaccines and novel vaccinal strategies against infectious diseases of livestock, wild and companion animals\u201d highlights advances and innovations in animal vaccines.Vaccination against infectious disease is an invaluable tool to protect humans against severe morbidity and mortality. For this reason, significant advances in human vaccines have propelled the field of vaccinology forward. Emerging and neglected diseases still pose an important challenge ; fortunaTargeted delivery of oral vaccine antigens to aminopeptidase N (APN) protects pigs against pathogenic Escherichia coli challenge infection\u201d describes the complications of oral subunit vaccines and the significant hurdles in overcoming the barriers of the gastrointestinal tract, limiting their development and efficacy. However, by utilizing APN-specific antibody-antigen fusion constructs, researchers have demonstrated the induction of both mucosal and systemic immune responses in a piglet model of bacterial infection, providing a stepping stone toward the realization of an effective and protective oral subunit vaccine targeting APN. The manuscript by Souto et\u00a0al. provides data to support the development of a bivalent vaccine candidate to protect fish from viral hemorrhagic septicemia (VHS) and viral encephalopathy and retinopathy (VER), major threats in aquaculture. By modifying the genome of viral hemorrhagic septicemia virus (VHSV) and introducing an expression cassette encoding the protective antigen domain of nervous necrosis virus (NNV) capsid protein, the authors successfully demonstrated the safety, immunogenicity, and protective efficacy of the recombinant VHSVs (rVHSV) in trout and sole. These findings hold promise for the development of a valuable bivalent live attenuated vaccine for commercially valuable fish species. Anotherstudy assessed the immune responses in calves to vaccines targeting Mycobacterium avium subspecies paratuberculosis (MAP), a cause of chronic enteritis in ruminants. Here, the authors analyzed the immune response induced by truncated MAP antigens as a fusion either on protein particles or as a soluble recombinant MAP (rMAP) fusion protein and compared this to a commercial vaccine. The rMAP fusion protein vaccine displayed the strongest immune response and showed promise in providing protective immunity against MAP infection while avoiding interference with bovine tuberculosis diagnostic tests. In another article, the authors describe a promising vaccination strategy for East Coast fever, a prevalent bovine disease in Africa caused by Theileria parva. In this study, using a recombinant lumpy skin disease virus (LSDV), the authors engineered virus-like particles (VLPs) containing a modified form of the T. parva p67 surface antigen and the bovine leukemia virus (BLV) gag gene. Studies in mice demonstrated the vaccine\u2019s immunogenicity, showing higher antibody titers in the group vaccinated with the recombinant LSDV. This encouraging progress paves the way for further investigations and potential applications of this dual vaccine candidate in cattle. Using recombinant bovine herpesvirus (BHV)-4 expressing nonstructural protein 5 (NSP5) and M fusion protein of porcine reproductive and respiratory syndrome virus (PRRSV), a study suggested that a T cell response induced in recombinant viral vector primed pigs can help in reducing PRRSV-1\u2013associated tissue damage without reducing the viral load. A separate study explored the potential of an adenoviral-vectored Epigraph vaccine as a promising alternative to current Swine Influenza A Virus (IAV-S) vaccines. Their findings demonstrated encouraging results, with the vaccine inducing robust and durable antibody responses in vaccinated pigs, as well as significant protection against viral challenge 6 months after initial vaccination.Within this Research Topic, both original research and review articles are presented. The original article \u201cRecent advances in antigen targeting to antigen-presenting cells in veterinary medicine\u201d outlines the dynamic field of veterinary medicine, where the quest for innovative strategies to combat challenging diseases has gained considerable momentum. Notably, groundbreaking advancements in antigen targeting, with a particular focus on antigen-presenting cells such as dendritic cells, through the use of DC peptides and MHC-II, have emerged as a beacon of hope. Moreover, another review describes the complications of vaccination in wildlife animals. Prion diseases, such as chronic wasting disease (CWD), pose significant challenges due to their unique biology and potential zoonotic risks. Current efforts to manage CWD have been largely ineffective, emphasizing the need for new tools such as vaccines. Despite the hurdles of overcoming immune tolerance and vaccinating wild animals, progress has been made in identifying safe antigens and effective strategies for formulation and delivery, including oral delivery to wild cervids.To complement the original research outlined above, this Research Topic also delves into important questions regarding new vaccine strategies and considerations for future approaches in detailed reviews. \u201cImmune responses in the uterine mucosa: clues for vaccine development in pigs\u201d explores the pursuit of effective strategies, with intrauterine immunization emerging as a promising approach, aiming to elicit localized or systemic immunity that safeguards against potential threats. Finally, Type I interferons (IFNs-\u03b1/\u03b2) are vital components of the innate immune response against viral infections. However, viruses have developed clever strategies to evade the antiviral effects of IFNs, compromising the efficiency of the immune system and vaccines. Understanding these evasion mechanisms can pave the way for the development of innovative vaccines that counteract viral IFN antagonism and induce robust immune responses for enhanced protection against a wide range of pathogens. The review article \u201cReprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses\u201d explores advances in developing IFN antagonism-deficient viruses, their immune evasion, and attenuated phenotypes in natural host animal species.The intricate immune system of the upper reproductive tract (URT) serves a remarkable purpose: shielding against sexually transmitted pathogens while simultaneously embracing immune tolerance toward sperm and the developing fetus. The review \u201cThis Research Topic brings a diverse selection of topics outlining advances in the field of veterinary vaccinology. The importance of generating protective vaccines against disease in animals is critical to ensuring their health and wellness, thus favoring production systems and reducing zoonotic disease risk .BP: Writing \u2013 original draft, Writing \u2013 review & editing. RM-R: Writing \u2013 review & editing. ST: Writing \u2013 review & editing. CC: Writing \u2013 review & editing. DA: Writing \u2013 review & editing."} {"text": "Verticillium wilt (VW), Fusarium wilt (FW) and Root-knot nematode (RKN) are the main diseases affecting cotton production. However, many reported quantitative trait loci (QTLs) for cotton resistance have not been used for agricultural practices because of inconsistencies in the cotton genetic background. The integration of existing cotton genetic resources can facilitate the discovery of important genomic regions and candidate genes involved in disease resistance. Here, an improved and comprehensive meta-QTL analysis was conducted on 487 disease resistant QTLs from 31 studies in the last two decades. A consensus linkage map with genetic overall length of 3006.59\u00a0cM containing 8650 markers was constructed. A total of 28 Meta-QTLs (MQTLs) were discovered, among which nine MQTLs were identified as related to resistance to multiple diseases. Candidate genes were predicted based on public transcriptome data and enriched in pathways related to disease resistance. This study used a method based on the integration of Meta-QTL, known genes and transcriptomics to reveal major genomic regions and putative candidate genes for resistance to multiple diseases, providing a new basis for marker-assisted selection of high disease resistance in cotton breeding. Upland cotton , the most widely cultivated cotton species in the world, has excellent qualities, high yield and is widely adaptable .The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} {"text": "Large proportion of patients with ADHD experience sleep problems. Well conducted, good quality clinical research could identify non-pharmacological sleep improvement interventions that would benefit patients with ADHD and would inform evidence based guidelines for sleep management in ADHD.To conduct a novel meta-research assessment of available clinical trials in the field of light therapy and non\u2011pharmacological sleep improvement interventions for people with ADHD.Peer-reviewed publications of clinical trials were analysed. An advanced literature search strategy was performed in major medical databases, including EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials and PsycINFO. Available data at WHO-approved clinical trial registries were searched and linked to the published literature. Detailed methodological assessment of results was conducted using the Cochrane Risk of Bias Tool version 2.0 (ROB2), conflict of interest, spin and favourability of findings. Reduction in ADHD symptom severity and improvement of sleep quality served as primary outcomes for the efficacy analysis. Any adverse events were recorded. Statistical analysis of the primary outcomes was conducted by calculating standardised mean difference and transformed as necessary. Publication bias was evaluated with contour enhanced funnel plots and the trim-and-fill procedure, and by summarising unpublished trials.Analysed clinical trials often had a high risk of bias . The primary outcome interpretation and overall trial conclusions frequently favoured the trial intervention. Clinical trials showed an association between primary outcome effect size and interpretation, and risk of bias. Clinical research in this field faces many of the same challenges identified for complex interventions in mental health, such as small sample size, lack of funding and difficulties with blinding.Clinical research regarding light therapy and non\u2011pharmacological sleep improvement interventions for ADHD patients indicates safety and effectiveness but studies often lack methodological rigour.None Declared"} {"text": "In this critical analysis, we investigate the profound impact of natural disasters and pandemics on the care and adherence to treating diabetic retinopathy, a severe complication of diabetes requiring continuous monitoring and treatment to prevent vision loss. Our study also sheds light on the social and economic context of Puerto Rico, emphasizing recent emergency events that have exacerbated existing public health challenges. Through a comprehensive review of relevant literature from PubMed, Google Scholar, and the George Washington University Himmelfarb Health Sciences Library database, we identified 31 pertinent articles out of 45 evaluated, focusing on the effects of these crises on healthcare delivery, diabetic retinopathy screening, and treatment. The evidence strongly indicates that during such emergencies, barriers to healthcare escalate, leading to significant treatment delays and a reduction in diabetic retinopathy screening and diagnosis, ultimately resulting in deteriorated visual outcomes. Thus, our review underscores the urgent need for the development of effective emergency plans tailored specifically to diabetic retinopathy, particularly in Puerto Rico, where diabetes prevalence and its complications are notably higher. Such plans should not only incorporate established emergency measures but also harness emerging technological advances in the field of ophthalmology to ensure optimal preparedness for future pandemics and natural disasters. Diabetes, characterized by elevated blood glucose levels, poses a global health challenge with both macrovascular and microvascular complications. The incidence of diabetes is rising worldwide, affecting vulnerable populations, especially in disaster-prone regions . The IntThe prevalence of DR is escalating, especially in regions like North America and the Caribbean, with Puerto Rico experiencing a notable burden ,8. This Prior research underscores the exacerbation of diabetes and its complications in disaster settings ,12. DiabDR management revolves around prevention and progression control . While bThis critical analysis aims to elucidate the influence of natural disasters and pandemics on DR care and adherence to treatment. Moreover, it sheds light on Puerto Rico's recent public health challenges, magnified by its susceptibility to disasters . ThroughMaterials & methodsA comprehensive literature review was conducted to identify relevant publications on managing DR during pandemics or natural disasters worldwide. The study also aimed to identify recent public health challenges in Puerto Rico that may have affected the care of DR on the island during and after Hurricane Irma, Hurricane Maria, the 2019-2020 earthquakes, and the COVID-19 pandemic. Additionally, the research sought to assess the presence of diabetes emergency preparation procedures on the island. Furthermore, given the ongoing COVID-19 pandemic, the literature review explored suggested methods and new technological breakthroughs for managing DR.Literature searches were conducted using PubMed, Google Scholar, and the George Washington University Himmelfarb Health Sciences Library database. The search queries focused on terms related to DR, as it is the primary disease of interest in this critical analysis. Similarly, words related to disaster preparedness were included. The search terms used had \"diabetic retinopathy\" (\"retinopatia diab\u00e9tica\"), \"retinopathy\" (\"retinopatia\"), \"retina,\" \"diabetes,\" \"diabetic eye disease,\" \"diabetes mellitus,\" and \"diabetics\" (\"diab\u00e9ticos\"), along with \"disaster preparedness,\" \"emergency preparedness,\" \"natural disasters\" , \"hurricanes\" (\"huracanes\"), \"Hurricane Maria\" (\"Hurac\u00e1n Maria\"), \"Hurricane Irma\" (\"Hurac\u00e1n Irma\"), \"earthquakes\" (\"terremotos\"), \"pandemic\" (\"pandemia\"), \"covid,\" \"covid-19,\" and \"coronavirus.\" Additional terms such as \"prevalence\" , \"Puerto Rico,\" \"intravitreal injections,\" \"anti-vascular endothelial growth factor,\" and \"anti-VEGF\" were used to achieve specific aims.Appendix A provides a list of combinations of the search terms mentioned above. Studies included in the literature review were limited to those written in English or Spanish, available as free full-text, and published from 2017 onwards.ResultsThis study conducted an extensive literature review spanning the period from 2017 to 2022, with the aim of delving into the intricate dynamics between natural disasters, pandemics, and the provision of care for DR. A meticulous analysis of 24 relevant articles provided valuable insights into the challenges faced by DR patients during times of adversity, as depicted in Figure Remarkably, as highlighted in Table\u00a0Intriguingly, the literature appeared to have a significant gap in the specific domain of disaster preparedness strategies tailored to DR during natural disasters\u00a0, a pointThe synthesis of the literature convincingly underscores the susceptibility of DR care to the disruptions posed by natural disasters and pandemics. The aftermath of events like hurricanes and the ongoing COVID-19 pandemic has underscored challenges in timely care provision, leading to delays in vital interventions such as anti-VEGF injections and DR screenings. These delays can potentially worsen the prognosis of DR and heighten the risk of vision loss. Of significant note, the region of Puerto Rico, having endured multiple natural disasters in the past decade alongside the ongoing pandemic, is a vivid example of the disproportionate impact on individuals with chronic illnesses. These crises have laid bare shortcomings in the healthcare system and accentuated the pressing need for robust contingency plans to mitigate considerable health and visual consequences. It is imperative that such plans encompass both established emergency protocols and the integration of emerging technological advancements within the field of ophthalmology.Impact of Pandemics and Natural Disasters on Diabetic Retinopathy: Challenges and Preparedness StrategiesThe ramifications of pandemics and natural disasters on DR care have garnered significant attention within the medical community. This section synthesizes key findings from the literature, shedding light on the barriers encountered by DR patients during these emergency situations and proposing effective preparedness strategies to mitigate their impact.Barriers to care during the COVID-19 pandemic: The COVID-19 pandemic highlighted several barriers that disrupted the continuity of DR\u00a0care. As depicted in Table Impact of recent emergency situations in Puerto Rico: Existing healthcare challenges and socioeconomic factors amplified Puerto Rico's vulnerability to emergencies. Table Proposed pandemic and disaster preparedness plan for DR: To address the challenges highlighted by the impact of emergencies on DR care, a multifaceted preparedness plan is proposed. Table DiscussionThe prevalence of DR, a significant microvascular complication of diabetes mellitus, presents a formidable challenge due to its potential to cause vision impairment and blindness among working-age individuals. This condition is chiefly characterized by diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), necessitating timely intervention and vigilant monitoring . The conTo mitigate the repercussions of these care disruptions, ophthalmological institutions have outlined recommendations for managing intravitreal anti-VEGF injections during pandemics . These gTelemedicine has proven invaluable when conventional medical access is limited, as witnessed in situations like natural disasters and infectious disease outbreaks. The COVID-19 pandemic has expedited the adoption of telemedicine, enabling remote healthcare delivery through digital platforms. Ophthalmology has particularly benefited from this shift, leveraging advanced hardware, sophisticated software, and high-speed communication technologies to remotely diagnose and manage eye conditions ,28. The Teleophthalmology, mainly via portable devices, has the capacity to bridge accessibility gaps in remote and underserved communities. Research has demonstrated the feasibility of cost-effective DR screening tools utilizing smartphones and telemedicine, resulting in improved DR screening coverage in rural areas . FurtherIn addition to leveraging telemedicine, public health initiatives should prioritize infrastructure enhancements to bolster visual healthcare accessibility. Strengthening hospitals, medical facilities, and primary care clinics, ensuring consistent power supply and backup generators, improving provider communication, expanding the healthcare workforce, enhancing surveillance systems, and refining patient records are imperative. Special attention should be directed toward\u00a0high-risk groups, such as elderly individuals with chronic conditions and immobile patients . ExpandiCommunity pharmacists play a pivotal role in disaster preparedness and response, offering access to medications and healthcare services, thereby mitigating barriers to care . They caNational-level protocols should be established to ensure uninterrupted critical treatment schedules for DR patients. These protocols must recognize the debilitating nature of the disease and prioritize patients at high risk of DR-related blindness, exempting them from lockdown measures and ensuring their protection . SimilarThe COVID-19 pandemic has instigated transformative shifts in care delivery and spurred innovative standards in ophthalmic care. As the global population ages, the prevalence of DR and similar conditions will escalate, further straining healthcare services. In regions like Puerto Rico, where diabetes mellitus is highly prevalent, and healthcare infrastructure and resources might be less stable, swift integration of alternative care methods, such as telemedicine, is crucial to alleviate patient burden while ensuring essential disease management . TelemedFinally, developing an emergency contingency plan for DR management is essential to provide uninterrupted care during crises. Clinicians bear a moral and ethical responsibility to devise strategies to minimize treatment interruptions. Key elements of such a plan include maintaining a comprehensive database of DR patients and their demographics for guided medication distribution and personnel deployment, implementing backup power sources for electricity outages, ensuring access to electronic medical records, and refrigeration for temperature-sensitive medications. Adequate medication and supply reserves ahead of disasters and establishing post-disaster patient communication methods are also vital.It is essential to acknowledge the limitations of this study, including the absence of specific data on the intersection of DR and natural disasters, as well as the lack of tailored recommendations for the unique circumstances in Puerto Rico. However, this critical analysis aims to provide guidance to ophthalmologists in Puerto Rico for effectively managing DR patients during responses to hurricanes, earthquakes, and potential future pandemics like COVID-19. The findings should inspire collaborative efforts among scientists and stakeholders in Puerto Rico to address barriers hindering patient access to teleophthalmology services, especially during times of crisis.In conclusion, given the heightened risks posed by pandemics and natural disasters, developing a robust emergency plan for managing DR is imperative. This urgency is underscored by the heightened vulnerability of regions like Puerto Rico, where the prevalence of diabetes and its complications is substantial. An effective plan should encompass established emergency measures and embrace emerging technological advancements within the field of ophthalmology."} {"text": "Opioid use for perioperative pain management in burn patients is associated with a high risk of developing chronic opioid use. Ketamine is commonly used as an analgesic adjunct due to its opioid-sparing effects. The purpose of this study is to determine whether analgesia with adjunctive ketamine reduces the risk of developing chronic opioid use in burn patients.Burn patients who underwent burn-related surgeries were identified using relevant ICD-10 Codes. Data were collected using the TriNetX Research Network, a national research database providing de-identified patient medical records.Burn patients undergoing surgical procedures were identified based on their use of opioids alone or in combination with ketamine as adjunctive analgesia. Both groups excluded patients with a prior history of opioid-related and psychiatric disorders to control for potential pre-existing conditions affecting the study outcomes. Outcome analysis included continued opioid use and related psychiatric disorders, including nicotine dependence and anxiety, up to one year after burn injury. Risk ratios for each outcome were then generated using a measure of association analysis through TriNetX.We identified 107,270 patients across 51 health care organizations who underwent burn-related surgeries within one month after burn injury. Excluded from the study were 3,296 (3.07%) patients who had a prior history of opioid-related and psychiatric disorders. The remaining 103,974 patients were sorted into respective groups that received opioids with ketamine and without ketamine . The two cohorts were balanced using (1:1) propensity score matching for age, sex, race, ethnicity, and burn surface area.Patients without ketamine had a higher risk of continuing opioid use , developing nicotine dependence , and developing anxiety disorders at least one year after burn injury.Burn patients whose pain management included adjunctive ketamine ceased opioid use sooner and demonstrated a lesser risk of developing various psychiatric disorders associated with chronic opioid use.This study supports the use of adjunctive ketamine as part of a multimodal approach to pain management in burn patients in order to minimize the risk of chronic opioid use."} {"text": "Ophiophagus hannah; Cantor, 1836) is distributed in diverse habitats, forming independent populations, which confer differing scale markings, including between hatchlings and adults. Furthermore, king cobra venoms possess unique cytotoxic properties that are used as a defensive trait, but their toxins may also have utility as promising anticancer-agent candidates. However, the impact of geographical distribution and age on these potential venom applications has been typically neglected. In this study, we hypothesised that ontogenetic venom variation accompanies the morphological distinction between hatchlings and adults. We used non-transformed neonatal foreskin (NFF) fibroblasts to examine and compare the variability of venom cytotoxicity between adult captive breeding pairs from Malaysian and Chinese lineages, along with that of their progeny upon hatching. In parallel, we assessed the anticancer potential of these venoms in human-melanoma-patient-derived cells (MM96L). We found that in a geographical distribution and gender-independent manner, venoms from hatchlings were significantly less cytotoxic than those from adults . This is consistent with neonates occupying a semifossorial habitat, while adults inhabit more above-ground habitats and are therefore more conspicuous to potential predators. We also observed that Malaysian venoms exhibited a slightly higher cytotoxicity than those from the Chinese cobra cohorts , which is consistent with Malaysian king cobras being more strongly aposematically marked. These variations are therefore suggestive of differential anti-predator strategies associated with the occupation of distinct niches. However, all cobra venoms were similarly cytotoxic in both melanoma cells and fibroblasts, limiting their potential medical applications in their native forms.Snake venoms constitute a complex, rapidly evolving trait, whose composition varies between and within populations depending on geographical location, age and preys (diets). These factors have determined the adaptive evolution for predatory success and link venom heterogeneity with prey specificity. Moreover, understanding the evolutionary drivers of animal venoms has streamlined the biodiscovery of venom-derived compounds as drug candidates in biomedicine and biotechnology. The king cobra ( Venom is generally defined as a functional trait: a complex secretion produced by a specialised gland tissue that is delivered into the body of another animal via a wound for use in antagonistic interactions . By thisThe scale of mining venoms for drug candidates is immense, as this mixture often contains hundreds of toxins and isoforms that undergo accelerated rates of evolution . This biStudying the natural history and evolution of venomous species provides key insights regarding the biological sources reflecting toxin diversity. Snake venoms function at the ecological and biochemical interface between predator and prey, aiming mainly to facilitate predation . This haOphiophagus hannah; Cantor, 1836) belongs to the Elapidae family and is widely distributed from India to southern China and Southeast Asia in numerous geographically isolated mainland and island populations. These populations form at least four genetically distinct lineages, which are likely separate species prism function. Data were graphed and analysed using GraphPad Prism version 9 for iOS . For the MTT assays, venom cytotoxicity data were normalised to the vehicle-treated cells (100% cell viability) to calculate the percentage of viable cells following venom treatment. Data were then tested for normality using Shapiro\u2013Wilk tests (significance set to"} {"text": "Perioperative management of estradiol therapy varies considerably among plastic surgeons performing aesthetic surgeries. This study aimed to review available literature regarding perioperative management of estradiol therapy in aesthetic surgery patients, and the risk it poses for developing VTE in the perioperative period.A literature search was performed using online databases to identify studies evaluating VTE in aesthetic surgery patients taking oral contraceptives (OCPs) or hormone replacement therapy (HRT), and transgender patients on feminizing hormone therapy undergoing non-flap feminization surgery . Reported outcomes were extracted from these studies and summarized.A systematic review of the literature yielded 225 studies. Five of these studies met inclusion criteria. One study that was excluded, referenced an article that met inclusion criteria, which was ultimately included in our review for a total of six studies, representing 3,635 patients.Data regarding perioperative management of estrogen therapy is limited in the literature, and standardized guidelines for aesthetic surgery patients have not been elucidated. This has led to inconsistencies in how estrogen is managed for elective, cosmetic procedures. Further research is needed to determine standardized practice guidelines. In the meantime, case-by-case evaluation of surgical appropriateness should continue. Surgeons should also consider risk-mitigating strategies, such as a focus on patient education, more intentional patient questioning regarding estrogen-containing product use, a preoperative coagulability workup for patients with a personal or family history indicative of possible coagulopathy, and specialty-wide efforts to create an aesthetics database and evidence-based guidelines."} {"text": "BackgroundMeniscal tears are the most common injury of the knee. Surgical treatment has fallen into contention recently and includes arthroscopic meniscectomy and meniscal repair. The primary aim of this study was to quantitatively evaluate patients with isolated meniscal tears and compare their outcomes with patients who have undergone arthroscopic meniscus surgery. The secondary aim of this study was to compare the clinical outcomes of patients who have undergone arthroscopic meniscectomy with patients who have undergone arthroscopic meniscal repair.MethodsThis comparative clinical study screened 334 patients to identify subjects who underwent arthroscopic knee surgery for isolated meniscal tears and compare them to patients with symptomatic isolated meniscal tears awaiting surgery using validated patient-reported outcome measures. These included the Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee Subjective Knee Form, Lysholm score, Tegner score, EuroQol-5 Dimension, and the 12-Item Short Form Health Survey.ResultsA total of 117 patients , Meniscectomy group (n=64), and Meniscal Repair group (n=17)) were included in the final data analysis. Both the Meniscectomy group and the Meniscal Repair group (mean 55-month follow-up) showed significantly better clinical outcomes than patients in the Meniscal Tear group (p<0.05). Overall, the Meniscal Repair group demonstrated superior clinical outcomes when compared to the Meniscectomy group (p<0.05).ConclusionArthroscopic knee surgery showed significant clinical benefit at medium-term follow-up in treating patients with isolated meniscal tears. When feasible, meniscal repair should be performed preferentially over meniscectomy. The menisci are crescentic wedge-shaped structures formed from fibrocartilage located within the medial and lateral compartments of the knee between the corresponding femoral condyle and tibial plateau ,2. MenisTreatment for meniscal tears broadly falls into two categories: conservative vs. surgical, the latter of which includes arthroscopic meniscectomy and arthroscopic meniscal repair. The choice depends on many factors including age, type and severity of tear, the presence of other pathology, and general patient fitness for anesthesia and surgery ,3,4. WheIn general, the treatment for traumatic meniscus tears differs from that of degenerative tears. The latter are less likely to be amenable to repair as by their very definition their blood supply is poor ,2. FurthSurgical management includes arthroscopic meniscectomy and meniscal repair. An arthroscopic partial meniscectomy (APM), in which only the torn section of the meniscus is removed, is now the most frequently performed orthopedic operation in the United States .As compared to meniscectomy, meniscal repair is a more biologically preserving procedure as it retains the native meniscal tissue within the knee joint. Multiple repair techniques have been described in the literature, the most common of which include all-inside, inside-out, and outside-in, with no significant differences in failure rates, complication rates, or clinical outcomes . OutcomeThe decision to proceed with either meniscectomy or meniscal repair involves evaluating both meniscus tear characteristics and patient factors . Meniscal repair has been shown to decrease the incidence of early chondral degeneration and better preserve the knee\u2019s biomechanical properties as compared to meniscectomy . Both prMeniscal repairs are more commonly performed in younger patients and have shown superior outcomes over meniscectomy in patients under 45 years of age . IncreasThere are a limited number of studies directly comparing clinical outcomes between meniscectomy and meniscal repair, with those identified only having short-term follow-up periods, meniscal repairs performed concomitant with anterior cruciate ligament (ACL) reconstruction, and a limited variety of patient-reported outcome measures (PROMs) included in the clinical evaluation.PROMs quantify clinical symptomatology as directly projected by the patients themselves. Varying from general health to disease-specific, PROMs aid clinical decision-making, inform health policy strategies, and develop and refine patient-centered care . GenericThe primary aim of this study is to quantitatively evaluate patients with isolated meniscal tears using validated PROMs and compare their outcomes with patients who have undergone arthroscopic meniscus surgery. The secondary aim of this study is to compare the clinical outcomes of patients who have undergone arthroscopic meniscectomy with patients who have undergone arthroscopic meniscal repair. The primary hypothesis is that arthroscopic surgery improves symptoms of meniscus tears. The secondary hypothesis is that arthroscopic meniscal repair has superior clinical outcomes as compared to arthroscopic meniscectomy.This is a retrospective observational clinical study. All the patients included in this study attended a specialist knee clinic and underwent arthroscopic knee surgery following clinical assessment and radiological investigation. This study was exempt from Institutional Review Board (IRB)/Ethics Committee approval as it was a pragmatic study evaluating the existing clinical practice of the senior author (consultant orthopedic surgeon). This study was registered with the hospital\u2019s Clinical Effectiveness Department (registration number CA9828). This therapeutic research study constituted the first author\u2019s Masters dissertation.This study compared the clinical outcomes of three separate groups. The Pre-Operative group included patients with isolated meniscal tears of the knee joint, the Meniscectomy group included patients who had undergone an arthroscopic meniscectomy, and the Meniscal Repair group included patients who had undergone an arthroscopic meniscal repair.Exclusion criteria consisted of further surgery or further injury to the affected limb, any functionally limiting illness or disease, advanced knee osteoarthritis and concurrent ACL, posterior cruciate ligament (PCL), or lateral collateral ligament (LCL) tears. The presence of any of these factors could confound surgical outcomes reported. Exclusion of these cases ensured any symptoms expressed were attributable only to the original meniscal injury and their surgical treatment. Patients with medial collateral ligament (MCL) tears were not excluded as concurrent MCL tears are relatively common with meniscus tears and the former are predominantly treated conservatively and unlikely to confound the outcome of meniscus surgery.Subjects in the Pre-Operative group constituted a cohort of patients currently on the waiting list for knee surgery who have been clinically and radiologically (magnetic resonance imaging (MRI)) diagnosed with an isolated meniscal tear and whose symptoms were refractory to conservative treatment . The Pre-Operative group allowed for a benchmark from which to compare both surgical treatment options.Surgically treated patients in both the Meniscectomy group and the Meniscal Repair group were identified through the consultant\u2019s surgical logbook and theatre records. All arthroscopic knee surgeries performed from August 2013 to June 2021 were reviewed using the hospital electronic health record system; MediTech version 6 . The Novel Coronavirus (COVID-19) global pandemic had implications for this study as all routine elective surgical procedures (including knee arthroscopies) were canceled for an extended period of time (March 2020 onward), reducing the number of potential participants that could be recruited into this study .o to 90o for six weeks in order to protect the meniscal repair site at the initial healing phase, thereafter the brace was discontinued, and full ROM progressed. All meniscectomies were performed using standard a basket punch followed by a motorized oscillating shaver (Smith & Nephew plc.) whereby only the torn and damaged area of meniscal tissue was resected back to a stable rim . Post-operative physiotherapy rehabilitation included full weight and full ROM without any knee brace or functional restrictions. Patient notes were perused to ascertain the type of arthroscopic knee surgery performed, conformance with the inclusion and exclusion criteria, and documenting intra-operative findings, including meniscus tear laterality , tear configuration, and specific anatomic location .All meniscal repairs included in this study were performed by using an all-inside technique using FAST-FIX 360 for tears located at the posterior horn and middle third (body) of the meniscus. For anterior horn meniscus tears, an outside-in meniscal repair technique was performed using a 1 PDS II (polydioxanone) violet suture . Microfracture around the margin of the intercondylar notch was performed at the same time in order to perforate the subchondral bone and introduce mesenchymal stem cells into the knee joint which in turn optimizes the biological milieu for the meniscal tissue healing process . Post-opData from validated patient-reported outcome measures (PROMs) regarding meniscus-related symptomatology was collected from all three groups. This included the Knee Injury and Osteoarthritis Outcome Score (KOOS) ,17, InteStatistical analysisPlotted histograms with fitted curve lines, box plots, normal Q-Q plots, and the Shapiro-Wilk statistic were used to test the normality of data distribution. Almost all the PROM data (continuous variables) displayed a skewed distribution and therefore the relevant non-parametric statistical tests were used for the data analysis. The Kruskal-Wallis H test accompanied with Dunn\u2019s post-hoc pairwise comparison test was used for the three-way group data analysis. The level of statistical significance was set at p<0.05. Statistical analysis was performed using SPSS for Windows version 26.0 .Figure Baseline demographics for all three groups are summarized in Table Table Figure This study has shown that patients with isolated meniscus tears clinically improved following arthroscopic knee surgery as determined by validated PROM scores. Overall, the clinical outcome of arthroscopic meniscal repair surgery was superior to that of arthroscopic meniscectomy.This study found significantly different outcomes between pre-operative patients with an isolated meniscal tear and those who had undergone either a meniscectomy or meniscal repair surgery. The highest scores across all PROMs were observed in the Meniscal Repair group, with the lowest scores mostly seen in the Pre-Operative group. This study is the first to quantitively evaluate pre-operative patients with isolated meniscal tears using a wide variety of validated PROMs , allowing a standardized benchmark from which to compare surgical interventions and other modalities aimed at treating meniscus pathology. The results from this study demonstrate significant clinical benefit from both meniscectomy and meniscal repair surgery at a mean 55-month follow-up, a finding also shown by a similar study by Engler et al. ,10,22. THistorically, APM has been used in a non-specific manner in patients with knee pain and any form of tear ,22. ThisThe secondary hypothesis of this study was affirmed, finding significantly superior scores in the Meniscal Repair group across almost all PROMs, suggesting Meniscal Repairs have superior outcomes to Meniscectomy for isolated meniscal tears at medium-term follow-up. This finding is corroborated by a meta-analysis by Xu et al. , which sThe superior outcomes observed in this study in the Meniscal Repair cohort could be attributed to preservation of the meniscal tissue and therefore retaining the three key functions they play in the knee. First, they absorb axial loading forces through the joint, by converting them into hoop stresses within the tissue. Second, the menisci stabilize the knee by improving articular congruency between the flat tibial plateaus and concave femoral condyles. Third, they modulate the gliding of the articular surfaces. The removal of the meniscal tissue by meniscectomy impacts its ability to perform such functions and could be attributed to the greater rate of secondary osteoarthritis other studies have observed in this group .The menisci are innervated by the posterior articular branch of the tibial nerve. Similar to the ACL, they too contain mechanoreceptors that contribute to the proprioceptive function of the knee . StudiesA general comparison between the two operations shows that despite meniscal repair having greater day-of-surgery costs , greaterThe main limitation of this study was patient participation and recruitment. This clinical research study was conducted during the novel coronavirus (COVID-19) global pandemic, during which all routine elective surgery had ceased due to nationwide restrictions, resulting in a reduction of individuals eligible to take part. Additionally, due to the nature of postal questionnaires, patients were understandably apprehensive about receiving an envelope that had originated from a hospital during this time, further reducing the compliance rate. This study did not analyze longitudinal patient data of the two surgical groups as pre-operative data was not collected for these patients specifically.\u00a0However, a suitable comparable group of pre-operative patients, refractory to conservative treatment, on a waiting list for meniscal surgery was identified and used as a benchmark from which to assess and compare surgical outcomes. The range of follow-up periods was relatively broad for both groups. However, with a mean follow-up period of 57 and 47 months for the meniscectomy and meniscal repair cohorts, respectively, this study provides a useful perspective on medium-term outcomes following meniscal surgery.Despite limitations forced upon clinical research studies performed during the global pandemic, this analysis is based on comprehensive selection criteria and contributes key interpretation regarding the direct comparison between meniscectomy and meniscal repair in isolated meniscal tears, something only a limited number of papers have done in the past ,35. ThesSuggestions for future research in this field include undertaking a multicenter study that can allow for a larger cohort of patients to be investigated, particularly in the Meniscal Repair group, whilst encompassing various meniscal surgical techniques, to provide more generalizable results. It is likely that specific patient subgroups benefit by varying amounts from each surgical procedure. Larger cohorts would also aid identification of these predictive factors, allowing adequate treatment selection. Implementation of a national database of meniscal operations, similar to the National Joint Registry and the National Hip Fracture Database in the United Kingdom, would also confer these benefits on a larger scale.This study has demonstrated a significant clinical benefit in patients with isolated meniscal tears undergoing arthroscopic knee surgery. The outcomes of meniscal repair\u00a0were superior to that of meniscectomy at medium-term follow-up. Meniscal repair is a more biologically preserving procedure of the knee joint and should be performed preferentially over meniscectomy in isolated meniscal tears when feasible. The findings of this study will greatly benefit both clinicians and patients regarding the management of meniscal tears and better inform public health resource allocation."} {"text": "Major depressive disorder (MDD) is a highly prevalent mental illness that often first occurs or persists into adulthood and is considered the leading cause of disability and disease burden worldwide. Unfortunately, individuals diagnosed with MDD who seek treatment often experience limited symptom relief and may not achieve long-term remission, which is due in part to our limited understanding of its underlying pathophysiology. Many studies that use task-based functional magnetic resonance imaging (fMRI) have found abnormal activation in brain regions in adults diagnosed with MDD, but those findings are often inconsistent; in addition, previous meta-analyses that quantitatively integrate this large body literature have found conflicting results.This meta-analysis aims to advance our understanding of the neural basis of MDD in adults, as measured by fMRI activation studies, and address inconsistencies and discrepancies in the empirical literature.We employed multilevel kernel density analysis (MKDA) with ensemble thresholding, a well-established method for voxel-wise, whole-brain meta-analyses, to conduct a quantitative comparison of all relevant primary fMRI activation studies of adult patients with MDD compared to age-matched healthy controls.We found that adults with MDD exhibited a reliable pattern of statistically significant hyperactivation and hypoactivation in several brain regions compared to age-matched healthy controls across a variety of experimental tasks.This study supports previous findings that there is reliable neural basis of MDD that can be detected across heterogenous fMRI studies. These results can be used to inform development of promising treatments for MDD, including protocols for personalized interventions. They also provide the opportunity for additional studies to examine the specificity of these effects among various populations-of-interest, including youth vs. adults with depression as well as other related mood and anxiety disorders.None Declared"} {"text": "To review the pathophysiology of allergic asthma and information on the pharmacology, clinical efficacy, safety profile, and direct drug costs for omalizumab to provide a basis for a defined role of this agent in allergic asthma therapy in managed care organizations.Omalizumab is a monoclonal antibody targeting the high-affinity receptor binding site on human immunoglobulin E (IgE). When bound by omalizumab, IgE does not bind to basophils. As a result, degranulation is attenuated and allergic asthma symptoms are reduced. In asthma trials, omalizumab reduced inhaled corticosteroid and rescue medication requirements and improved asthma control and asthma quality of life in moderate-to-severe allergic asthmatics with disease poorly controlled by inhaled corticosteroids. Omalizumab has generally been well tolerated. However, injection site reactions occur in nearly 1 of every 2 patients, a problem that generally becomes less with continued dose administration. Severe injection site reactions are reported in 12% of patients. Other adverse events commonly reported in clinical trials include viral infections (23%), upper respiratory infections (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). Because the acquisition cost of omalizumab is high , its use is cost-prohibitive in all but the most severe, poorly controlled allergic asthmatic patients who are utilizing large amounts of emergency health care resources to manage exacerbations. Experience with use of this drug beyond 52 weeks is lacking.Although omalizumab has demonstrated efficacy and safety in adults and adolescents with uncontrolled moderate-to-severe allergic asthma, its use should be restricted to a narrowly defined population of allergic asthmatics who utilize large amounts of health care resources. If targeted only toward this population, cost-of-care studies suggest that the high cost of this product in these patients could be offset by savings resulting from the less frequent use of high-intensity medical services for asthma exacerbations. The use of omalizumab beyond 52 weeks needs evaluation."} {"text": "Mental Illness Stigma is a barrier in access to healthcare. Stigma also influences population health outcomes by worsening, undermining adequate processes. The healthcare professionals show several stigmatising behavirous and cognitions, which may impair the adequate provision of care of this population with mental illness.We aimed to measure mental health stigma in healthcare professionals at a portuguese hospital center.A cross-sectional study of health profissionals was performed using a survey that included socio-economic and job related questions, personal and familiar questions regarding mental health, and Attribution Questionnaire 27 (AQ-27), a translated and validated stigma questionnaire with nine stigma sub-scales .The sample included a total of 388 participants. The majority of the respondants were female . The age ranged from 22 to 69 . According to the job place distribution, we found statistically significant differences in various stigma subscales among several healthcare settings within our center. The inpatient unit professionals showed lesser stigmatising attitudes in anger, coercion, segregation and avoidance domains; and higher stigmatising attitudes in pity and help domains. However, professionals who work at surgery room showed higher stigmatising attitudes in danger and fear, but lesser levels of help domains. We also found differences in five stigma subscales among various health professions. The study didn\u2019t show differences in stigma domains regarding personal or professional contact with mental illness, neither academic studies in mental health.Our findings suggest that workplace environment and profession may impact mental ilness stigma levels in healthcare professionals. We propose that future studies could be done to investigate methods to mitigate mental illness stigma, tailored to address different stigma domains in different workplace settings.None Declared"} {"text": "Alzheimer's disease (AD) is classified as a tauopathy and is the most common neuropathological correlate of dementia/cognitive impairment. AD is neuropathologically characterized by the presence of beta-amyloid immunoreactive senile plaques and tau positive neurofibrillary tangles. Neuropsychiatric symptoms of AD however continue to be underscored, and therefore, neuropathological correlates of these neuropsychiatric symptoms are not readily studied. Presented here is a case of 60-year-old female who initially presented with anxiety and depression, and continued to be the predominant symptoms although mild cognitive impairment was noted as per the available clinical notes. Postmortem examination of the brain revealed severe Alzheimer's type neuropathological changes, which included significant tau and beta-amyloid pathology in limbic regions, which were thought to represent correlates of the patient's depression and anxiety. This case report illustrates the possible neuropathological correlates of neuropsychiatric symptoms in patients with AD. The author hopes that such a case will promote more in-depth studies into the pathophysiology of neuropsychiatric manifestations in AD. Alzheimer's disease (AD) is regarded as a tauopathy associated with cognitive and functional decline in typically elderly (>65\u2009years) patients although cases of early-onset (before age of 65\u2009years) are possible . NeuropaLimited clinical information was available on the electronic medical chart. As per the information available, this female patient who was 60\u2009years-old at first presentation reported difficulty with short-term memory along with difficulty sleeping. Psychiatric history included depression and anxiety. Neurological examination was notable for mini mental status (MMSE) of 25/30. The patient was clinically diagnosed with mild cognitive impairment based on the MMSE score. Unfortunately, no additional clinical information regarding her cognition could be found. With regards to her depression and anxiety, the patient reported feeling sad about some aspects of her life, and the episodes of sadness were exacerbated by difficulty in her first marriage and from having to switch employment. Clinically, she was diagnosed with major depressive disorder, generalized anxiety disorder, and mild cognitive decline.The patient passed away at hospice facility. After passing, a restricted autopsy limited to postmortem examination of the brain was requested to determine the etiology of her cognitive impairment.The weight of the unfixed brain was recorded at 1330\u2009g. The cerebral hemispheres did not seem to display any significant atrophy. The coronal slices of the cerebral hemispheres did not reveal evidence of atrophy. Ventricular caliber appeared unremarkable. Hippocampus and amygdala did not appear shrunken. Pigment was visible in both the substantia nigra of the midbrain and locus ceruleus of the pons.Histologic examination with immunohistochemical work-up revealed evidence of cerebral amyloid angiopathy in the form of thickened blood vessels in the leptomeninges that were stained by beta amyloid immunohistochemistry. Sampled sections from the cerebral hemispheres showed several beta amyloid positive diffuse plaques and moderate amount of senile plaques throughout neocortex, including cingulate, calcarine, and entorhinal cortices, as well as in the thalamus. There were also scattered tau positive neurofibrillary tangles, neurites, and neuropil threads throughout the cortical gray matter including the superficial and deep layers of the calcarine cortex and entorhinal cortex. Thickened blood vessels that were not stained by beta amyloid immunohistochemistry, and hence consistent with arteriolosclerosis, were noted in the subcortical white matter. Left amygdala showed scattered tau positive neurofibrillary tangles, pretangles, neurites, neuropil threads, and argyrophilic grains. There were also numerous beta-amyloid positive diffuse and senile plaques in the amygdala. Examples of these findings are shown in Midbrain showed some beta amyloid positive diffuse and senile plaques. Although beta amyloid staining was observed in blood vessels of the cerebellar leptomeninges, no definite beta amyloid staining is seen within the cerebellar parenchyma.The final neuropathological diagnosis was reported as Alzheimer's type neuropathological changes ; Braak (neurofibrillary tangle) stage\u2009=\u20096 of 6; CERAD (senile plaque) score\u2009=\u2009C2 (moderate)); cerebral amyloid angiopathy; relatively mild arteriolosclerosis.n\u2009=\u2009906) that psychotic symptoms were more strongly related to the continuum of AD-associated cognitive dysfunction than other neuropsychiatric symptoms. The group also observed a negative correlation between psychotic symptoms and brain volume [n\u2009=\u20091038) that included AD and Lewy body disease pathology. The authors reported higher neurofibrillary tangle (NFT) stages to be associated with depression and agitation and hallucinations associated with higher Lewy body stages [To the author's knowledge, this case is one of the first case examples to demonstrate neuropathological correlation between Alzheimer's type neuropathological changes and clinical history of neuropsychiatric symptoms. Neuropsychiatric symptoms are described in patients with Alzheimer's disease, and animal models have suggested that behavioural and psychological symptoms increase with progressive neuropathology . Depressy stages . These rAPOE-region, respectively. Association analysis excluding the APOE-region identified numerous SNPs corresponding to 40 genes, 9 of which were known LOAD-risk loci primarily in chromosome 11 regions containing the SPI1gene and MS4A genes cluster, and others were novel pleiotropic risk-loci for LOAD conditional with MDD [Interestingly, genetic etiologies shared between AD and depression have been reported. Chiba\u2010Falek et al. performed pleiotropy analysis using genome-wide association studies (GWAS) from publicly accessible websites of AD GWAS and major depressive disorder (MDD) GWAS. The group found moderate enrichment of single nucleotide polymorphism (SNP) associated with late-onset AD (LOAD) across increasingly stringent levels of significance with the MDD GWAS association (LOAD|MDD), of maximum four and eight-folds, including and excluding the Herein, the author has presented neuropathologically severe Alzheimer's type neuropathological changes in a patient whose predominant presentation seems to be neuropsychiatric in the form of anxiety and depression. It is hoped that such a case will encourage further studies of the neuropathological correlates and pathophysiology of neuropsychiatric symptom in AD and other neurodegenerative disorders."} {"text": "During the COVID-19 pandemic, mental health services often used remote technology to deliver care. However, the rise in remote consultation was largely unplanned. Furthermore, while many patients found remote technology a useful way to access care, others did not. Going forwards, remote technology will continue to play an important role in the delivery of mental healthcare. Research on the most effective ways for mental health services to implement remote technology is thus urgently needed.Electronic health records (EHRs) have been widely adopted in mental healthcare services. EHRs not only support individual patient care, but also open the door to largescale research through the analysis of de-identified clinical data. The South London and Maudsley (SLaM) Biomedical Research Centre (BRC) Case Register is a large EHR dataset comprising structured and unstructured clinical information on patients receiving specialist mental healthcare. In this talk, I will present findings from an analysis of the SLaM BRC Case Register using the Clinical Record Interactive Search tool (CRIS) to evaluate the uptake of remote mental healthcare during the COVID-19 pandemic and its association with medication prescribing. I will discuss the implications of these findings for psychiatrists delivering community mental healthcare and how mental health services can harness remote technology to optimise clinical outcomes.R. Patel Grant / Research support from: NIHR (NIHR301690); MRC (MR/S003118/1); Academy of Medical Sciences (SGL015/1020); Janssen, Consultant of: Induction Healthcare Ltd; Holmusk"} {"text": "Teaching Point: Subarachnoid hemorrhage is a rare complication of spinal dural arteriovenous fistulas (dAVF) with very characteristic imaging features, knowledge of which is crucial for positive diagnosis and rapid management. We report the case of 45-year-old male without a known history of neurological disease, presenting progressive weakness of lower limbs and tingling-like paresthesia. The evolution of the disease is marked by the onset of thunderclap headache. An endocranial computed tomography (CT) performed in the emergency department showed no particular anomaly. Then, a cerebral magnetic resonance imaging (MRI) was performed showing on axial images hyperintensity in the subarachnoid compatible with a peri mesencephalic subarachnoid hemorrhage space on T2 FLAIR with a normal time of flight (TOF) angiography .Cerebral angiography showed no specific findings.A medullar MRI was then suggested and demonstrated on T2-sagittal MRI intramedAlso, it showed on axial T2 and postPatient was put under surveillance with symptomatic treatment and showed a recovered partial recovery of his motricity and sensitivity.Spinal dural arteriovenous fistulas (dAVF) are the most common spinal vascular malformations (75 to 80%) and more frequently affect male subjects over 50 years that exhibits arteriovenous shunting at the level of the internal leaflet dura mater, corresponding to an abnormal connection between the arterial supply from the medullary dura mater and the medullary venous system and no exact etiology has been fully elucidated .The clinical presentation of sdAVF is often progressive and non-specific mimicking demyelinating or degenerative diseases of the spine, which explains a frequent delay in diagnosis, resulting in an irreversible damage despite an endovascular or surgical intervention.Hemorrhage is very rare but occasionally encountered and may be a source of unexplained subarachnoid hemorrhage.MRI shows an association of centrally located hyperintense signal on T2-weighted images on TSE sequence, corresponding to chronic hypoxic congestive myelopathy attributable to venous hyper pressure hindering venous circulation, dilated peri medullary vessels, hypointense \u2018flow void\u2019 phenomena hypo intense in T2w images, appearing as enlarged and serpiginous veins anteriorly and/or posteriorly to the cord, enhancing after administration of gadolinium The absence of dilated peri medullary vessels do not formally eliminate the diagnosis of Davf. Dynamic MRA (angio-MRI) sequences are more sensitive assets to detect this abnormality.Principal differential diagnosis on imaging includes intramedullary neoplasm, spinal arteriovenous malformation where hemorrhage is common with acute onset, affecting males and females equally.Our case is unique as it depicts the importance of including spinal cord malformations in unexplained cerebral sub arachnoid hemorrhages."} {"text": "ObjectiveCaregivers support individuals undergoing cancer treatment by assisting with activities, managing care, navigating healthcare systems, and communicating with care teams. We explored the quantity and quality of caregiver participation during recorded clinical appointments in women with metastatic breast cancer.MethodsThis was a convergent parallel mixed methods study. Caregiver participation quality was operationalized using a summative thematic content analysis to identify and sum caregiver roles performed during appointments. Caregiver participation quantity was measured by calculating the proportion of speaking time. Participation quality and quantity were compared to patient activation, assessed using the Patient Activation Measure.ResultsFifty-three clinical encounters were recorded. Identified caregiver roles included: General Support; Management of Treatment or Medication; Treatment History; Decision-Making; Insurance or Money; Pharmacy; Scheduling; Travel Concerns; General Cancer Understanding; Patient Specific Cancer Understanding; Caregiver-Initiated or Emphasis on Symptom Severity; and Caregiver Back-Up of Patient Symptom Description. Caregivers averaged 5 roles (SD 3): 48% of patients had low quality (<\u20095 roles) and 52% had high quality (>\u20096 roles). Regarding quantity, caregivers spoke on average for 4% of the encounter, with 60% of patients having low quantity (<\u20094%) and 40% of patients having high quantity (>\u20094%). Greater quality and quantity of caregiver participation was associated with greater patient activation.ConclusionsCaregivers perform a variety of roles during oncological decision-making visits aiding both patient and provider. Greater participation in terms of quantity and quality by the caregiver was associated with greater patient activism, indicating a need for better integration of the caregiver in clinical decision-making environments."} {"text": "Populations face a suite of anthropogenic stressors acting simultaneously, which can combine additively or interact to have complex effects on population persistence. Yet we still know relatively little about the mechanisms underlying population-level responses to multifactorial combinations of stressors because multiple stressor impacts across organisms\u2019 life cycles have not been systematically considered in population models. Specifically, different anthropogenic stressors can have variable effects across an organism\u2019s life cycle, resulting in non-intuitive results for long-term population persistence. For example, synergistic or antagonistic interactions might exacerbate or alleviate the effects of stressors on population dynamics, and different life-history stages or vital rates might contribute unequally to long-term population growth rates. Demographic modelling provides a framework to incorporate individual vital rate responses to multiple stressors into estimates of population growth, which will allow us to make more informed predictions about population-level responses to novel combinations of anthropogenic change. Without integrating stressors\u2019 interactive effects across the entire life cycle on population persistence, we may over- or underestimate threats to biodiversity and risk missing conservation management actions that could reduce species\u2019 vulnerability to stress. As humans alter multiple facets of the environment simultaneously, addressing multiple, potentially interacting stressors will be critical for predicting species' responses. Yet the effects of multiple stressors across organisms' life cycle has not been systematically considered in demographic studies. Here, Zettlemoyer proposes a framework to explore the role of multiple stressors on population dynamics in order to make realistic predictions about population viability under different conservation scenarios. Specifically, demographic modelling provides a method to integrate stressors' potential additive and non-additive effects across the entire life cycle, provide mechanistic explanations of species loss and spread under combinations of novel conditions, and improve conservation and management plans. Reviews report that only 136 studies integrate multiple vital rate responses into plant demographic models interactions among anthropogenic stressors and (ii) counteracting effects of stressors on different vital rates might influence population dynamics. Finally, I outline potential experimental designs that integrate multiple stressor effects across the life cycle to predict extinction risk under future environmental conditions.sensuadditive effects, wherein the combined effects of two stressors are equal to the sum of their individual effects (Alliaria petiolata (garlic mustard) interacts additively with deer herbivory to reduce population growth rates of Trillium erectum , only the combination of high levels of interspecific competition and insect herbivory results in population decline and Viola palustris .Eurybia furcata (forked aster), but only when site-level woody encroachment and deer herbivory are high (Cypripedium candidum (white lady\u2019s slipper) under moderate climate change scenarios. However, as drought stress increases, protecting groundwater recharge zones in sites near this hydrologically sensitive species becomes increasingly important (\u03bb as a function of multiple interacting (a)biotic environmental conditions . In order to examine differences in \u03bb between multiple stressors and determine the most relevant vital rate, log-transforming \u03bb will help interpret the impact of vital rates on \u03bb can quantify the sensitivity of \u03bb to changes in each vital rate and/or environmental variable drive differences in \u03bb. For example, invasion and deer herbivory affect multiple vital rates in T. erectum (red trillium), including growth and seedling recruitment, but an LTRE revealed that decreases in fertility largely drive declines in plant fitness , growth and survival show compensatory responses to warming that buffers overall population growth , compensatory responses of ramet growth and clonal reproduction buffer populations from the effects of grazing and harvest , density-dependent mortality due to post-dispersal seed consumption decreases seedling density, resulting in increased fecundity and therefore compensating for low seedling numbers (Pityopsis aspera var. aspera (pineland silkgrass), increasing density decreases \u03bb, but this effect is alleviated by fire . Thus, IPMs, by incorporating environmental covariates in sub-regressions and allowing the use of size-based regression than discrete size classes, can overcome potential pitfalls of underpowered designs or smaller datasets , temperature and precipitation affect fecundity but not growth or survival matrix population models, which use stage- or age-structured state variables and (ii) IPM, which use continuous (often size-dependent) state variables to predict population growth rates as well as (iii) population viability analyses that estimate population size (e.g. count data) from one monitoring event to the next.Vital rates: Rates corresponding to an organism\u2019s individual life stages or progression through development .Additive effects: Type of interaction when the combined impact of two or more stressors on an ecological response is equal to than their algebraic sum; in this case, studies of single stressors can be added to estimate their combined effect.Non-additive interactions: Type of interaction when the combined impact of two or more stressors on an ecological response is not equal to their algebraic sum, such that the intensity of response to one stressor changes with the presence of the other; can be synergistic or antagonistic.Synergistic: Type of non-additive interaction when the combined impact of two or more stressors on an ecological response is greater than their algebraic sum; one stressor can exacerbate the effects of another.Antagonistic: Type of non-additive interaction when the combined impact of two or more stressors on an ecological response is less than their algebraic sum; one stressor can alleviate the effects of another.Perturbation analyses: Demographic analyses exploring how population growth rates respond to changes in vital rates; types of perturbation analysis include (i) prospective analyses (e.g. sensitivity and elasticity) that test how much \u03bb depends on vital rates independent of variability and (ii) retrospective analyses (e.g. LTRE) that decompose variance in \u03bb as a function of variance in vital rates.Demographic compensation: Opposing vital rate responses to stressors wherein the positive effects of one vital rate can negate the negative effects of another.Density-dependent processes: Population-level processes that are sensitive to fluctuations in population density .Kernel: A probability density function that maps the change in the size distribution of individuals at time t to the size distribution after one timestep (t + 1)."} {"text": "Acne vulgaris is a common skin condition that affects both adolescents and adults worldwide and frequently results in acne scars . AtrophiA 2016 Cochrane study providedData from some of the included RCTs showed that fractional laser, chemical peeling (with and without skin needling), and injectable fillers were more effective than comparator treatments. Many studies that compared other treatment modalities to each other or to placebo concluded no significant difference in either participant-reported or investigator-assessed scar improvement. This review found moP=.0005). Another multicenter, randomized, prospective study [P=.0136). These studies further support the efficacy of injectable fillers for treating acne scars, though additional research with long-term follow-up is warranted to assess the durability of outcomes.Results of clinical trials published subsequent to this review provide"} {"text": "Angioleiomyoma, a rare variant of leiomyoma, is a benign tumor of mesenchymal origin. Angioleiomyomas of the female urogenital tract are extremely rare, with only six cases of uterine cervical angioleiomyoma previously reported in the literature. In this case study, we report on a 49-year-old female patient who presented with menorrhagia whose initial magnetic resonance imaging (MRI) findings suggested cervical squamous cell carcinoma (SCC). However, following the hysterectomy, histological examination confirmed the lesion to be angioleiomyoma. To the best of our knowledge, there have been no previously reported cases of angioleiomyomas presenting with MRI findings that are suggestive of uterine SCC. Recognizing that angioleiomyomas can mimic uterine malignancies on MRI may prove beneficial for future diagnostic and treatment strategies."} {"text": "Background: Measles is a highly transmissible respiratory virus that presents with nonspecific prodromal symptoms followed by a characteristic cephalocaudal rash. In the prodromal phase, children with measles can be challenging to differentiate from children with other circulating respiratory viral infections. A measles outbreak in Central Ohio starting in October 2022 coincided with a national surge in children with viral respiratory infections which presented unique challenges in preventing healthcare transmission in the pediatric ambulatory setting. Methods: Following initial identification of presumed community transmission of measles in Central Ohio in November 2022, a multidisciplinary measles response team was convened at Nationwide Children\u2019s Hospital (NCH) to prevent secondary healthcare transmission via rapid-cycle quality improvement. Prevention efforts were focused broadly across NCH ambulatory locations in Central Ohio, including the main campus and offsite emergency departments, regional urgent cares, and primary care network. Preliminary risk factors were identified via chart review of initial cases, which included vaccine status, ZIP code of residence, and known daycare or household exposure. These risk factors were used to guide an intervention bundle comprising enhanced screening at registration and triage, creation of electronic medical record alerts to identify at-risk patients, increased clinician education, and expanded community messaging. As the outbreak evolved, risk factors were updated, and interventions were adjusted to adapt response. Outcome metrics included total patient exposures as well as the relative exposure score. The exposure score was an internal metric derived using the vaccine status of exposed patients and ventilation at the site of exposure to assess likelihood of secondary cases occurring from an exposure. Results: In total, 65 patients with measles were seen at NCH facilities between October 29 and December 8, 2022. The outbreak response was divided into 4 periods: (1) cases identified retrospectively prior to first diagnosis , (2) initial case discovery , (3) implementation of prevention bundle , and (4) updates to the response . Ambulatory healthcare exposures and incidence of secondary cases decreased over the outbreak periods in response to implementation of the prevention bundle . Conclusions: An outbreak of measles occurring simultaneously with peak respiratory viral season presented challenges in early identification of suspected cases and mitigation of healthcare exposure. Transmission was effectively prevented following rapid deployment of a prevention bundle adjusted in real-time through rapid-cycle quality improvement. Ongoing longitudinal vaccination efforts are needed to sufficiently mitigate transmission risk in communities with under-vaccinated populations.Disclosures: None"} {"text": "Background: A sustainable, continuous supply of alcohol-based hand rub (ABHR) is essential for healthcare workers in health facilities. The WHO provides guidance for production in individual health facilities. In Uganda, using this guidance, an innovative approach was implemented at the district local government level to produce and subsequently distribute ABHR to primary-care health facilities that have limited capacity for local facility-level production. This project was supported by the CDC in collaboration with the Infectious Diseases Institute (IDI) and targeted governmental or district engagement with local partners to ensure sustainability. Methods: District stakeholders were engaged to obtain buy-in and define roles and responsibilities. Overall, 4 staff members in each of 6 supported districts were nominated by District Health Officers for training: 2 staff members were trained to produce ABHR and conduct internal quality control and 2 were trained on external quality control. Districts provided ABHR production-unit facilities and facilitated integration within the government essential supplies delivery system, National Medical Stores in Uganda, which supports last-mile delivery to facilities. An implementing partner purchased initial raw materials necessary for production. The cost of materials for local production was compared to the price of commercial ABHR available in Uganda. Results: Between January and August 2021, 23 staff members were trained, and 380 batches of quality-assured ABHR were produced and distributed to 278 health facilities. Consumption of ABHR in the first distribution was used to benchmark predicted ABHR consumption per targeted facility in subsequent months. Increased demand for ABHR due to the COVID-19 pandemic and the Ebola virus disease outbreak in central Uganda (September 2022) was addressed through emergency requests on a case-by-case basis. ABHR local production costs $3 per liter for materials, less than half of commercial ABHR ($8 per liter). Conclusions: Early results suggest that this approach is potentially sustainable but requires national advocacy as well. Leveraging existing distribution systems while building local capacity for ABHR production and distribution may improve longevity of such innovations in similar resource-limited settings.Disclosure: None"} {"text": "Mild traumatic brain injury is a complex neurological disorder of significant concern among athletes who play contact sports. Athletes who sustain sport-related concussion typically undergo physical examination and neurocognitive evaluation to determine injury severity and return-to-play status. However, traumatic disruption to neurometabolic processes can occur with minimal detectable anatomic pathology or neurocognitive alteration, increasing the risk that athletes may be cleared for return-to-play during a vulnerable period and receive a repetitive injury. This underscores the need for sensitive functional neuroimaging methods to detect altered cerebral physiology in concussed athletes. The present study compared the efficacy of Immediate Post-concussion Assessment and Cognitive Testing composite scores and whole-brain measures of blood oxygen level\u2013dependent signal variability for classifying concussion status and predicting concussion symptomatology in healthy, concussed and repetitively concussed athletes, assessing blood oxygen level\u2013dependent signal variability as a potential diagnostic tool for characterizing functional alterations to cerebral physiology and assisting in the detection of sport-related concussion. We observed significant differences in regional blood oxygen level\u2013dependent signal variability measures for concussed athletes but did not observe significant differences in Immediate Post-concussion Assessment and Cognitive Testing scores of concussed athletes. We further demonstrate that incorporating measures of functional brain alteration alongside Immediate Post-concussion Assessment and Cognitive Testing scores enhances the sensitivity and specificity of supervised random forest machine learning methods when classifying and predicting concussion status and post-concussion symptoms, suggesting that alterations to cerebrovascular status characterize unique variance that may aid in the detection of sport-related concussion and repetitive mild traumatic brain injury. These results indicate that altered blood oxygen level\u2013dependent variability holds promise as a novel neurobiological marker for detecting alterations in cerebral perfusion and neuronal functioning in sport-related concussion, motivating future research to establish and validate clinical assessment protocols that can incorporate advanced neuroimaging methods to characterize altered cerebral physiology following mild traumatic brain injury. et al. report that blood oxygen level\u2013dependent signal assessed by functional MRI outperforms a standard post-concussion neurocognitive test for classifying concussed athletes and predicting post-concussion symptoms. Blood oxygen level\u2013dependent signal variability may hold promise as a neurobiological marker for alterations in cerebral perfusion and functioning following concussion.Anderson Athletes with minimal physiological and neurocognitive symptoms may therefore be cleared to return-to-play prematurely, which can exacerbate symptoms, increase risk for severe secondary injuries and complicate or prolong recovery.8 Thus, current research aims to discover neurobiological markers that can be used to objectively assess the presence and severity of SRC and to determine when the brain has recovered sufficiently to permit safe return-to-play.Clinicians rely on a variety of assessments to diagnose SRC, including brief neurological examinations, symptom checklists, neurocognitive tests 9 Acute biomechanical injury\u2014sudden stretching of neuronal and axonal membranes\u2014triggers a cascade of neurometabolic changes including the abrupt release of neurotransmitters, ionic fluxes and unregulated extracellular glutamate release, ultimately leading to hyperglycolysis and axonal injury or cell damage.8 This intricate \u2018neurometabolic cascade\u20198 can manifest sequelae including dizziness, nausea, headache, insomnia, amnesia, attentional issues and other physiological and neurocognitive symptoms.11Concussion symptoms reflect a complex series of neurometabolic events that occur during and after the initial impact. Physiological damage from SRC typically occurs in stages, starting with the initial impact or change in velocity and subsequent structural deformation.13 Repetitive TBI in these areas is a particularly serious concern in SRC, as secondary blows that occur during this vulnerable metabolic window can produce catastrophic secondary impairments,14 highlighting the need for accurate diagnostics for safely clearing individuals to return to normal activity following a concussion.Several brain regions, including anterior frontal and temporal areas, medial temporal structures, corpus callosum and subcortical white matter pathways, are particularly vulnerable to bruising and injuries caused by inertial forces.15 researchers have increasingly utilized more advanced functional neuroimaging techniques to elucidate underlying changes in neuropathology post-injury.16 Functional MRI (fMRI) has shown promise for characterizing alterations in neural function post-mTBI across multiple domains. Task-based fMRI studies have demonstrated changes in activation in the parietal cortex, dorsolateral prefrontal cortex and the hippocampus in concussed athletes relative to healthy controls.17 Further, functional connectivity assessed from resting-state fMRI revealed altered connectivity within the default mode, fronto-parietal and motor-striatal networks relative to controls in individuals with mTBI.19 fMRI methods may provide objective biomarkers of neurophysiological injury, affording greater sensitivity and specificity for SRC diagnoses. Recent research suggests that while structural imaging and neurocognitive tests did not accurately discriminate mTBI patients from controls, resting-state functional connectivity measures correctly classified SRC status and predicted long-term cognitive sequealae.20 Functional neuroimaging methods may facilitate SRC evaluation through identification of altered haemodynamics and neurometabolism, detecting impaired neurovascular coupling, cerebral blood flow (CBF) and oxygen metabolism associated with abnormal brain function.21As neurobiological correlates of cognitive and mental health dysfunction from SRC are difficult to detect with standard axial neuroimaging techniques ,23 and that patterns of variability as measured from blood oxygen level\u2013dependent (BOLD) signal are closely linked to neural information processing, cognitive function and brain health.25 Recent studies have demonstrated that BOLD variability can detect vascular pathologies in cerebral small vessel disease,26 Alzheimer\u2019s disease,27 post-traumatic stress disorder28 and stroke29 by capturing underlying differences in cerebrovascular compliance26 that alter haemodynamic function and neurovascular coupling, motivating the investigation of BOLD variability for detecting neurophysiological alterations in mTBI.Neuroscience evidence demonstrates that regional brain activity is inherently variable over time31 increased reactivity of smooth muscle in microvessel walls32 and reduction in the density and diameters of capillaries both proximal and distal to the site of injury.33 Furthermore, altered BOLD variability can indicate sites of neural proliferation and synaptogenesis, indexing post-mTBI neuroplasticity that drives changes in neural signalling and BOLD activation during recovery.15 BOLD variability may therefore serve as a biomarker of changes in individuals\u2019 cerebral vascular status during and following traumatic neurophysiological insult, potentially assisting in the diagnosis of SRC.Mechanisms that may alter BOLD variability following mTBI may include changes in cerebral perfusion,The aim of the present study is to compare regional measures of BOLD variability and cognitive assessment scores for their complementary roles in the evaluation of SRC. Neuroimaging indices of BOLD variability may represent a novel lens for objectively evaluating SRC status by detecting functional disruption, providing information beyond conventional neuropsychological assessment batteries that may improve the detection and management of concussion pathology. While clinically informative, neurocognitive assessments remain limited in their ability to assess the extent of injury or identify neurophysiologically vulnerable individuals. To investigate the potential role of neurocognitive testing and functional neuroimaging in SRC diagnosis, we examined group differences in regional BOLD signal variability and neurocognitive performance on ImPACT in athletes diagnosed with SRC (compared against age-matched control athletes without SRC). We then applied a supervised machine learning algorithm (bagged ensemble random forests) to assess whether whole-brain BOLD variability measures, ImPACT module scores or BOLD and ImPACT composite scores together can discriminate healthy, concussed and repetitive concussion patients. We further applied bagged random forests to assess the extent to which regional BOLD variability measures and ImPACT scores in isolation or combination accurately predict clinical symptom load. Our study therefore assessed BOLD variability in both classification and regression machine learning frameworks for detecting SRC status or post-concussion symptoms from functional neuroimaging data .This study was carried out in accordance with the recommendations and approval of the University of Birmingham Research Ethics Committee. The protocol was also approved by the National Institute of Health Research Centre for Surgical, Reconstruction and Microbiological Research Centre (NIHR SRMRC\u2014Ethics Ref. 11-0429AP28). All subjects gave written informed consent in accordance with the Declaration of Helsinki. Deidentified data from this cohort may be made available by the authors on request.34 Participants included 29 semi-professional rugby athletes diagnosed with SRC and 6 additional rugby athletes diagnosed with repetitive SRC over a 21-day window. Athletes were excluded if they required hospital admission after initial assessment for concussion; presented with intracranial blood, brain tissue injury or non-concussion\u2013related pathologies on initial CT/MR scan; or had history of neurodegenerative pathology or chronic alcohol or drug abuse. In addition, 15 age-matched controls who have not received a concussion in the previous 3 months were enrolled. Other study design features are reported in Yakoub et al.34Study participants were recruited through the Surgical Reconstruction and Microbiology Research Centre (SRMRC), based at Queen Elizabeth Hospital of Birmingham (United Kingdom), as part of the repetitive concussion in sport (RECOS) study.1-weighted magnetization-prepared gradient echo structural image was acquired for each participant .All data were collected on a 3 Tesla Philips Achieva MRI scanner in Birmingham University Imaging Centre (BUIC). A high-resolution multi-echo T35 sensitive to BOLD contrast .The functional neuroimaging data were acquired using an accelerated single-shot gradient echo echoplanar imaging (EPI) sequenceDuring the resting-state fMRI scan, participants were asked to keep their eyes closed. Visual contact could be established at any time to the control room via a coil-mounted reverse mirror. All participants were instructed to lie still, keep their eyes closed and to try and think of nothing.fMRIPrep 20.2.037 and XCP Engine 1.0.39 Pre-processing entailed slice timing correction, motion correction, spatial smoothing [3\u2005mm full width at half maximum (FWHM) kernel], nuisance signal regression, temporal bandpass filtering, linear registration of functional images to structural images and non-linear registration of structural images to a standard-space MNI152 brain template (2\u2005mm isotropic voxel resolution).All MRI data processing was performed using containerized processing pipelines for reproducible analysis of neuroimaging data. Pre-processing steps were performed using 40 All nuisance variables were modelled via a single generalized linear model (GLM), to remove spurious correlations and noise introduced by head motion and variables of no interest. In addition to ICA-AROMA components classified as noise, these included head motion correction parameters, individual volume motion outliers estimated using DVARS41 with outliers flagged above 1.5 standardized DVAR, framewise displacement exceeding 0.5\u2005mm and mean white matter and cerebrospinal fluid signals averaged across all voxels identified from the segmentation of the high-resolution magnetization-prepared rapid gradient echo (MPRAGE). The fully pre-processed resting-state fMRI data were taken as the residuals from this GLM model. The residual image was transformed into normalized MNI152 space and resampled to 4\u2005mm isotropic voxels.Head motion parameters were accounted for using independent component analysis with automatic removal of motion artefacts (ICA-AROMA) analysis.43 BOLD signal variability was computed as the standard deviation of successive differences in the time-series signal extracted for each of the 200 grey matter regions defined by the Schaefer parcellation atlas.44 MSSD mean-centres the amplitude of difference in BOLD signal between frames, providing a more reliable metric of BOLD variability than standard deviation by avoiding inflated estimates of variability. The Schaefer 200 atlas provided sufficient spatial resolution and functional homogeneity within each parcel for examining regional MSSDBOLD signal across the entire cortex.Resting-state mean square successive difference (MSSD)45 The test was designed in the early 1990s specifically to assess concussed players of the National Football League46 and is now a Food and Drug Administration (FDA)\u2013approved neuropsychological testing tool in SRC.47 Inclusion of this particular cognitive test has been demonstrated to increase the sensitivity of post-concussion assessment beyond symptomatic evaluation and physical examination.48Participants completed the 25\u2005min computerized ImPACT assessment under identical administration conditions. ImPACT is a multi-domain online neuropsychological test that has been used as a standard technique documenting baseline cognitive function, characterizing the effects of concussive injury and monitoring the progress of recovery.49 and test\u2013retest reliability.50ImPACT includes a demographic survey, a brief medical history questionnaire and a post-concussion symptom scale consisting of 22 commonly reported symptoms. All participants indicated whether they endorsed each symptom and rated the extent of symptom severity on a seven-point Likert scale (0 = \u2018not experiencing the symptom\u2019 to 6 = \u2018severe\u2019). Scores were summed with higher scores reflecting more post-concussive symptoms. The six neurocognitive ImPACT sub-tests consist of word memory, design memory, X\u2019s and O\u2019s, symbol match, colour match and three letters. Five neurocognitive domain scores are derived from the sub-tests: verbal memory, visual memory, visual\u2013motor processing speed, reaction time and impulse control. Higher scores on the verbal memory, visual memory and visual\u2013motor processing speed composites reflect stronger performance, whereas a higher score on the reaction time composite reflects slower or worse performance. The impulse control composite provides a measure of errors on testing and is used to determine test validity. Test scores were converted to percentile measures and adjusted for age, gender, learning disability and level of education. ImPACT has adequate psychometric properties, including good construct validity34 Measures collected include Digit Span,51 Digit Symbol Coding and Symbol Search,52 a nine-hole peg test of fine motor dexterity53 and balance assessments including a virtual reality system,54 gait analysis56 and the modified balance error scoring system (mBESS),57 facilitating precise concussion diagnosis. Additional assessments, inventories and neuroimaging components collected by the RECOS protocol are reported in Yakoub et al.34As part of the RECOS study protocol, study participants completed additional screening and assessment inventories to examine clinical presentation of SRC.BOLD measures and ImPACT module composite scores, statistical unpaired t-tests were performed and corrected for multiple comparisons using Benjamini\u2013Hochberg control of the false discovery rate (FDR). These comparisons provide for interpretable identification of the specific ImPACT scores and modules most readily associated with SRC status, assessing for group-level effects of SRC and repetitive mTBI that emerge in variables used by our machine learning framework.To identify between-group differences in regional MSSD58 RF machine learning achieves high prediction accuracy when presented with a large number of input variables relative to the sample size,60 as is the case for our neuroimaging data, while still performing well with small numbers of input variables (as is the case for ImPACT scores). This importantly affords the ability to directly compare predictions of concussion status and post-concussion symptoms made by modelling BOLD variability and ImPACT composite scores using the same machine learning approach. Other motivations for selecting RF machine learning for this study include RF\u2019s understood performance, ease of use and resistance to outliers, as well as its capability to consider all BOLD variability regions jointly, avoiding an initial feature selection or engineering step in support of the exploratory nature of this study. Critically, this approach avoids using the results from between-group feature comparisons of BOLD variability to subset regional BOLD variability features that build a smaller and better-performing RF model, as feature engineering BOLD variability metrics is not a goal of the present study.BOLD variability indices and ImPACT composite scores were further assessed for their ability to differentiate healthy, concussion and repetitive concussion subjects and predict clinical symptom load using a random forest (RF) machine learning approach. RF is an ensemble machine learning method that trains an ensemble (i.e. forest) of decision trees to perform either classification or regression.BOLD measures and ImPACT composite scores were used variously as input features (i.e. independent variables), with output features (i.e. dependent variables) being group membership (classification) or post-concussion symptoms (regression). Each RF ensemble was parameterized using leave-one-out crossfold validation, with the minimum leaf size being the only tuned parameter. For ImPACT score models, minimum leaf size was tuned to 5 (preventing overfitting); otherwise, minimum leaf size was tuned to 20. Trees were grown by splitting input variables to maximize reduction in the Gini impurity index,61 repeated iteratively until maximum depth is reached or when all samples belong to a single class. The number of decision trees was increased until mean squared error (MSE) of out-of-bag (OOB) classification or regression predictions stabilized . Forests were grown to 5000 trees total.In our approach, bagged RF regression and classification were performed using built-in functions in MATLAB R2021a. MSSDK from a model fold (i.e. bag) that has been trained with resampling from all other athletes in our data set N, affording a direct test of RF models\u2019 ability to generalize their training data to unseen test set (i.e. OOB) subjects. The overall OOB prediction performance of RF machine learning evaluate three separate sets of input features: (i) ImPACT module composite scores, (ii) whole-brain MSSDBOLD measures and (iii) ImPACT score and MSSDBOLD measures jointly combined. This approach allows us to assess the utility of BOLD variability or ImPACT scores in isolation or combination when predicting SRC status and post-concussion symptoms. One versus all receiver operating characteristic (ROC) curves were calculated for the classification of each group across the three classes of RF models, indicating the true positive rate (i.e. correctly predicting group membership) versus the false positive rate (i.e. incorrectly predicting group membership in the next most likely classification).Individual RF machine learning predictions were generated from an ensemble of OOB decision trees, where the ensemble of decision trees that generate a prediction did not include the test subject\u2019s data in any resampled training data set. Restated, the set of decision trees used to make a prediction for test predicts subject The ROC area under the curve (AUC) was computed for all combinations of group and model to diagnose the overall prediction performance of each class. This AUC is the integral of the ROC curve\u2014i.e. the probability that the conditional probability of a random positive observation is greater than the conditional probability of a random negative observation. Thus, larger probabilities represent greater sensitivity and specificity for the positive label, suggesting greater utility for detecting SRC.For regression models, RF machine learning was instead trained to predict total reported post-concussion symptoms from the same combinations of input BOLD variability and ImPACT score variables (while ignoring group membership). Importantly, control subjects may incidentally report low levels of concussion symptoms in the absence of SRC\u2014further motivating the investigation of functional neuroimaging metrics for detecting SRC status.P value = 0.11). Impulse control is a measure of test validity, used to discard tests with a value above 30. The highest observed impulse control score in our sample was 15 , suggesting all ImPACT scores represent valid administrations and should be included in our analysis.Statistically significant between-group differences were not observed for ImPACT\u2019s composite measures of verbal memory, visual memory, visual\u2013motor processing speed, reaction time and impulse control between healthy control, concussed individuals and repetitive concussion individuals. BOLD measures for concussion or repetitive concussion athletes compared with healthy controls. In contrast with ImPACT score findings, reliable regional differences in MSSDBOLD signal are found in occipital and inferior temporal lobes, premotor areas and the ventral anterior cingulate. We observe that regional MSSDBOLD values are significantly decreased in concussed subjects relative to healthy controls, displaying significantly less fluctuation in BOLD signal amplitude over time. In contrast, all significant regions in repetitive concussion patients show greater MSSDBOLD than in healthy controls, reflecting significantly more pronounced variability in regional BOLD signal relative. This dissociation between BOLD signal decreases in concussion and increases in repetitive concussion suggests that unique pathophysiological mechanisms that implicate functional alterations may underlie the more severe sequelae observed in repetitive SRC.BOLD metrics and ImPACT scores were used to train RF machine learning models. BOLD demonstrated the highest classification accuracy, with ImPACT scores alone producing models with the lowest classification accuracy.Despite evidence for group-level differences in regional BOLD signal variability, no feature selection was performed prior to training RF classifier models, and therefore, all regional MSSDBOLD data. Only the model trained on ImPACT scores alone under-performs this baseline value for classifying concussion subjects . Here, we observe the greatest difference in classification performance between ImPACT scores and MSSDBOLD measures, suggesting BOLD variability is both a more sensitive and specific index of signal associated with repetitive SRC than ImPACT scores.BOLD variability in combination). Ground truth positive labels are reflected along rows, with OOB classification labels in columns . Label confusion suggests this best-performing RF model (correctly classifying 31/50 athletes in our sample) is most sensitive for detecting concussion and repetitive concussion. However, the RF model also displays markedly lower specificity for concussion, misclassifying a majority (11/15) of healthy control subjects as concussed. This suggests that while BOLD variability indeed facilitates detection of SRC and repetitive mTBI, models trained to include BOLD variability measures may require more targeted feature engineering to better distinguish between health controls and subjects with lower SRC severity, as has been shown using functional connectivity data.20 This model\u2019s performance for classifying control subjects (4/15) is also an improvement over the RF model trained using only ImPACT composite scores, which misclassifies all control subjects as concussion subjects (0/15). This performance likely reflects the large label size of concussion athletes and the lack of reliable between-group differences observed with ImPACT scores. These results suggest that MSSDBOLD measures indeed contribute to a classification model with improved prediction accuracy for distinguishing healthy and concussed individuals.BOLD holds promise as a sensitive biomarker for detecting symptomatic abnormalities in cerebrovascular status in athletes with SRC. We briefly review the findings with respect to regional MSSDBOLD and ImPACT modules by examining (i) between-group differences, (ii) their classification accuracy using the categorical RF model and (iii) their regression accuracy using the continuous RF model.The present study demonstrates that MSSD12 Our results identify several cortical areas in those regions that demonstrate significant differences in MSSDBOLD measures in the presence of SRC or repetitive mTBI. Specifically, MSSDBOLD measures in occipital and inferior temporal regions and midline structures (premotor cortex and anterior cingulate) significantly differ between control and concussed athletes. These regions are particularly vulnerable to injury due to inertial forces, either front to back or rotational. We also observed a dissociation in the directionality of BOLD variability changes. Concussed athletes displayed universally decreased BOLD variability across affected brain regions. In addition to reflecting altered neurovascular coupling, patterns of low regional BOLD variability observed for concussion patients may also in part reflect functional hyperconnectivity commonly observed following mTBI,62 such that stronger functional coupling of distal regions entrains BOLD signal amplitude to a more limited band. In contrast, repetitive concussion subjects display uniformly elevated BOLD signal variability in affected regions. As the elapsed duration between most recent SRC and clinical assessment is comparable for concussion and repetitive concussed athletes . In these models, the majority of features ranked as highly important represented BOLD variability measures, not ImPACT scores. Classification based on the categorical RF models demonstrated a higher sensitivity or true positive rate for accurately identifying individuals with repetitive concussions when using BOLD variability (AUC = 0.66) than was observed using ImPACT scores (AUC = 0.25). Overall multi-label classification accuracy was also increased when BOLD variability data were included, with classification error decreasing from 46% to 38% when ImPACT scores and BOLD variability were jointly modelled. This was partially due to increases in classification accuracy for identifying subjects with high overall symptom loads as belonging to concussion or repetitive concussion groups. Classification accuracy of control subjects, while still low, also increased when BOLD variability data were included in the RF models, suggesting that BOLD variability may have greater specificity than ImPACT for detecting SRC. The left middle frontal gyrus, left frontal pole and temporal occipital fusiform gyrus had the largest effects in the RF model classification, which is in line with research suggesting regions in the frontal and temporal lobes are commonly affected in mTBI.BOLD data in a single model produced the best prediction performance with a MSE of 26.9. Feature importance scores indicated that the main variables used to generate predictions for this model were BOLD variability measures, suggesting that variance associated with ImPACT scores is of lower importance than BOLD variability during forest growth and model training. Results from these continuous RF models indicate that MSSDBOLD is a more sensitive predictor of post-concussion symptom totals and that jointly considering functional and neurocognitive data together is a useful approach for machine learning models to improve the accuracy of predictions for total SRC symptom load.Prediction accuracy was highest for RF models trained to predict the total number of post-concussion symptoms using the combination of ImPACT composite scores and BOLD variability variables. The continuous prediction model trained only on ImPACT scores converges during training to a MSE of 30.5 when predicting post-concussion symptoms, showing the largest error and the worst performance. A continuous RF model that trained only on BOLD variability data demonstrated lower MSE (28.7), reflecting improvements to predictive performance. Jointly including ImPACT and MSSDBOLD can be generalized to other populations (i.e. children and adolescents with SRC and non-athletic populations with mTBI). Second, MSSDBOLD cannot currently be used to assess severity of an injury itself, only the extent of the symptom load that it produces, and additional screening methods involving structural neuroimaging techniques will be still required to reveal the extent of injury and changes in pathology during recovery. Third, the analysis approach using MSSDBOLD cannot reveal the actual damage to the vasculature and surrounding neural cells at the site of injury. Fourth, while our study observes high performance for predicting total clinical symptom load in healthy and SRC athletes, our SRC classification models will often mistake healthy controls for concussed subjects. This may be due to our sample\u2019s imbalance between control (N = 15) and concussion (N = 29) subjects or may suggest that more a more precise feature selection step is required to identify MSSDBOLD regions more specific for SRC, possibly requiring higher-resolution cortical parcellation schemes. On the other hand, mismatches in performance may potentially be addressed by methods that do heavily subset BOLD variability as an initial feature selection step, potentially inducing parity in the number of BOLD and ImPACT input variables to afford comparison of prediction accuracy through alternative ML approaches . While random forests appear to be sufficient for our purposes in this manuscript, we do not intend to suggest they are necessary. Fifth, there may be other representations of variability besides MSSDBOLD that better capture the extent of underlying functional alterations in SRC, including representations that jointly consider resting static or dynamic functional correlation or large-scale intrinsic brain network organization. Future research should consider investigating these elements at a fine-grained level to further elucidate neurobiological pathologies in SRC. Sixth, and finally, functional MRI acquisition remains prohibitive in many outpatient clinical settings, though we believe our results at do least motivate further exploration of BOLD variability for monitoring athletes before and after SRC, particularly from a personalized or precision medicine perspective.In this study, we demonstrate that BOLD signal variability holds promise as a diagnostic biomarker for detecting functional neural alterations following SRC. While our approach motivates systematic exploration into BOLD variability\u2019s utility for detecting injury in clinical neuroimaging of concussion, there are several limitations and challenges to this approach. First, given that the concussed group is a highly homogenous athletic population, future studies should examine whether the observed deviations in MSSD73 consistent with the present findings. Executive dysfunction can be a pernicious consequence of TBI,75 implicating alterations to network topology and dynamics in neurological sequela following mTBI.76 Future research may wish to examine brain network alterations for their impact on other cognitive domains or as a potential neurobiological marker of injury and recovery status.These findings emphasize the need for future research to examine how network topology and dynamics are altered by TBI. Recent research has highlighted the importance of global brain network topology for facilitating cognitive abilities,BOLD assessed from resting-state fMRI are sensitive to abnormalities in cerebrovascular status in athletes with SRC. Further, we show that regional MSSDBOLD measures can more sensitively and specifically identify concussed and repetitive concussed individuals within a RF machine learning framework compared with standardized neurocognitive tests. In contrast, ImPACT composite scores do not capture reliable between-group differences in concussion status and cannot be used in isolation to build an RF model that discriminates between concussion, repetitive concussion and healthy athletes. Combining BOLD variability and ImPACT scores leads to the highest prediction performance, supporting the claim that altered BOLD variability provides novel information about altered cerebral vascular status that can aid diagnosis and return-to-play decisions when collected alongside existing assessment protocols for the detection of SRC. Further, we provide evidence that MSSDBOLD contributes to prediction of total post-concussion symptoms, outperforming ImPACT scores across healthy and concussed patients. In conclusion, this paper provides initial evidence that BOLD variability holds promise as a potential clinical marker for SRC, motivating a more systematic exploration of BOLD variability as a candidate biomarker in future work. To investigate the sensitivity and efficacy of MSSDBOLD in diagnosing SRC, future neuroimaging research may wish to deploy MSSDBOLD measures alongside neuropsychological testing protocols and structural neuroimaging methods, providing a more complete assessment of athlete health that includes cerebrovascular alterations and associated cognitive deficits to better facilitate detection of injury in SRC and guide return-to-play decisions.Diagnosis of SRC can be difficult due to the low sensitivity of assessments designed to identify cognitive deficits in athletes with suspected injuries. In addition, clinical evaluation of SRC using structural imaging methods is limited to characterizing anatomic pathology and cannot detect haemodynamic or neurometabolic disruptions. In this work, we provide evidence that functional neuroimaging indices of MSSD"} {"text": "Sparsity finds applications in diverse areas such as statistics, machine learning, and signal processing. Computations over sparse structures are less complex compared to their dense counterparts and need less storage. This paper proposes a heuristic method for retrieving sparse approximate solutions of optimization problems via minimizing the [[EQUATION]] quasi-norm, where $0
80% . SimilarHowever, such concepts cannot be directly transferred to FVCA, since preoperative outcome simulation needs to integrate the donor's and patient's facial features at the same time. Subsequently, reliable predictions can only be made once the donor is identified. Automated facial landmark recognition systems such as Emotrics or 3D VECTRA could be used for quick and precise facial measurements , 20. FolThe potential advantages of AI are substantial, particularly for intricate procedures such as FVCA. The degree to which preoperative planning can be detailed and meticulously executed largely predicts the potential success of the outcome.Precision and real-time feedback are essential pillars of contemporary surgical practice. These elements are considerably amplified with the integration of AI into intraoperative image-guidance systems . These aDuring FVCA, the precise fitting of the donor tissue onto the recipient's facial structure is paramount for the success of the procedure , 27. AI Real-time feedback plays a significant role during surgery, a role that might be efficiently fulfilled by AI-integrated intraoperative imaging systems. These systems provide surgeons with real-time data, enabling immediate adjustments to their surgical approach, which can prove invaluable during complex procedures like FVCA . More prDespite distinct advancements in the perioperative patient management including more patient-specific risk profiles, novel biomarkers, and targeted immunosuppressants, allograft rejection persists as a major burden in transplant surgery still affecting more than 15% of solid organ transplant (SOT) patients , 35. MorIn SOT, ML and DNN have been successfully investigated to identify risk patients for transplant rejection. Thongprayoon et al. performed ML consensus cluster analysis for 22,687 Black kidney transplant recipients identifying four distinct clusters. Interestingly, the authors found that the risk for transplant rejection was significantly increased in highly sensitized recipients of deceased donor kidney retransplants and young recipients with hypertension . In liveAcross the different vascularized composite allograft (VCA) surgery subtypes, 85% of VCA patients experience at least one rejection episode one year post transplantation with more than 50% of cases reporting multiple rejection episodes . Such epCancer represents a widely recognized complication of both SOT and VCA, since there is a two to four-fold elevated risk of malignancies following organ transplant. Remarkably, transplant recipients are at a 100-fold higher risk for developing skin cancer . While tAI technology has been shown to provide a versatile and precise screening platform for diverse cancer entities and detect mammographic abnormalities with comparable accuracy to radiologists and reduce radiologist workloads \u201370. Yi eFollowing FVCA, one transplant recipient patient was diagnosed with basal cell carcinoma of the native facial skin six years post-transplant, while another FVCA patient presented with a B cell lymphoma which was treated with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone . DespiteFVCA has emerged as a novel and versatile reconstructive technique to provide adequate therapy for patients with devastating facial wounds and trauma , 87. Whi"}
{"text": "Dystonia syndromes are diverse movement disorders characterized by disabling, painful, and sustained involuntary muscle contraction.Various neurosurgical interventions have been trialled for the treatment of dystonia, including peripheral denervation, intrathecal baclofen infusion, and ablating the basal ganglia or thalamus. However, deep brain stimulation (DBS) primarily targeting the globus pallidus internus (GPi) and the subthalamic nucleus (STN) has evolved as a covetable option with the ability to provide personalized, reversible, and titratable neuromodulation. The available literature has recently been reviewedIn the current edition of the Arquivos de Neuro-Psiquiatria, Listik et al.Similarly, intraoperative target selection has been further refined by studies employing stimulation-outcome mapping in large cohorts. Elias et al.Insights into outcome variation in DBS therapy have also come from the functional magnetic resonance imaging literature. Loh et al. demonstrate that optimal DBS programming engages a functional network resulting in sensorimotor cortex deactivation in 15 cervical dystonia patients with GPi-DBS.There is growing scientific evidence demonstrating the safety and efficacy of DBS for the treatment of medically refractory dystonia, however, optimal patient and surgical target selection remains unclear. Here multiple examples are presented that demonstrate how advances in neuroimaging are contributing to the understanding of DBS therapy in dystonia. These advances may lead to improved patient and target selection and DBS programming."}
{"text": "We present the first documented case of a fistula between the treated zone and the appendix after RFA in a patient with HCC. Contrast-enhanced CT and MRI revealed a subcapsular hepatic nodule with image findings of HCC located adjacent to the ascending colon and cecum. An ultrasound-guided core needle biopsy was subsequently performed to distinguish between hepatic metastasis and HCC. Post-RFA imaging identified a low-attenuating ablated area adjacent to an air-filled appendix. The patient later experienced complications, including increased liver enzymes and an abscess at the ablation site. Imaging revealed a fistulous tract between the RFA zone and the appendix. Over the following months, the patient underwent conservative treatment involving intravenous antibiotics and repeated percutaneous drainage, exhibiting eventual symptom relief and an absence of the fistulous tract upon subsequent imaging. This case highlights the rare complications that can arise during RFA due to peculiar anatomical variations, such as a subhepatic appendix, resulting from midgut malrotation and previous surgery. It is imperative for operators to be cognizant of potential anatomical variations when considering RFA treatment, ensuring comprehensive pre-procedural imaging and post-procedure monitoring. This case also emphasizes the potential viability of nonoperative management in complex scenarios in which surgical interventions pose significant risks."}
{"text": "Rates of late allograft loss have improved slowly in the last decades. Well described traditional risk factors that influence allograft survival include cardiovascular events, rejection, infections and post-transplant neoplasia. Here, we critically evaluate the influence of several non-immunological, non-traditional risk factors and describe their impact on allograft survival and cardiovascular health of kidney transplant recipients. We assessed the following risk factors: arterial stiffness, persistent arteriovenous access, mineral bone disease, immunosuppressive drugs residual levels variability, hypomagnesemia, glomerular pathological alterations not included in Banff criteria, persistent inflammation and metabolic acidosis. Recent high-level evidence confirms the superiority of transplantation in reducing all-cause mortality for most patients with end-stage kidney disease . In the We searched three databases: Medline, EMBASE and Cochrane Library, and included studies from January 2000 to December 2022 with the following terms: \u201ckidney graft survival\u201d, \u201ckidney graft loss\u201d, \u201cfailed kidney transplant\u201d, \u201cchronic allograft nephropathy\u201d, \u201crisk factors\u201d, \u201cchronic kidney disease progression\u201d.Late allograft failure is a heterogenous background picture of several multifactorial pathogenic entities that all contribute to kidney dysfunction in transplant patients. Naesens et al. elegantly described data derived from failing grafts: Importantly, one quarter of biopsies exhibit more than one coexisting disease, and almost one third of patients with lost allograft had no specific diagnosis on the last biopsy performed but highlighted the important prognostic capacity of the extent of chronic damage . ConsequRecent efforts have focused on better characterization of allograft loss and described a more complex picture of the multifactorial pathogenic processes. A study conducted by Mayrdorfer et al. examining 303 death-censored graft losses among 1642 transplant recipients discriminated primary failure causes (responsible for more than 50% persistent estimated glomerular filtration rate decrease) from secondary failure causes (contribution to less than 50% estimated glomerular filtration rate decline) and analyzed data in a time-dependent manner. Late allograft failure was mainly attributed to intercurrent medical events, defined as cardiovascular events or infections conducting to prominent decline in renal function, and representing almost 40% of late graft failures. Moreover, antibody-mediated rejection met increasing frequencies with time as a primary failure cause (48.6% of graft failures at more than 10 years from transplant intervention) while T-cell mediated rejection had a sharp decline with transplant vintage. Interestingly, calcineurin-inhibitors toxicity was isolated in only two cases as a primary cause, but it was described as the most frequent secondary cause responsible for graft loss (64 of 240 late graft failures). The authors once again highlighted the multifactorial etiology of transplant failure .The ability to predict the evolution of the transplanted kidney is of great significance and has been the center of some valuable research. Search of prognostic factors begins even before implantation with evaluation of donor quality. Preimplantation histology may provide important clues but clinical decisions of implanting or discarding the kidney based on this data have shown conflicting results. In a recent large multinational study, discarded kidneys due to biopsy alterations could have been offered to patients with improved survival and quality of life. Data shows 70% of implanted similar grafts matched with the refused grafts due to biopsy were functioning at 10 years .Prediction models can be computed by means of artificial intelligence and deep learning models to predict evolution of estimated glomerular filtration rate after kidney transplantation. Raynaud et al. identified, after performing multinomial regression models, seven significant determinants of progression: donor age, estimated glomerular filtration rate, proteinuria, graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation and circulating anti-HLA donor specific antibodies. Resulting computed trajectories were significantly associated with progression to allograft loss .Other techniques proved good forecast capability utilizing sequence-to-sequence modelling in order to create a machine learning algorithm-based prediction model that is based on inputting repeated estimated glomerular filtration rate measurements .Recently, an interesting dynamic prediction tool that incorporates histological, immunological and clinical parameters together with repeated measurements of graft function was validated in multiple cohorts and proved superior prediction performance of allograft survival compared to other similar systems. Individualized parameters that altered survival were estimated glomerular filtration rate, proteinuria, delay between transplant and evaluation, Banff categories , mean fluorescence intensity of anti-HLA donor specific antibodies and repeated measurements of eGFR. The iBox system has proved good prediction ability of graft survival and it has been validated as a valuable endpoint in clinical trials in transplantation ,15.Cardiovascular disease has recently gained well-deserved attention since it represents the main driver of comorbidity and mortality in kidney transplant recipients. Pregnant emphasis was attributed to defining and addressing traditional cardiovascular risk factors in improving survival outcomes in this population. Management of these associated relevant comorbidities have been reviewed elsewhere and they do not meet the purpose of this paper 16,17].,17.16,17The association between increased values of arterial stiffness and eGFR decline has been noted in the general chronic kidney disease (CKD) population and suggests that the resulting hemodynamic stress insults the kidney by means of endothelial dysfunction and microvascular ischemia. Chronic inflammation, oxidative stress and overactivation of the renin\u2013angiotensin systems may represent other possible mechanistic underpinnings . Aortic Continuous functioning arteriovenous fistula after kidney transplantation has the potential to worsen the maladaptive remodeling changes in the cardiovascular system and alter kidney function. A meta-analysis addressing the impact of ligating the arteriovenous fistula showed that patients undergoing access occlusion had better cardiac morphological parameters and better kidney allograft function .Furthermore, patency at 5 years was only 61% and arteriovenous fistula-related complications were frequently reaching about 30% of patients. On the other hand, preservation of the vascular access may provide the advantage of an optimal backup strategy if transition to dialysis is needed. Consequently, decisions should be individualized on several parameters, mainly based on renal and cardiac functions and on selecting complications-prone profile of patients .After kidney transplantation, particularly older patients find themselves at an increased risk for pathological fractures. The fractures appear multifactorial in nature and are associated with unfavorable outcomes, such as subsequent graft loss or mortality. It remains unclear whether only the high end of mineral bone disease spectrum (fractures) is linked to allograft survival decline or if other biologic entities contribute as well .Persistent mineral abnormalities after kidney transplantation mainly include hypercalcemia and hypophosphatemia. Previous severe hyperparathyroidism and high levels of circulating PTH and FGF-23 are established risk factors for altered mineral metabolism post-transplantation. However, impact on outcomes is unclear. As they may not contribute directly to allograft loss and rapid eGFR decline, they are the main drivers of vascular calcifications affecting graft vessels and, interestingly, of tubulointerstitial calcifications on allograft biopsies ,31.Cinacalcet has proven its ability to correct persistent hyperparathyroidism after kidney transplantation and the associated metabolic derangements but without impact on bone mineral density or allograft survival . Data frBiphosphonate therapy in kidney transplant recipients has the clear benefit of improving bone mineral density. Recent studies have proven low rates of adynamic bone disease, strengthening the safety profile of this medication. However, there is no clear data on rates of fractures and there are no benefits or harms related to renal function evolution in kidney transplant recipients .Assessment of pre-transplantation profile of mineral bone disease phenotype may predict survival and high-risk patients. In a cohort of more than 11,000 patients, recipients that exhibited higher levels of pre-transplant serum alkaline phosphatase (>120/U/L) were subject to increased post-transplant mortality. No association was found between circulating PTH or calcium and post-transplant evolution .The negative correlation between graft survival and vitamin D deficiency has been described in an observational manner . InsuffiCurrent therapeutic armamentarium provides means to effectively correct mineral abnormalities in kidney transplant recipients. However, impact of described treatments on graft survival have been insufficiently studied and proved no significant benefits.Excessive immunosuppression contributes to significant complications linked to allograft loss; infections, malignancy and polyoma virus nephropathy account for about one third of graft losses . BecauseInterestingly, another tool available for the evaluation of drug exposure is the time in therapeutic range\u2014addresses the interval of time that a patient is exposed to correct predefined range of values of immunosuppression. Patients with high variability and time in therapeutic range < 40% were at increased risk of de novo donor-specific antibodies and at an estimated four times greater risk of graft loss by 5 years .Hypomagnesemia represents one of the most frequent electrolyte disturbances post-transplantation . SeveralMagnesium deficit exhibits diabetogenic effects and it represents a proven independent risk factor for post-transplant diabetes mellitus ,49. ReceReports on mortality are conflicting and derived from observational retrospective studies. There have been signals of the possible interaction between hypomagnesemia and graft dysfunction . RecentlMagnesium metabolism, however, is important and may have implications in long-term outcomes as it interferes with glycemic alterations, endothelial dysfunction and cardiovascular abnormalities. In addition, correction is cumbersome and magnesium levels may not reflect true stores. No significant trials regarding supplementation and the associated impact on graft function have been conducted .Overall, due to conflicting results and the presence of many confounders, such as the use of CNI, nutritional status, measurement issues, other additional studies addressing this problem will evaluate true impact.The kidney transplant biopsy interpretation is submitted to a well described and standardized score system\u2014Banff classification. Diagnostic entities are established by pathologists after grading several acute and chronic lesions . HoweverDenic et al. conducted a study with repeated biopsies in well-functioning transplant recipients at 5 years post-implantation. Three parameters previously linked to unfavorable graft outcomes were examined: glomerular volume, global glomerulosclerosis and ischemic appearance of glomeruli. All three parameters combine successfully predicted death-censored graft failure at 5 years. Moreover, glomerular ischemia is significantly associated with allograft loss, even after adjustment for Banff scores .Moreover, other recent data highlight the impact of early subclinical inflammation detected on surveillance biopsies on allograft survival. Patients with subclinical inflammation and tubulitis were exposed to a higher hazard of acute rejection and death-censored allograft loss .Implantation of the kidney allograft is often realized in uremic patients exhibiting a state of inflammatory milieu. Moreover, inflammation is enhanced by perioperative events and induced by other stressors. For example, brain death is linked to increased cytokine excretion and ischemia-reperfusion injury can lead to delayed graft function. All forms of rejection are responsible for elevated markers of inflammation, and viral infections could be a source of enhanced cytokine production leading to overreactive innate immunity . AtherosThe persistent inflammatory state is multifactorial and contributes to graft dysfunction by several mechanisms: triggering chronic hypoxia, extracellular matrix deposition and extending graft fibrosis . FurtherMetabolic acidosis identifies as one of the most common complications in kidney transplant recipients. The fall of bicarbonate and pH levels with a decrease in serum partial pressure of carbonic dioxide occurs mainly when the glomerular filtration rate falls under 30 mL/min in patients with chronic kidney disease. This threshold is higher in kidney transplant recipients, showing that metabolic acidosis may occur at higher GFRs in these patients ,64. The Data on allograft survival are pointing to metabolic acidosis as a risk factor for graft dysfunction in the long term. Park et al. conducted a study that showed that low TCO2 concentrations 3 months after transplant are associated with an increased risk of graft loss and death-censored graft failure . FurtherThus, these associations require the application of therapeutic measures to correct acidosis. From this point of view, the data are limited, with most studies focusing on alkali therapy. If supplementation with sodium bicarbonate is effective in patients witch chronic kidney disease, the data in kidney transplant recipients are limited. Schulte at al. evaluated the effect of sodium bicarbonate in kidney transplant recipients with chronic metabolic acidosis. Treatment with sodium bicarbonate was associated with an increased risk of graft failure with no changes in mortality. Authors speculated that the interference with gastric acid pH of oral bicarbonate intake may lead to altered absorption of mycophenolate mofetil. Consequently, patients may be exposed to lower plasma concentrations of mycophenolic acid . The recLong-term survival of kidney allografts is altered mainly by cardiovascular disease, malignancy and infections. However, in order to maximize survival, other relevant pathogenic entities need to be addressed. Care of kidney transplant patients is complex and needs to be centered also on many potential risk factors that can influence long-term survival, consisting of the following: metabolic derangements such as hypomagnesemia, metabolic acidosis and mineral bone disease after transplantation, cardiovascular disease manifesting as arterial stiffness, immunosuppressive drug metabolism and non-adherence, persistent inflammation and glomerular changes not highlighted by Banff criteria. ."}
{"text": "A 72-year-old man presented with painful enlargement of the scrotum and weight loss. Physical examination revealed that the right testicle and epididymis were hardened and tender. Hematology and chest radiography results were normal. Pelvic computed tomography (CT) revealed bilateral hydrocele and an irregular right testicle and epididymis with peripheral contrast enhancement and central necrotic hypodense portions . Radical,Genitourinary tuberculosis is the second most common form of extrapulmonary tuberculosis after lymph node involvement; however, tuberculous orchiepididymitis is rare. Ultrasound may show focal or diffuse areas of hypoechogenicity in the testicle and epididymis, with increased surrounding vascularity on color Doppler imaging, and a hydrocele. CT usually shows irregular testicular masses with heterogeneous or peripheral contrast enhancement, and a hydrocele, with or without calcification"}
{"text": "More than 8 million people contract typhoid annually, resulting in about 100\u2009000 deaths. Despite associated sociopsychological and economic fallouts,,The most frequent co-endemic acute undifferentiated febrile illnesses are flaviviral illnesses, scrub typhus, malaria, leptospirosis and acute viral hepatitis.Several actionable insights emerge from these gaps that are relevant to future diagnostic test development and evaluations. First, investigators must aim to integrate clinical and laboratory results in diagnostic test evaluations. Clinicians are aware that the diagnosis of acute fever requires a combination of several clinical, physiological and contextual parameters. Systematic assessments of the discriminative power of various tests are important to determine the true added value of rapid tests. Second, researchers should use modelling approaches to identify algorithms worth evaluating in trial settings. Models can inform the incremental value and post-test probabilities of rapid diagnostic tests within clinical algorithms based on pretest accuracies of combinations of clinical signs. To improve testing algorithms for multiple pathogens, the global health community needs renewed data mining efforts to inform modelling approaches. Third, implementers should tailor diagnostic test interventions to the needs and preferences of end-users. Guidelines cannot be translated into interventions unless contextualized to specific practice settings. Qualitative studies should therefore be undertaken in high-burden settings to understand drivers of test use and physician-patient preferences to avoid translation failures. Fourth, funders should incentivize diagnostic research. As new infectious challenges emerge, it is important that funding focus does not shift away from this common cause of illness and death.The recent World Health Assembly resolution on strengthening diagnostics capacity"}
{"text": "In this issue of the Journal, Guadamuz et al. considerCancer care delivery research typically aspires to execute intervention studies targeting modifiable clinical and practice-level factors in the care delivery environment , but GuaThe built environment may particularly predict chronic disease , with hoEarlier research indicated that profit and affluence predict for-profit hospitals\u2019 locations, thus intentionally marginalizing Medicaid and uninsured patients ,25. MoreMultilevel policies may beget care access benefitting cancer prevention and survivorship, but enhanced facility proximity and care reimbursement, although necessary, is likely insufficient for optimizing care for patients residing in low area-level socioeconomic status locales. Health-care organizations and their care teams may create and sustain care equity threats. Workforce conditions, such as unfavorable patient to clinician ratios potentiaWe encourage hypothesis testing that considers relationships between the built environment, practice norms , and cancer treatment initiation and survival. How might we design studies to test these relationships? Cancer care delivery espouses advancing beyond traditional randomized clinical trial paradigms to embrace pragmatic trial methods that prioritize external validity and the relevance of community practice . MoreoveGuadamuz et al. reveal a"}
{"text": "On November 7, 2022, dengue virus (DENV), which is not endemic in the continental United States , MCESD, and Arizona Department of Health Services locally acquired mosquitoborne disease response plan, MCDPH and MCESD activated an incident command office on November 10. MCDPH took the following actions: 1) prioritized prospective investigations of health care provider and laboratory reports of DENV and suspected arboviral visits queried from the National Syndromic Surveillance Program's BioSense Platform (BioSense)Aedes aegypti mosquitoes and breeding sites; mosquitoes collected in a professional BG-Sentinel mosquito trapAfter discussions with CDC\u2019s Dengue Branch and Florida Public Health (Coordinated surveillance and response activities identified the first locally acquired human DENV infections in Maricopa County, Arizona. Established partnerships and preexisting plans were essential to mounting a rapid, coordinated response to nonendemic arboviral transmission. MCDPH and MCESD will enhance future surveillance activities to identify and prevent autochthonous DENV transmission, including additional mosquito trap placement around patient residences and public mosquito exposure prevention education."}
{"text": "These on-site sanitation systems, a positivestep toward improved household WASH services, are used by 43% of theglobal population, mainly comprising low- and middle-income countries(LMICs).3 There is an urgent need to expand decentralized(non-sewered system) surveillance as LMICs are currently being overlookedin pandemic prevention as it is currently focused on SARS-CoV-2 wastewaterfrom centralized (sewered) systems.The availabilityand accessibilityof water, sanitation, and hygiene (WASH) services are key in preventingdisease transmission.Wastewater surveillanceof centralized systems presents a vastlydistinct set of challenges compared with fecal sludge surveillance.For example, sewers also contain gray water and sometimes stormwater,and wastewater is commonly sampled as a composite volume over a 24h period, whereas fecal sludge is most commonly grab sampled. Broadeningthe focus of non-sewered sanitation surveillance (NSSS) should accommodatefecal sludge analysis to support globally relevant public health strategies.4 Unfortunately, interest in fecal sludge researchhas been largely limited to a small group of researchers funded bya few core donors. The pandemic has renewed the focus of both scienceand policy. Surveillance of pathogens in fecal sludge may need tobe adapted and could include Vibrio cholerae or poliovirus;however, this should be determined by assessing localized needs. Thepotential of the public health impact in LMICs can be amplified byusing fecal sludge data in addition to clinical data in multipathogendisease surveillance and continuous local monitoring for early warningsof a pandemic.Even before the COVID-19 pandemic, fecal sludge was used as a valuablesource of information for understanding community health.5 but possibly more complex in the Southern Africansanitation field with five decades of human waste research.6 With no formal global network, internationalnonprofit institutions can fill this role by bringing together academicresearch partners and public health officials for interdisciplinaryand collaborative research and increased awareness of NSSS. Such partnershipscan enable these settings to innovatively adapt academic or healthcarelaboratory operations while maintaining high-quality data and alsopromote peer-reviewed literature originating from resource-limitedlaboratory settings.Research partnerships are required to progressfrom individualclinical patient samples to pooled community samples in terms of fecalsludge. The importance of research partnerships is not new,Timelier and better-quality global epidemiologicaldata sets arerequired for better pandemic preparedness in the future. There isa need in LMICs for the different, but unique, value of NSSS comparedto that of wastewater surveillance, built-in capacity at local laboratoriesthat can include fecal sludge as part of continuous multipathogendisease surveillance, and long-term global research collaborationsfocused on creating systems with data-driven approaches. Challengeswill remain, including importation and lengthy delays in suppliesand equipment (such as polymerase chain reaction primers and probesthat are not manufactured in many LMICs), repurposing existing LMIClaboratory spaces for fecal sludge samples, and limited LMIC accessto biosafety level 3 and 4 laboratories for sample processing, therebylimiting pathogen target lists. We recommend that LMICs navigate throughthese barriers to ensure that fecal sludge surveillance benefits publichealth, generates local policy-relevant information for future pandemicprevention and control, and holistically supports global WASH services."}
{"text": "Recently, an empiric Cone-beam Computed Tomography (CBCT)-guided transarterial embolization (TAE) technique has been investigated for lower gastrointestinal bleeding (LGIB). Although this empirical strategy reduced the rate of rebleeding in hemodynamically unstable patients compared to a \u2018wait and see\u2019 strategy, the specified technique is challenging and time-consuming.We present two methods to perform a prompt empiric TAE in LGIB when catheter angiography is negative. Based on the pre-procedural Computed Tomography Angiography bleeding site and using vessel detection and navigation software tools that are integrated in contemporary angiosuites, the culprit bleeding artery could be targeted with only one selective intraprocedural CBCT acquisition.The proposed techniques are promising to reduce procedure time and facilitate the implementation of empiric CBCT-guided TAE in clinical practice when angiography is negative. Empirical transarterial embolization (TAE) is a well-known strategy in interventional radiology (IR). In upper gastrointestinal bleeding, when primary endoscopic hemostasis has failed, endoscopy-directed empiric TAE of the left gastric or gastroduodenal artery is recommended if angiography is negative and vasopressor requirements upon arrival, subsequent inferior mesenteric Digital Subtraction Angiography (DSA) and CBCT angiography failed to demonstrate active bleeding. Because of hemodynamic instability and risk of bleeding recurrence, an empirical TAE (illustrated in Fig.\u00a038y old female patient with history of a lateral pancreatojejunostomy after pancreatic trauma was admitted because of recurrent RBPA and one-time hematemesis. Initial upper gastrointestinal endoscopy and CTA could not identify an active bleeding focus. However, because of progressive hemodynamic instability, the patient was transferred the following day to our tertiary referral hospital. A new CTA now did reveal an active bleeding proximally in the Roux-en Y jejunal loop and the patient was immediately transferred to the angiosuite. Nevertheless, superior mesenteric DSA and CBCT failed to identify a bleeding focus. Regarding inaccessibility for endoscopy, empirical TAE (illustrated in Fig.\u00a0Recent guidelines emphasize the importance of CTA and TAE in the management of active or hemodynamically unstable LGIB (Triantafyllou et al. The use of vessel detection and navigation software could be promising to reduce procedure time and facilitate the implementation of empirical TAE in clinical practice. However, safety and efficacy of this approach should be verified on a larger scale."}
{"text": "Pseudomonas aeruginosa. Fungal infections in MEO are also likely but extremely rare. And conventional microbiology tests is difficult to diagnose.Most of malignant external otitis (MEO) cases reported in the literature are attributed to Aspergillus by metagenomic Next-Generation Sequencing (mNGS) and recovered after comprehensive treatment including operation and voriconazole. The antifungal treatment was delayed due to repeated cultures of secretions being negative and pathological examination showed granulation tissue proliferation with extensive neutrophil infiltration.Two patients were diagnosed with Fungal malignant external otitis (FMEO) due to mNGS might be helpful for patients suspected with FMEO, especially when conventional microbiology tests were negative. Pseudomonas aeruginosa , previously diagnosed otitis externa not responsive to therapy.Aspergillus is also frequently isolated from external auditory canal smears and diagnosis of FMEO should be based on histopathologic confirmation on deep tissue biopsy for the publication of any potentially identifiable images or data included in this article. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.QW: patient management, data collection, and writing original draft. RH and YZ: patient management and data collection. WZ: review and modify the article. HJ: review and modify the article. All authors contributed to the article and approved the submitted version."}
{"text": "Orcinus orca) to quantify patterns of fine-scale foraging movements and their relationships with demography. We reveal striking interpopulation differences in patterns of individual foraging behavior. Females from the endangered Southern Resident (SRKW) population captured less prey and spent less time pursuing prey than SRKW males or Northern Resident (NRKW) females, whereas NRKW females captured more prey than NRKW males. The presence of a calf (\u22643 years) reduced the number of prey captured by adult females from both populations, but disproportionately so for SRKW. SRKW adult males with a living mother captured more prey than those whose mother had died, whereas the opposite was true for NRKW adult males. Across populations, males foraged in deeper areas than females, and SRKW captured prey deeper than NRKW. These population-level differences in patterns of individual foraging behavior challenge the existing paradigm that females are the disproportionate foragers in gregarious resident killer whales, and demonstrate considerable variation in the foraging strategies across populations of an apex marine predator experiencing different environmental stressors.In cooperative species, human-induced rapid environmental change may threaten cost\u2013benefit tradeoffs of group behavioral strategies that evolved in past environments. Capacity for behavioral flexibility can increase population viability in novel environments. Whether the partitioning of individual responsibilities within social groups is fixed or flexible across populations is poorly understood, despite its relevance for predicting responses to global change at the population and species levels and designing successful conservation programs. We leveraged bio-logging data from two populations of fish-eating killer whales ( Rapid environmental change may disrupt cost\u2013benefit tradeoffs of foraging strategies in cooperative species, yet whether populations differ in the partitioning of individual responsibilities within social groups is poorly understood. By combining fine-scale movement and sound data from bio-logging tags and demographic data from long-term population censuses, we reveal opposite patterns of individual foraging behavior between killer whale populations with divergent population trajectories, demonstrating variation in the partitioning of foraging responsibilities in an apex marine predator. Orcinus orca , primarily Chinook (O. tshawytscha) and to a lesser extent chum (O. keta) and coho . We also collected prey remains using fine-meshed dip nets in MATLAB v R2016b to calibrate sound and movement data based on sensor characteristics and tag orientation on the whale and the marmap R package and Fisheries and Oceans Canada (NRKW) to assign demographic variables. These databases contain extensive maternal familial relationships established through field observations and genetic testing in R v.3.6.3 using thFor the model examining the relationship between the presence of a living mother and the number of prey capture dives by adult males model h, , we addiWe were unable to use available salmon abundance indices due to 1) spatial incongruency between the salmon stocks/regions where these abundance data were sampled and the prey consumed by NRKW and SRKW during our study period and location, 2) issues with sporadic coverage and the degree to which effort had been accounted for in some of the existing salmon indices, and 3) reliability issues with applying widely used salmon data from the Albion Test Fishery situated on the Fraser River e.g., , becauseWe analyzed 186.8 h of dive data from 52 Dtag deployments or maximizing energy obtained from foraging (optimizing) . For SRKThe finding that adult SRKW males captured more prey if their mother was alive highlights the opposite patterns of foraging behavior we observed for adult males between the two populations. Males require more energy due to their larger size , and theIt is worth considering an alternative, nonmutually exclusive hypothesis related to the role of group leadership by post-reproductive females to explain the increased prey capture by SRKW males with living mothers. Given that post-reproductive females typically lead groups and thatDifferences in prey abundance and availability between populations could have contributed to the differences in foraging strategies we document here. However, we could not use existing indices of salmon abundance in our analyses because these metrics do not address spatiotemporal uncertainty in the distributions of Chinook salmon returning along one of two paths to the Fraser River. The nuances of migration paths taken are directly related to accurately estimating salmon availability for each population, yet data at this fine-scale spatiotemporal resolution are not currently available. We suggest that future research should elucidate the complex relationships between 1) environmental factors including location, prey distributions, and availability, 2) the behavioral context of the animal at the time of tagging, and 3) differential population-level impacts of anthropogenic pressures, including impacts from tagging and vessel presence, on foraging behavior e.g., , 2021b. This study revealed considerable differences in sex-based and demographic patterns of individual foraging strategies, demonstrating that these strategies are not fixed across two ecologically similar populations of a gregarious marine predator. The total number of prey capture dives and proportion of time capturing prey was female biased in the growing NRKW population, and male biased in the endangered SRKW population. The presence of a calf reduced female foraging activity across populations, but disproportionately so for SRKW females. Adult SRKW males with a living mother exhibited increased foraging behavior, possibly as a compensation strategy to offset their pod\u2019s caloric deficits and/or as an outcome of matriarch-led navigation to areas that promote greater prey capture by their adult sons. Interpopulation differences in individual roles within social groups may have arisen with the loss of key individuals as populations shrink, or may provide small, unbalanced populations experiencing environmental stressors the necessary flexibility to respond to novel and unpredictable environments caused by human-induced rapid environmental change. Indeed, interpopulation variation in individual roles may be an important evolutionary strategy for promoting resilience in the face of change.arad002_suppl_Supplementary_MaterialClick here for additional data file."}
{"text": "To the Editor: Fetal alcohol syndrome (FAS) is characterized by a range of structural birth defects, including facial dysmorphia, central nervous system growth deficits , and prenatal/postnatal growth restriction, which correlate with the magnitude of prenatal alcohol exposure .Due to the development of grossly observable alcohol-induced phenotypes consistent with clinical presentations of FAS, mouse models have become a powerful resource for investigating the development of alcohol-induced dysgenesis . TherefoWe first employed geometric morphometric analyses to contrFurthermore, our analyses revealed that alcohol-induced changes predominantly centered on the lower portions of the face, including the mandible (lower jaw), maxilla (upper jaw), and positioning of the ear . As in cTo validate our observations, we examined offspring for alterations in established measures of alcohol-induced craniofacial defects . ConsistFinally, we conducted a dose-response analysis, contrasting offspring snout-occipital distance and body weight\u2013normalized brain weights with the parental average daily ethanol dose (g/kg). We identified a significant correlation between both measurements and parental alcohol dose for male offspring across the PatExp and DuelExp treatments . In contIn 1981, the US Surgeon General issued a public health advisory warning that alcohol use by women during pregnancy could cause birth defects. Since this time, maternal alcohol use during pregnancy has remained the sole explanation for alcohol-related birth defects. In contrast, paternal drinking and lifestyle choices remain unexamined. Using a physiologically relevant mouse model, our studies are the first to our knowledge to demonstrate that male drinking is a plausible yet completely unexamined factor in the development of alcohol-related craniofacial abnormalities and growth deficiencies. Our study demonstrates the critical need to target both parents in prepregnancy alcohol messaging and to expand epidemiological studies to measure the contributions of paternal alcohol use on children\u2019s health."}
{"text": "Cell-to-cell communication is a critical process that ensures interaction between adjacent and distant cells to maintain cellular homeostasis in normal physiology and pathophysiological conditions. Two adjacent cells communicate to transfer ions and small molecules via Gap junctions, small selective ion channels. Distant cells establish long-range communication via endocrine/paracrine secretions, extracellular vesicles (EVs) and tunneling nanotubes (TNTs) , that membrane-bound exosomes attached to the plasma membrane of brain endothelial cells (BEC), participate in TNT formation between the cells, and facilitate in vitro blood brain barrier (BBB) genesis. Research has also shown that exosomes released by BECs transfer specific cargo to recipient brain cells (Banks et al., Mentor and Fisher suggested TNT-mediated trans-permeability between BEC cells. Recently another study has shown that thrombospondin-1-containing exosomes released from breast cancer cells promote biogenesis of TNTs (Mahadik and Patwardhan, Another issue is the interplay between exosomes and TNTs to harness synergistic effect on intercellular communication. In this context, the work of In conclusion, the synergistic interplay between exosomes and TNTs in long-range intercellular transfer is rapidly evolving as a promising area of cellular communication. Several important questions have been raised by recent advancements in this emerging field of research. What molecular mechanisms govern their on-demand biogenesis in response to cellular toxicities to rescue pathologies? How are exosomes selectively incorporated into TNTs? Do specific pathophysiological conditions enhance or restrict biogenesis of these intercellular conduits and their functionality? Addressing these questions could provide valuable insights into intercellular communications and their complexities, and will open up new avenues for therapeutic intervention.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "Managed care pharmacists utilize clinical guidelines to assist themin identifying acceptable treatment and management of chronic diseases. For thepast several months, an expert panel representing the National Asthma Education andPrevention Program (NAEPP) has discussed updated asthma guidelines, which couldchange future medication management of patients with asthma.To identify new guidelines for asthma control.Taking control of asthma is a foremost objective in managed care, asnew guidelines are debated, and asthma disease management programs identifymore effective models of asthma disease management. Within an effective asthmadisease management program, managed care practitioners, including but not limitedto physicians and pharmacists, must have a thorough understanding of the mostrecent clinical guidelines as well as current knowledge of the current consensusamong opinion leaders regarding asthma treatment and management. This ongoingeducation is critical in order to allow managed care practitioners to perform theirrole and function within their organizations. With the advent of changing asthmapractice guidelines and processes, managed care practitioners need current informationto recognize and apply guidelines-based asthma control.Appropriate asthma treatment requires adherence to currentmanagement guidelines. Approximately one third of asthmatics will not respondto standard asthma treatment and may even worsen while on therapy. Monitoring,close tracking, and regular evaluation of asthma patients at every health careprovider visit is a strategy that can be utilized to generate improved asthma control."}
{"text": "Prosthetic aortic valve dehiscence is an uncommon complication of prosthetic valve endocarditis that may occur in patients who have undergone aortic valve replacement (AVR). The concurrent presence of aortic root pseudoaneurysm may further complicate the clinical presentation through the external compression of coronary arteries. Thus, patients may present with clinical features of coronary ischemia. Echocardiogram and coronary angiography are useful in establishing diagnosis. Treatment involves a multidisciplinary approach involving cardiologists, infectious disease specialists, and cardiothoracic surgeons. The authors of this study discuss a 51-year-old male who presented with anginal chest pain and was found to have a new left bundle branch block, elevated troponins, and left main coronary artery compression complicating aortic root aneurysm. He ended up requiring a re-do AVR, repair of the pseudoaneurysm, and coronary artery bypass graft. Prosthetic aortic valve infection with dehiscence is a major complication in patients with prior valve replacements . This coA 51-year-old male was referred from an outside facility on account of dyspnea, anginal chest discomfort and elevated troponins. His medical history was significant for intravenous (IV) drug use, hepatitis C, and multiple cerebrovascular accidents (CVAs) that necessitated patent foramen ovale closure. His cardiac history was significant for infective endocarditis-related valve dysfunctions status-post bio-prosthetic aortic valve replacement (AVR) and mitral valve repair with an annuloplasty ring.His vital signs included a blood pressure of 130/74 millimeters of Mercury, a pulse rate of 86 beats/minute, and a temperature of 98.6 degrees Fahrenheit. Examination findings were notable for crackles on lung auscultation. Initial lab results showed an elevated high-sensitivity troponin I level of 327 picogram per milliliter (pg/ml) (reference range 3-58 pg/ml). Rapid plasma reagin was negative. Computed tomography (CT) of the lungs suggested pulmonary septic emboli. Electrocardiogram (ECG) showed sinus rhythm and a new left bundle branch block (LBBB) that was not present on an ECG obtained three months earlier. Both ECGs are shown in Figures The cardiology service was consulted. A transthoracic echocardiogram (TTE) was performed and showed an abnormal prosthetic aortic valve function with rocking motion, prosthesis stenosis with peri-valvular regurgitation, pseudo-aneurysm of the aortic root, and ejection fraction of 25%. A transesophageal echocardiogram (TEE) was pursued and showed prosthesis stenosis, high sense of aortic valve more than 180 degrees detached with severe perivalvular regurgitation, and sewing ring dehiscence in the prosthetic aortic valve. It also showed a 4.7 cm by 4.3 cm aortic root pseudoaneurysm communicating with the aortic sinus was subsequently performed and showed external compression of the left main coronary artery (LMCA) and proximal left circumflex artery from the pseudoaneurysm as shown in Figure The aortic root pseudoaneurysm was believed to be the cause of the external pressure on the LMCA as demonstrated in the coronary angiogram; coronary artery bypass graft (CABG) was thus not planned initially. The plan, however, changed during the aneurysmal repair when the patient developed elevated pulmonary artery (PA) pressure and a visibly distended heart. CABG with saphenous vein graft to the left anterior descending artery was therefore performed. PA pressure normalized after the CABG. The dehiscent aortic valve is shown in Figure Unlike an atherosclerotic disease, external compression of the LMCA is a much less common cause of coronary ischemia. Etiologies include pulmonary artery in the setting of primary pulmonary hypertension, perivalvular abscess of the aortic valve, aneurysm of the aortic root, and left ventricular aneurysm -4. PatieProsthetic valve endocarditis (PVE) can result in valve dehiscence and mycotic aortic root aneurysm . The incThe diagnosis is usually made using echocardiography. It is important to remember that a negative TEE does not rule out the presence of vegetation. Large vegetation is a later event and the detection of smaller vegetation by a transesophageal echocardiogram (TEE) can be challenging due to the shadowing effect and reflection of the prosthetic material . MoreoveThe current case faced a distinctive complication involving compression of the left main coronary artery and proximal left circumflex artery by the aortic root pseudoaneurysm. ECG showed LBBB which was concerning for acute coronary syndrome necessitating coronary angiogram. LHC will usually show the area of external compression of the LMCA like in our patient. Surgical treatment of the aneurysms relieves the mechanical compression of the coronary arteries. Surgical management for PVE is not without challenges with some series reporting mortality rates of 20-60% and infection recurrence rate of about 7% . Long-teAortic root aneurysm causing external compression of LCA is an important but unusual cause of myocardial ischemia. Patients may be asymptomatic or present with chest pain and dyspnea. Management requires a multi-disciplinary approach. Since the clinical presentation is varied, clinicians need to be aware of the various presentations and challenge of variation in anatomic structure observed in management of such patients. Therefore, this is an important differential diagnosis to consider in the right clinical scenario: patients with PVE and aneurysmal aortic root, especially those with minimal to no atherosclerotic risk factors."}
{"text": "We also found that youth-reported positive parenting buffered against the association between childhood stress and decreased hippocampal volumes such that youth who experienced high levels of childhood stress and who reported increased levels of positive parenting did not exhibit smaller hippocampal volumes. Our work identifies positive parenting as a resilience factor buffering youth against the deleterious impact of stressful childhood experiences on problem behaviors and brain development. These findings underscore the importance of centering youth perspectives of stress and parenting practices to better understand neurobiology, mechanisms of resilience, and psychological well-being.Childhood stress has a deleterious impact on youth behavior and brain development. Resilience factors such as positive parenting (e.g. expressions of warmth and support) may buffer youth against the negative impacts of stress. We sought to determine whether positive parenting buffers against the negative impact of childhood stress on youth behavior and brain structure and to investigate differences between youth-reported parenting and caregiver-reported parenting. Cross-sectional behavioral and neuroimaging data were analyzed from 482 youth who participated in an ongoing research initiative, the Healthy Brain Network (HBN). Regression models found that youth-reported positive parenting buffered against the association between childhood stress and youth behavioral problems ( Childhood stress (e.g. the death of a loved one or illness) can have a negative impact on mental health and well-being; it is therefore critical to investigate resilience factors that might protect against stress. We consider positive (i.e. warm and supportive) parenting as a buffer against the impacts of childhood stress on youth behavior problems and corticolimbic structure. Youth perceptions of positive parenting moderated the association between childhood stress and (i) youth behavioral problems and (ii) hippocampal volumes. No significant associations emerged from interactions with caregiver-reported positive parenting or amygdala volumes. We conclude that positive parenting may function as a key resilience factor protecting youth from the deleterious impact of stressful experiences and that youth perspectives are critical to understanding how life stress shapes neurodevelopment and behavior.Stress in childhood and adolescence can significantly compromise mental health and well-being . A growiResilience factors such as relationships with caregivers can significantly protect against the many deleterious developmental outcomes associated with childhood stress, with more positive caregiver\u2013child connections being associated with better adjustment and fewer problem behaviors among youth , 13. Varslower amygdala growth over time for youth experiencing high levels of positive parenting and high stress, accelerated amygdala growth for youth experiencing high levels of positive parenting and less stress, and no significant effects of stress and parenting on hippocampal volumes and typically focus on stressful contexts (i.e. socioeconomic disadvantage) and not the actual experience of stress . We were particularly interested in investigating differences between youth versus caregiver perceptions of positive parenting, predicting stronger interactive effects for youth reports of positive parenting compared with caregiver reports.\u03b1 > 0.7, as detailed in our Data from 482 participants between the ages of 10\u201317 years with T1-weighted structural images were analyzed from the ongoing Healthy Brain Network (HBN) research initiative , a checklist measuring family-, community-, and school-based stressors . Due to Youth report and caregiver report of positive parenting were measured using the positive parenting subscale from the Alabama Parenting Questionnaire (APQ) . For eacYouth behavioral functioning was operationalized by the Youth Self-Report (YSR) Total Raw Score. The YSR is a well-validated and widely used 112-item instrument for problem behaviors across the internalizing and externalizing spectrums among children aged 11\u201318 .High-resolution T1-weighted anatomical MRI scans were collected from four sites in the New York City area. We performed standard-processing approaches from FreeSurfer (version 7.1) and excluded participants with low-quality images and high-motion scans . Regression models examined the interactions of stress and parenting in predicting youth behavioral problems and included sex, age, and scanning site as covariates. We fit linear mixed-effects models (LMEMs) for each brain region of interest due to potential variations in research sites and scanners. LMEMs included a random effect of the imaging site and sex, age, and estimated total intracranial volume as covariates. We ran separate models testing interactions between negative life events and a) youth-reported positive parenting and b) caregiver-reported positive parenting for each brain region of interest. For significant interaction terms, we conducted simple slope analyses . Across models, we tested for differences between any significant and nonsignificant interaction terms (see N = 226) anerms see and psycerms see . We ran pproach) .Descriptive statistics are found in Table \u03b2 = 0.14, Praw < 0.001, Pcorrected = 0.017) and a significant main effect of positive parenting . We also found a significant interaction between negative life events and positive parenting . Simple slope analyses indicated that the association between negative life events and behavioral problems was significant at lower and average levels of positive parenting, but not at high levels of positive parenting. There was no relation between stress and behavioral problems when youth were exposed to the highest levels of positive parenting, suggesting a buffering effect. We considered a similar model examining the interaction between stress and positive parenting on behavioral problems using caregivers as the informant of positive parenting. We found no buffering effect of positive parenting against the association between stress and behavioral problems using the caregiver report measure of positive parenting. Models without interaction terms and caregiver report measures of behavioral problems and negative life stress can be found in the We first considered the moderating effect of youth-reported positive parenting on the association between negative life events and youth-reported behavioral problems Fig. . Results\u03b2 = \u22120.07, Praw = 0.029, Pcorrected = 0.042) on the total hippocampal volume. As predicted, there was a significant interaction between youth-reported positive parenting and stress . There was no effect of youth-reported negative life events on hippocampal volumes for participants reporting above-average positive parenting. This finding underscores the stress-buffering role of positive parenting given that reports of negative life events had a negative association with hippocampal volumes only in the presence of below-average and average levels of positive parenting, and not in the presence of above-average positive parenting. Sensitivity analyses testing left and right hippocampal volumes individually can be found in the We next considered the moderating effect of youth-reported positive parenting on the association between negative life events in childhood and hippocampal volumes on total hippocampal volume. We tested differences between interaction terms for our two models on total amygdala volume. There were also no interactive effects between negative life events and youth-reported positive parenting on total amygdala volume .There was not a significant main effect of negative life events (N = 226). In this subsample, adding the presence of a mental health diagnosis was not significantly associated with the total hippocampal volume.We constructed additional models to determine the robustness of our effects see . These aWe ran additional analyses examining associations with several markers of socioeconomic status given connections between socioeconomic status and hippocampal volumes. Results indicated that the potentially comorbid and stressful experience of the socioeconomic environment did not account for observed effects of negative life events and positive parenting on youth behavioral problems and hippocampal volumes see . To accoWe found three major results: (i) negative life events and youth perceptions of positive parenting are associated with behavioral problems, (ii) negative life events are significantly associated with smaller hippocampal volumes, and (iii) positive parenting moderates this association such that youth who reported high levels of positive parenting did not show smaller hippocampal volumes even with increasing levels of stress. Only youth perspectives of positive parenting interacted with childhood stress (measured through negative life events) to predict hippocampal volumes; caregiver report of positive parenting was not related to neurobiology as either a main effect or in an interaction with stress. Such findings underscore the importance of including youth as reporters of their own experiences to better understand consequences for neurodevelopment and behavior . We did Our results underscore well-replicated connections between exposure to childhood stress and smaller volumes in the hippocampus , 32. ThePositive parenting can provide youth with a stable environment to learn social skills, feel supported, and practice cognitive and behavioral regulation. Other work examining interactive effects between childhood stress and parenting on brain volumes has not found evidence of a buffering effect of parenting, instead suggesting that warm and supportive parenting was a compounding positive force in the context of low stress . In contThe protective effect of parenting against the deleterious neurobiological impacts of stress may function through modulating biological and socioemotional processes such as hypothalamic\u2013pituitary\u2013adrenal (HPA) axis responsiveness, cortisol reactivity, and self-regulation. Longitudinal work has found that parenting influences HPA axis and cortisol reactivity, which in turn impacts hippocampal volume during development . In addir = 0.22) between youth and caregiver reports of positive parenting in this sample aligns with previous work establishing small to moderate correlations between youth and caregiver reports of behavioral and emotional functioning , suggesting that the observed interaction between childhood stress and youth-reported positive parenting on hippocampal volumes in our larger sample is not explained by comorbid psychopathology. Similarly, we considered associations with various operationalizations of socioeconomic status considering that socioeconomic disadvantage can be an experience of stress that has been associated with altered corticolimbic structure for consistency in findings (We note several limitations that could serve as important directions for future research. First, we report significant associations that are small in magnitude, with effect size estimates indicating that childhood stress at below-average parenting explains 0.06% of the variance in youth behavioral problems; similarly, childhood stress at below-average parenting explains 0.02% of the variance in total hippocampal volumes. Youth behavioral problems and total hippocampal volumes were also not significantly associated in our supplemental analyses. Of note, we did find a significant association between youth behavioral problems and left hippocampal volumes (detailed in our findings and apprfindings .Our findings have implications for understanding the impact of childhood stress as well as the factors that buffer youth against the noxious consequences of stress. Given the critical role of the hippocampus in memory and goal-directed behavior, alterations in this structure may create vulnerabilities for later negative outcomes. While additional research is needed to clarify complex relations between stress, parenting, and the brain, our data provide insight into how environmental forces may interact to influence neurobiology.pgad145_Supplementary_DataClick here for additional data file."}
{"text": "Spectroscopy imaging machine learning for crop stress.\u201d By exploring these cutting-edge research findings we can gain valuable insights into the application of these technologies to enhance agricultural resilience productivity.Crop stress poses a huge challenge to food security necessitating innovative approaches for early detection monitoring management of stress. In recent years the integration of spectroscopy imaging machine learning techniques has emerged as a promising avenue for detecting various types of crop stress. This editorial work introduces recent publications within the field included in the Research Topic \u201cXiao et\u00a0al. focused on the use of visible and near-infrared spectroscopy combined with deep learning to estimate leaf nitrogen concentration in cotton leaves. The study employed random frog, weighted partial least squares regression and saliency map to select characteristic wavelengths. The models based on convolutional neural network showed excellent performance for both qualitative and quantitative prediction of leaf nitrogen. These findings highlight the potential of deep learning and visible and near-infrared spectroscopy within accurate and real-time assessment of cotton leaf nitrogen content, enabling farmers to make applicable fertilization decisionsWu et\u00a0al. employed an unmanned aerial vehicle (UAV) to obtain multispectral images of a rice canopy and analyzed the response of multispectral reflectance features and physiological parameters including net photosynthetic rate (Pn), plant height (PH), and SPAD to different nitrogen treatments or leakage conditions at various growth stages of the crop. The study extensively analyzed the correlation between vegetation indices (VIs), texture indices (TIs), and Pn based on UAV multispectral images. The techniques and findings presented in this paper provide valuable insights within field-scale photosynthetic monitoring in rice cultivation and improve stress detection and yield prediction.Choudhury et\u00a0al. introduces two innovative algorithms, namely VisStressPredic and HyperStressPropagateNet, to predict the onset and propagation of drought stress in plants using camera-captured image sequences in visible light and hyperspectral modalities. The algorithms analyze visible light sequences at discrete intervals and utilize a deep neural network and hyperspectral images to propagate stress over time, which demonstrate a strong correlation between soil water content and the percentage of stressed plants. These algorithms are evaluated on a dataset of cotton plant image sequences and offer valuable support for studying abiotic stresses in diverse plant species, promoting sustainable agricultural practices.Hu X. et\u00a0al. propose a novel approach called Class-Attention-based Lesion Proposal Convolutional Neural Network (CALP-CNN), utilizing a class response map to locate the main lesion object and identify discriminative lesion details in visual light images. Through a cascade architecture, CALP-CNN effectively handles complex background interference and misclassification of similar diseases. Experimental results on a self-built dataset demonstrate CALP-CNN achieves good classification performance and outperforms the existing fine-grained image recognition methods, highlighting its efficacy in field identification of strawberry diseases.Hu Y. et\u00a0al. presents an enhanced encoder-decoder framework based on DeepLab v3+ analysis of images to accurately identify crops with diverse planting patterns. The network utilizes ShuffleNet v2 as the backbone for feature extraction and incorporates a convolutional block attention mechanism to fuse attention features across channels and spatial dimensions. The enhanced network achieves significant improvements and requires fewer parameters and computational operations compared to other networks. This study demonstrates the effectiveness of Deep-agriNet in identifying crops with different planting scales, making it a valuable tool for crop identification in various regions and countries.The combination of spectroscopy, imaging, and machine learning has a high potential for improving crop stress analysis and management. By utilizing these technologies, we can enhance our understanding of crop stress dynamics, develop precise and targeted stress detection methods, and improve decision-making processes for farmers. Ongoing research, technological advancements, and collaborative efforts are necessary to unlock the full potential of spectroscopy, imaging, and machine learning in mitigating crop stress and ensuring global food security.The\u00a0author\u00a0confirms being the sole contributor of this work and has approved it for publication."}
{"text": "A 60-year-old male patient underwent coronary angiography for acute myocardial infarction. Angiograms revealed significant multivessel disease and an abnormal branch arising from the proximal right coronary artery and extending backwards, likely to the right lung A. Both iIsolated DOPA is a rare vascular malformation that may remain undiagnosed until advanced age, often manifesting with nonspecific symptoms such as recurrent bronchopneumonia, haemoptysis, and dyspnea.,Lack of a connection between the main and affected branch PA, resulting from the involution of the ventral sixth aortic arch, led to the erroneous definition of unilateral pulmonary artery agenesis.\u2022Chest radiograph may provide relevant clues to the diagnosis of DOPA.\u2022CTPA is the method of choice for noninvasive diagnostic confirmation.\u2022Key diagnostic findings are a well-formed but hypoplastic pulmonary artery and a ductal diverticulum on the aortic arch or the base of an epiaortic vessel.Interestingly, DOPA could be suspected by jointly considering the anomalies detected by coronary angiography and chest radiograph. Despite not providing direct visualization of DOPA, these diagnostic modalities could offer subtle but important clues to this rare malformation, ultimately confirmed by CTPA."}
{"text": "Gastrointestinal cancers represent a major challenge to public health. Pancreatic cancer is the most lethal cancer among all gastrointestinal cancers. Most patients cannot meet the criteria of resection at diagnosis, indicating these patients will have dismal prognosis.Neoadjuvant chemotherapy helps some patients regain the opportunity of radical resection. An optimal regimen of chemotherapy is one that maximizes the anti-tumor efficacy while maintaining a relatively manageable safety profile. The development of surgical procedures further improves the outcomes of these patients.Combination therapies in a multidisciplinary manner that involves modified chemotherapy regimen, radical resection, and intestine auto-transplantation may provide the currently best possible care to patients with locally advanced pancreatic cancer. Gastrointestinal cancers account for around 25.8% of newly diagnosed cancers annually. Among them, pancreatic cancer is the most lethal cancer, with a 5-year overall survival rate of only around 12%. There are more than 495,700 new cases of pancreatic cancer each year [Liang and colleagues proposed a modified FOLFIRINOX regimen, consisting of 85% oxaliplatin, 75% irinotecan, and zero fluorouracil bolus . This moThe modified FOLFIRINOX regimen was also applied as a neoadjuvant treatment to borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) for downstaging and creating surgical opportunity. According to the LAPACT trial that applied gemcitabine plus nab-paclitaxel to LAPC, the neoadjuvant induction therapy achieved a 15% conversion rate of radical resection . The medThe expanded surgical resections after neoadjuvant therapy are critical to the improvement of the radical resection rate in LAPC. For LAPC involving the pancreatic body/tail and the celiac trunk, radical resection can be achieved by the modified Appleby procedure . This group is one of the leading groups that focus on intestine auto-transplantation and liver cancer surgery , 8. As fLiang\u2019s integrated treatment strategy by combining modified FOLFIRINOX with sequential radical resection has established an excellent model of multimodal treatment against pancreatic cancer, and extended criteria of surgical resectability, which would benefit more pancreatic cancer patients at locally advanced stages. The success of this strategy implies that for pancreatic cancer patients, especially those who cannot meet the resectability criteria, the combination of modified chemotherapy and surgical intervention would provide an increased survival benefit. Furthermore, the interim analysis of a prospective phase 3 clinical trial conducted by Liang\u2019s group , compariIn summary, gastrointestinal cancers represent a major challenge to public health. Most patients cannot meet the criteria of resection at diagnosis, indicating these patients will have dismal prognosis. Neoadjuvant chemotherapy helps some patients regain the opportunity of radical resection. The development of surgical procedures further improves the outcomes of these patients. Combination therapies in a multidisciplinary manner that involves modified FOLFIRINOX regimen, radical resection plus intestine auto-transplantation, targeted therapy and immunotherapy may provide the best possible care to patients with LAPC.The modified FOLFIRINOX regimen is currently an optimal treatment option for pancreatic cancer patients. Combination of the modified FOLFIRINOX regimen, radical resection, and intestine auto-transplantation provides the currently best possible survival benefit for those who have otherwise lost the opportunity of surgery. The addition of immunotherapy, targeted therapy, and radiotherapy may further increase the efficacy of the combination therapy."}
{"text": "How adult tissue-specific stem cells with indicated markers contact the adjacent lineage with indicated markers is of significance to be studied. Novel methods bring future findings. Recent advances in lineage tracing, synthetic receptor systems, proximity labeling, and transcriptomics have enabled easier and more accurate cell behavior visualization and qualitative and quantitative analysis of cell-cell interactions than ever before. These technological innovations have prompted researchers to re-evaluate previous experimental results, providing increasingly compelling experimental results for understanding the mechanisms of cell-cell interactions. This review aimed to describe the recent methodological advances of dual enzyme lineage tracing system, the synthetic receptor system, proximity labeling, single-cell RNA sequencing and spatial transcriptomics in the study of adult tissue-specific stem cells interactions. An enhanced understanding of the mechanisms of adult tissue-specific stem cells interaction is important for tissue regeneration and maintenance of homeostasis in organisms.Adult tissue-specific stem cells play a dominant role in tissue homeostasis and regeneration. Various Adult tissue-specific stem cells interactions can be viewed as communication modalities that play a central role in regulating cell behavior and function .In this paper, we first discuss the methods for studying adult tissue-specific stem cells interactions in two directions: bioinformatics analysis and visualization analysis. Specifically, these techniques or methods include lineage tracing, synthetic receptor systems, proximity labeling, and transcriptome analysis. In addition, there are few systematic descriptions of the mechanisms of stem cell interactions. Therefore, this paper also combs the biological understanding of adult tissue-specific stem cells interactions. We do not provide a summary assessment of all relevant literature, and references throughout the text tend to be more illuminating examples. Based on the latest literatures, stems cells referred in this review focus on adult tissue-specific stem cells.in vivo single-cell analysis because of its efficiency and spatiotemporal specificity during long bone formation is clearly illustrated to regenerate the bronchoalveolar junction region after an injury has been demonstrated using dual-recombinase-activated lineage tracing (DeaLT) system, reiterating previous findings . Applyinustrated . It has ustrated . In lungustrated . Updatedustrated .Based on the Cre: Dre dual recombinase reporter system, Lingjuan We also note the contribution of optogenetic genetic engineering to the content of our work, which is widely used to study and control cells and has been previously described . OptogenInspired by the natural cell-signaling paradigm, researchers have implemented artificially designed synthetic receptor systems to manipulate signal translation to control cellular functions, including artificially tunable cellular sensing and subsequent transcriptional responses . The devThe synNotch receptor system, which detects cell-cell contact, was developed during the development of synthetic receptor systems . The synDrosophila model genetically engineered to be expressed in decoy cells to transfer the markers to prey cells . This laThe FucoID protocol installs the glycosyltransferase directly onto the decoy cell without gene expression on the cell membrane . This enProtocols using photocatalysts have greater temporal control and remote manipulation than enzymatic proximity-labeling systems . These pin situ studies of cellular interactions in animal models act as alveolar adult tissue-specific stem cells in response to injury . AT2 celin vivo triggers EphB2 signaling attenuation in adjacent radial neural stem cells (rNSCs) through direct cell contact, leading to rNSC activation and the generation of new neurons . Conversin vitro . TranscrInteractions between immune cells and stem cells have also been reported. The fate of intestinal stem cells (ISC) is regulated by adhesion signals from immune cells . BindingThe paracrine effects of stem cells are also influenced by the cell-cell contact between stem cells and other cells. For example, the immunomodulatory effects of MSCs are enhanced upon contact with pro-inflammatory macrophages . AdditioMoreover, immune cell function is affected by intercellular contact between stem cells and immune cells. This may be due to the secretion of cytokines that affect stem cells . There aStem cells can also regulate immune cell functions through paracrine and intercellular contacts . TGF-\u03b2 Min situ.\u201dIn bone marrow tissue, bone marrow regeneration after radiation clearance is inseparable from the transfer of mitochondria from hematopoietic stem cells to bone marrow mesenchymal stromal cells through intercellular contacts . HematopMechanical signals include both the structure and properties of the ECM and forces generated by the cell through various connections . This inDrosophila, the proliferation and differentiation of all stem cells that ectopically express Piezo are promoted by a mechanism that is inseparable from calcium signaling (Mechanically gated Piezo1 channels are expressed in both neural stem cells and astrocytes and regulate adult neurogenesis . In Drosignaling . Piezo1 ignaling . Furtherignaling . During ignaling . When thignaling . Adult mignaling . The NotWnt and Src-YAP signaling cooperate to drive intestinal regeneration . Additiovice versa in favor of endocrine cell fate (Physical signaling with tunable properties that act immediately and locally is an object of interest to regulate the differentiation of stem cells into specific lineages . The ECMell fate . MSCs arell fate . Smallerell fate . The intell fate . Moreoveell fate . The intell fate .Indeed, numerous researchers have shed a light on how mechanical information affects cell behavior. We are currently studying the mechanisms underlying stem cell interactions to improve the application of stem cells in regenerative medicine. To systematically and precisely elucidate these mechanisms, technologies with higher spatial and temporal resolutions, more realistic simulations of the stem cell microenvironment, and more specific stem cell population differentiation and tracing are required. This demand has led to many powerful technologies that elucidate the mechanisms of stem cell interactions. We discuss how lineage tracing, synthetic receptors, proximity labeling and transcriptome data analysis tools can be applied in the study of CCI. The techniques presented in this paper include but are not limited to using stem cells as research models, and using non-stem cells as research models has complementary and reference significance. In addition, we note some other techniques. For example, SPEAC-seq based on CRISPR-Cas9 with microfluidic microarrays to identify cell signaling pathways . It provThe study of stem cell interactions is in a rapidly evolving stage, especially in the context of rapid iterative updates in biotechnology. Although, the biological understanding of stem cell interactions sorted out in this paper is not sufficient to elaborate a comprehensive picture of stem cell behavior during mammalian development or injury repair, it contributes to a complete description of stem cell interaction mechanisms in the future."}
{"text": "Cerebrovascular injuries resulting from frontobasal head trauma represent a range of imaging and clinical presentations. Severe cerebrovascular injuries such as vessel transection commonly present with profound neurological deficits and are often easily identified with routine imaging. However, small intimal injuries and dissections may be challenging to detect and may be clinically silent or masked by additional injuries in the setting of polytrauma. The onset of symptoms and complications from cerebrovascular injuries may be delayed from the time of initial presentation, and failure to recognize and diagnose these injuries may result in devastating outcomes if management is delayed. In this case report, we present a case of frontobasal craniofacial trauma that resulted in an anterior cranial fossa dural arteriovenous fistula (ACF-dAVF) and supraclinioid segment internal carotid artery (ICA) pseudoaneurysm.\u00a0 Vascular injuries have been identified in 8.5% of skull base fractures in some case series, particularly when the sella turcica-sphenoid sinus complex and the petrous carotid canal are involved ,2. ResulDural arteriovenous fistulas (dAVF) are uncommon vascular lesions with abnormal connections between arteries and leptomeningeal veins or a dural venous sinus\u00a0. They maTraumatic intracranial aneurysms represent fewer than 1% of all intracranial aneurysms . AlthougA 45-year-old male presented with extensive frontobasal and craniofacial injury after an all-terrain vehicle (ATV) rollover. Initial trauma computed tomography (CT) scans depicted bilateral naso-orbito-ethmoid complex fractures with fracture planes extending to the bilateral sphenoid sinus walls. Multi-compartmental intracranial hemorrhage, including subarachnoid hemorrhage and hemorrhagic contusions with basifrontal predominance, were also present. Subsequent CT angiography (CTA) of the neck revealed vessel wall irregularities and non-flow limiting stenosis involving the left supraclinoid ICA, and prominent cortical veins along the right ACF Figures , 2. The Cerebrovascular injury from blunt trauma can be subtle and difficult to detect at initial presentation. It can be stratified using a five-point scale Biffl cerebrovascular arterial injury grading scale\u00a0based on the severity of vessel injury from mild intimal injury (Grade I) to vessel transection (Grade V) Table 11]. Gr. Gr11]. In this case, the patient developed an ACF-dAVF within three days of the initial encounter, which is to our knowledge the first case report of a patient presenting with this condition within one month of the initial injury. In ACF-dAVFs, the cribriform plate is commonly the fistula point, in which afferent arterial supply arises from the distal ophthalmic artery and both anterior and posterior ethmoidal arteries, and venous drainage occurs through frontal cortical veins into the superior frontal sinus or posteriorly into the cavernous sinus or basal vein of Rosenthal ,15. In tTraumatic intracranial aneurysms may be true or false aneurysms. True aneurysms have preserved adventitia and partially disrupted and damaged intima, internal elastic lamina, and media, whereas false aneurysms/pseudoaneurysms result from disruption of all arterial wall layers and are contained by adjacent hematoma and perivascular connective tissues . In partThis report is a description of a rare case of ACF-dAVF and ICA pseudoaneurysm that developed in the days following significant frontobasal craniofacial trauma as an opportunity to discuss the clinical presentation and associated imaging findings of these lesions, and to provide a better understanding of the pathogenesis and management of these and related post-traumatic cerebrovascular injuries and complications."}
{"text": "Scar pregnancy is a rare and potentially life-threatening condition that occurs when an embryo implants and grows within a previous cesarean section scar or other uterine scars. This unique form of ectopic pregnancy poses significant diagnostic and management challenges for healthcare providers. Scar pregnancies are associated with an increased risk of uterine rupture, massive hemorrhage, and other complications, underscoring the importance of early detection and appropriate management strategies . Scar pr"}
{"text": "Discoid lupus erythematosus (DLE) is a chronic variant of cutaneous lupus erythematous developing on sun-exposed areas in multi-morphic forms making diagnosis challenging. Clinical suspicion and prompt treatment are necessary to avoid permanent disfigurement, progression to systemic involvement and poor quality of life. We report a case of delayed DLE diagnosis in a 45-year-old man who presented with a new skin lesion mimicking the early stages of mycosis fungoides that prompted further investigation. Histopathological examination confirmed DLE and appropriate treatment was initiated. However, the atypical clinical presentation led to disseminated DLE and refractory disease control, resulting in scarring and cosmetic disfigurement. Lupus erythematosus (LE) is an autoimmune disease existing on a spectrum of cutaneous and systemic manifestations. Discoid lupus erythematosus (DLE) is the most common variant of chronic cutaneous LE that can present in a variety of morphologies . UnderstA 45-year-old male presented with a new erythematous plaque on the left upper chest after an initial diagnosis of photodermatitis due to the presence of erythematous patches and plaques on the scalp . The newA 4-millimeter punch biopsy from lesional skin showed an orthokeratotic and mildly atrophic epidermis with extensive vacuolar degeneration of the basal layer. There was a dense superficial dermal lichenoid-type of lymphocytic inflammatory infiltrate with scattered melanophages and presence of colloid bodies . Marked Histopathological findings coupled with serological findings were corroborative of DLE and thus the patient was started on short-term oral steroids with prednisolone (20\u00a0mg daily), oral hydroxychloroquine (HCQ) and high-potency topical steroid clobetasol propionate. Treatment included photoprotection recommendations.At a 6-week follow-up, new cutaneous lesions appeared on the back and the Patient\u2019s systemic evaluation was negative to date. The patient is under regular follow-up with dermatology and rheumatology.DLE renders difficulty in clinical suspicion and definitive diagnosis as skin lesions resemble common dermatoses. It can lead to permanent disfigurement with hair loss, dyspigmentation and scarring if not treated early or adequately controlled. The chronic nature of the disease imposes a psychological burden and high morbidity on patients, often requiring psychosocial support , 4. Diag"}
{"text": "Neural oscillatory activity has emerged as a central Research Topic in neuroscience and phase . Despite their conceptually clear-cut operationalization, analyses of these parameters are confronted with an inherent problem: For which frequency range should these parameters be calculated and how should this range be determined? Initially, a priori-defined frequency ranges centered on a prominent power peak were linked to behaviorally relevant functions , has the potential to overcome the above-mentioned limitations. Computation of PF allows definition of recording-specific frequency peaks based on the empirical data, which can be used to compare individuals and/or experimental conditions. Additionally, when paired with novel tools correcting for aperiodic signal components and discrete perception . Correlation analyses revealed no systematic connection between individual alpha PF and the latency of neural markers of visual processing. These findings indicate that individual alpha PF does not systematically shift early sensory processing in time.Two of the four contributions to this Research Topic examine the link between individual alpha PF and visual processing. Strang et al. assessed if individual alpha-band PFs over occipitoparietal and sensorimotor areas are linked to autism spectrum disorders. EEG recordings of neurotypical participants during motor execution and movement observation revealed that individuals with slower sensorimotor PFs exhibited higher autism-spectrum traits. This finding adds important information about potential biomarkers, since research so far largely focused on the classical alpha rhythm. The work by Sponheim et al. recorded individual alpha-band PFs with MEG during rest and visual processing in participants with psychotic psychopathology, their biological siblings, and healthy controls. Alpha PF varied widely across participants and remained temporally stable across multiple months. Moreover, slowed alpha PF was linked to longer visual percept duration in participants with psychopathology, as well as to lower IQ estimates and higher symptom severity. This study shows how fundamental research can inspire a directed functional assessment of neural markers as indicators of clinical symptom severity.Two other contributions studied the link between PFs and trait variables related to neuropsychiatric disorders. The systematic and hypothesis-driven analysis of PF holds the potential to provide exciting and novel roles of neural oscillatory activity. It promises to strengthen the analysis of oscillatory power and phase by providing an empirically-informed frame of reference instead of rigid a priori defined frequency definitions. We hope that this Research Topic has increased the visibility of PF in the neuroscientific audience and motivated future research.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "Cell, Gungabeesoon and colleagues1 demonstrated that a specific subpopulation of neutrophils, characterized by a distinct Sellhi (CD62Lhi) phenotype with an interferon gene signature, acutely accumulates in tumors during successful immunotherapy and is associated with better treatment outcome. These findings enhance our understanding of the neutrophil heterogeneity within the tumor context and highlight their potential in cancer immunotherapy.In a recent study published in Traditionally, neutrophil infiltration of tumor tissue has been primarily associated with tumor progression. However, the remarkable heterogeneity of neutrophils allows them to play multiple roles in this process. In addition to their typical pro-angiogenic and immunosuppressive functions, neutrophils can also have protective roles, such as direct cancer cell killing or stimulation of adaptive immune responses. Importantly, various anti-cancer therapies directly or indirectly (by modulation of tumor microenvironment), impact neutrophil responses and activity. Nevertheless, some immunotherapies fail to induce clinical responses in certain patients, prompting extensive efforts to understand the underlying mechanisms.1 analyzed neutrophil phenotypes expanded after successful immunotherapy. These cells had been previously overlooked in single-cell transcriptomic research due to unintended elimination during standard preparation of the sample. The authors observed that therapy-induced neutrophils expressed high levels of Sell transcripts, encoding the protein Selectin L . These neutrophils exhibited a more immature phenotype (CD101lo), associated with increased cytotoxicity and upregulated expression of genes responsible for regulation of neutrophil degranulation, suggesting their potential immunostimulatory activity. This aligns with prior observations indicating anti-tumoral properties of immature neutrophil populations.2Sellhi neutrophils also exhibited a distinct interferon (IFN) signature, including interferon regulatory factor 1 (IRF1), a crucial driver of their anti-tumor phenotype, and appeared to be essential for the successful therapy , was sustained in tumors after treatment, even as Sellhi neutrophils increased. SiglecFhi neutrophils were previously shown to have pro-tumorigenic properties.5 Here the authors showed that these neutrophils were characterized by multiple gene signatures that support their pro-tumorigenic roles, including expression of genes that promote tumor proliferation, remodeling of extracellular matrix, angiogenesis, suppression of antitumor immunity, and recruitment of myeloid cells, and thus reported to be responsible for metastasizing, sustained in tumors after treatment. Therefore, this study suggests that therapies should aim not only to expand anti-tumor neutrophils, but also to eliminate pro-tumor counterparts. Further human studies will be needed however to understand the dynamics of these populations in a relevant clinical setting following therapy. Human studies should also allow evaluating whether the abundance of these neutrophil populations predict progression and outcome in human cancers.The authors also noted that another population of neutrophils, Single-cell transcriptomics has revolutionized our understanding of neutrophil biology by unraveling the phenotypical and functional diversity of neutrophil subsets across various organs. The pursuit of selective strategies to therapeutically enhance beneficial neutrophil populations while concurrently eliminating tumor-supporting neutrophils remains a compelling approach in immunotherapy. Rather than complete depletion of neutrophils, successful immunotherapy should focus on modulating the tumor microenvironment to favor anti-cancer repolarization of neutrophils. This approach holds the potential to establish an effective strategy for achieving optimal anti-tumor responses and enhancing the outcomes of cancer patients."}
{"text": "Dear colleagues,Pediatric minimally invasive surgery (MIS) epitomizes a dynamic and continuously evolving field that encompasses a broad range of procedures. From fetoscopic interventions in the prenatal population to robotic-assisted bariatric surgeries in overweight adolescents, the spectrum of techniques and patients encountered in pediatric MIS reflects its inherent intricacy and the fascination it inspires.In the context of this particular Special Issue, our primary objective revolved around an extensive exploration of the expansive landscape of pediatric MIS. This comprehensive investigation encompassed a wide range of relevant aspects, including well-established procedures, pioneering and audacious concepts\u2014even those yielding unfavorable outcomes, breakthrough technological advancements, potential hazards and challenges, contentious procedures, and invaluable insights drawn from our counterparts in the realms of general, thoracic, and visceral surgery.Our intention was to transcend a simple retrospective appraisal by eschewing the common narrative of \u201cwhat has been accomplished thus far?\u201d. Instead, our aim was to assemble a compendium of reports from pioneering colleagues from diverse medical disciplines. These individuals have forged innovatively ahead, propelling developments in minimally invasive surgical interventions in order to enhance the welfare of pediatric patients.We are pleased to say that our endeavors have borne fruit, and we believe that we have achieved our objective.To improve the wellbeing of pediatric patients even before their birth, Thomas Kohl delves into the study of fetal surgery, offering insights into both established and emerging minimally invasive approaches. Expanding upon this, Susanne Eva Brunner provides an exhaustive review comparing bimanual techniques and procedures in fetal surgery with single-instrument interventions. Additionally, Lidya-Olgu Durmaz sheds light on the use of minimally invasive techniques in fetal surgery for the treatment of gastroschisis.Regarding infants and congenital malformations, Anne-Sophie Holler describes the endoscopic magnetic-assisted anastomosing technique, specifically designed for the repair of esophageal atresia. Additionally, Julia K\u00fcppers presents an innovative approach termed \u201cendoscopic percutaneous rectal anoplasty\u201d, which has garnered considerable attention from the esteemed Alberto Pena, a prominent authority on anorectal malformation repair, prompting subsequent scholarly discourse. In a closely related context, Ulrike Metzger provides valuable insights into a recently modified approach involving transanal endoscopic-assisted pull-through colectomy targeted toward pediatric patients afflicted by high intestinal aganglionosis. These developments in pediatric surgical interventions offer promising avenues for improved outcomes and enhanced patient care.When it comes to general pediatric surgical procedures, this comprehensive compilation includes many notable contributions. Hanna Noemi Stundner Ladenhauf presents a meticulous evaluation of the minimally invasive approach in managing traumatic pancreatic ruptures, shedding light on its efficacy and potential benefits. Armin-Johannes Michel provides a detailed account of the thoracoscope-guided pericostal suture technique, showcasing its efficacy as a robust fixation method for closing congenital diaphragmatic hernias. The state-of-the-art of advancements in the field of minimally invasive repair of pectus excavatum (MIRPE) is expertly detailed by Frank-Martin Haecker, as he reveals the current developments and techniques employed in this realm. In a similar vein, Christian Tomuschat delves into the boundaries and limitations encountered in laparoscopic partial splenectomy, providing valuable insights into the challenges associated with this minimally invasive procedure.The domain of pediatric surgery encompasses not only general procedures but also extends to minimally invasive urological interventions. In this context, Frank-Martin Haecker contributes valuable insights by reporting on the combined antegrade and retrograde endoscopic injection technique into the bladder neck employed in children with neurogenic bladder disorders. Furthermore, Christian Kruppa presents a fascinating approach to vesicoscopic cross-trigonal ureteral reimplantation, specifically addressing vesicoureteral reflux. This innovative technique offers a compelling avenue for the treatment and resolution of this condition. These advancements in minimally invasive urological procedures within pediatric surgery hold great promise for enhanced patient outcomes and an improved quality of care.Mareike Grosshauser contributes an insightful examination of interdisciplinary knowledge transfer within the study of minimally invasive pediatric surgery. Similarly, Tatjana Tamara K\u00f6nig delves into the topic of telementoring in the context of minimally invasive esophageal atresia repair, shedding light on the potential benefits and implications of this approach. Expanding our understanding, Andrea Schmedding presents a comprehensive nationwide assessment of the current landscape surrounding laparoscopic pediatric inguinal hernia surgery, drawing upon an extensive dataset. Furthermore, Ma\u0142gorzata Sobol offers a unique perspective by focusing on the parental experience of minimally invasive surgery, specifically examining the role of parents\u2019 time perspective as a predictive factor for their child\u2019s postsurgical pain and emergence delirium, and the potential manifestation of post-traumatic stress disorder in parents.The integration of robotic-assisted surgery will be pivotal element in the future landscape of minimally invasive pediatric surgical procedures. Ewan Brownlee and Mark Slack delve into this paradigm-shifting subject, offering an insightful report on the novel Versius surgical robotic system developed by Cambridge Medical (CMR), exploring its potential utility within the pediatric population. In a related investigation, Marit Kayser presents an evaluation of the Versius system for pediatric surgery, employing inanimate models that simulate small infants and, thus, providing valuable insights into its feasibility and effectiveness. Within the pages of this publication, we also encounter a groundbreaking contribution by J\u00fcrgen Holzer, who provide the world\u2019s inaugural account of a pediatric pyeloplasty performed using the Senhance\u00ae robotic system. This pioneering achievement marks a significant milestone in the application of robotic technology in the pediatric surgical domain. Additionally, Elisabeth Ammer explores the phenomenon of \u201crobotic anxiety\u201d and elucidate parents\u2019 perception of robot-assisted pediatric surgery and its impact on their children. This investigation sheds light on the psychological aspects and human factors associated with the adoption of robotic systems in pediatric surgical contexts. Finally, Thomas Krebs offers a comprehensive review encompassing diverse aspects of robotic-assisted pediatric surgery. Our collective insights and synthesis of existing knowledge serve to enrich our understanding and foster advancements in this rapidly evolving field.Nevertheless, the possibilities of minimally invasive pediatric surgery transcend the traditional boundaries of abdominal and thoracic procedures. Within the field of pediatric orthopedics and orthopedic trauma, Karsten Krohn unveils a pioneering technique involving the dual pre-bending of an intramedullary nail to treat diametaphyseal fractures of the distal radius in children. This innovative approach not only renders the procedure and osteosynthesis less invasive but also holds promise for improved patient outcomes. Moreover, the use of resorbable implants presents an intriguing possibility for circumventing the need for subsequent explantation surgeries; this is an area explored by Christoph Roeder. Through a pilot study, he investigates the application of biodegradable intramedullary nailing, specifically for forearm fractures in the pediatric population. His findings shed light on the feasibility and potential benefits of this approach, paving the way for future advancements in pediatric orthopedic interventions. Similarly, Pascal Heye contributes to this line of inquiry by delving into the utilization of resorbable implants for osteosynthesis in pediatric cases. His research further expands our understanding of this evolving field, exploring possibilities for enhanced treatment modalities and improved patient outcomes. Furthermore, Mathis Wegner presents his insights into a minimally invasive orthosis designed to address a fixed equinus deformity following a modified transverse Vulpius procedure. This novel orthosis holds promise in rectifying this deformity while minimizing invasiveness, thus offering potential benefits to pediatric patients.These contributions to the knowledge of minimally invasive pediatric surgery collectively underscore the constant pursuit of innovative techniques and advancements aimed at optimizing patient care and improving long-term outcomes.This remarkable collection merits great attention, as it encompasses 27 pioneering works by surgeons who fearlessly expand the horizons of minimally invasive pediatric surgery.We thank all the contributors, and congratulate them on their excellent work.Best regards from Sankt Gallen, Switzerland and Kiel, Germany.Thomas Franz Krebs and Robert Bergholz."}
{"text": "Injection drug use using nonsterile equipment can lead to transmission of viral, bacterial, and fungal infections. Frontline healthcare workers (HCW) are at high risk for substance use disorder due to unprecedented job stress and access to injectable controlled substances. The Tennessee Department of Health (TDH) developed a collaborative investigative process to determine the risk of bloodborne pathogen (BBP) transmission from licensed HCWs engaging in drug diversion. This program recommends public health action and provides consultation to improve drug diversion programs.In 2019 TDH formed a drug diversion investigation team (DDIT) consisting of pharmacists, epidemiologists and medical directors from the HAI and HIV/STI/Viral Hepatitis programs. The DDIT responds to notification by the Health-Related Boards (HRB) of a licensed HCW under investigation for diversion of injectable products. The DDIT interviews the investigator and meets the facility drug diversion program to review drug diversion policies and processes. Based on the suspected method(s) and, if known, the individual\u2019s Hepatitis B/C and HIV status, recommendations are made regarding the need for patient notification and testing.From 2020\u20132022 the DDIT received notification of 49 licensed HCWs under investigation for diversion of injectable products. Patient notification and testing was recommended in seven facilities for CDC Category A infection control breaches; in two cases, later HCW testing negated the need for further action. Among the 34 facilities queried, only five (14.7%) had existing policies for for-cause BBP testing. Other recommendations to improve diversion programs include infection prevention participation and releasing \u201cnot eligible for rehire\u201d status to other facilities.The TDH DDIT facilitates communication with HRB on reported cases of injectable drug diversion. Joint investigations with facilities raise awareness of the risk of BBP transmission and improve facility diversion programs. Tennessee facilities are adding for-cause BBP testing to their investigation procedures. The TDH DDIT model receives mostly positive responses from facility and health system drug diversion teams and may be considered by other public health jurisdictions.All Authors: No reported disclosures"}
{"text": "Breast cancer is the most common cancer worldwide, and advanced breast cancer with metastases is incurable mainly with currently available therapies. Therefore, it is essential to understand molecular characteristics during the progression of breast carcinogenesis. Here, we report a dataset of whole genomes from the human mammary epithelial cell system derived from a reduction mammoplasty specimen. This system comprises pre-stasis 184D cells, considered normal, and seven cell lines along cancer progression series that are immortalized or additionally acquired anchorage-independent growth. Our analysis of the whole-genome sequencing (WGS) data indicates that those seven cancer progression series cells have somatic mutations whose number ranges from 8,393 to 39,564 compared to 184D cells. These WGS data and our mutation analysis will provide helpful information to identify driver mutations and elucidate molecular mechanisms for breast carcinogenesis. They were clonally selected to yield seven HMEC lines ([Breast cancer is the most common cancer diagnosed among women in the United States (excluding skin cancers). It is the second leading cause of cancer death among women after lung cancer . It is cigenesis to isolate gDNA from HMEC cultures. The quantity of the extracted gDNA was analyzed with an ND-1000 spectrophotometer . For WGS library construction, we used the TruSeq DNA library Prep Kit according to the manufacturer\u2019s instructions. For WGS, paired-end sequencing was performed on the Illumina HiSeq X Ten sequencing instrument, yielding ~150-bp short sequencing reads.Raw sequence reads were aligned to the human reference genome 19 using Burrows Wheelers Aligner , and duphttps://kobic.re.kr/kona) and Sequence Read Archive public database with the accession number PRJKA220370 and PRJNA913438.The whole-genome data are available in the Korean Nucleotide Archive . Then, we performed the driver mutation analysis using the IntOGen cancer mutation browser and obseIn this study, we generated WGS data and analyzed mutation profiles in the HMEC cancer progression series because genetic mutations are one of the most significant factors in determining breast cancer progression and therapeutic management . We hope"}
{"text": "Rhinella marina) that is particularly successful in human-altered landscapes. There have been numerous investigations of the cane toad diet, but most of these studies identified prey items at lower taxonomic resolutions . We used higher resolution for prey identification and multiple dietary measures of prey consumption to assess the ecological role of cane toads in the urban landscape of southwest Florida. Prey taxa commonly considered urban pests dominated the diet of cane toads inhabiting golf course communities, and there were differences in prey consumed during the wet and dry seasons of this region. We provided a better understanding of the potential relationships between cane toads and their prey in the urban environment.Urban ecosystems provide habitat to many species, including invasive species such as the cane toad (Rhinella marina) inhabiting urbanized areas in southwest Florida to provide high taxonomic resolution of prey items, contrast toad diets between sampling seasons and sexes, and assess this invasive species\u2019 ecological role in the urban landscape. A pest control agency collected cane toads from two golf course communities in Naples, Florida, USA during November\u2013December 2018 (early dry season) and June\u2013July 2019 (early wet season), and faunal stomach contents were quantified from a random subsample of 240 adult toads . Yellow-banded millipedes (Anadenobolus monilicornis), big-headed ants (Pheidole spp.), and hunting billbugs (Sphenophorus venatus vestitus) were the most frequently consumed prey items and had the highest total numbers and/or volume with corresponding highest indices of relative importance. There was considerable overlap in the seasonal prey importance values for each golf course community and little if any difference in the importance values between toad sexes in each community. Nonetheless, big-headed ants were the most important prey in both communities during the wet season, while yellow-banded millipedes were the most important dry season prey in one community and hunting billbugs the most important in the other. Despite limited spatiotemporal sampling effort, our results indicated that cane toad was consuming arthropod taxa considered pests in the urban ecosystem. Further studies are needed to investigate the potential effects of human activities and environmental variability on the cane toad diet and to determine whether cane toads act as a biological control for pest populations.We investigated the diet of cane toads ( Rhinella marina) is one such invasive species that has demonstrated an affinity to human habitation [Urban areas are often seen as ecologically inferior to their natural area counterparts; however, in the age of rapid urbanization, these developed areas have nonetheless become complex ecosystems inhabited by many species with their own adaptations to the novel urban conditions ,2. An adbitation ,10,11,12The cane toad is a large, toxic amphibian with a native range from southern Texas, USA and western Mexico, through Central America, and into central Brazil . This NeKnowledge of a species\u2019 diet is crucial to understanding its interactions with other species and, in some cases, function in the urban ecosystems it may inhabit ,25. DextAnaxyrus terrestris). Rossi [There have been three diet studies for cane toads in Florida, all of which were conducted in urban ecosystems. Krakauer characte). Rossi focused The purpose of our study was to examine the dietary composition of cane toads inhabiting residential golf course communities in southwest Florida. The objectives were to provide fine-scale taxonomic resolution of prey items, contrast cane toad diets between sampling seasons and sexes, and assess this invasive species\u2019 ecological role in the urban landscape.Our study was located in Naples, Collier County on the southwest coast of Florida, USA . Herein,A licensed pest control agency was contracted by the golf course communities to remove cane toads from their respective properties. Toads were collected by hand between 22:00 and 01:00 during November\u2013December 2018 (early dry season) and June\u2013July 2019 (early wet season). Captured toads were kept in ventilated buckets and later euthanized via cooling then freezing . We selet-test.For toad sexes, differences in SUL between seasonal collections in the golf course communities were analyzed with Welch\u2019s ANOVA and Games\u2013Howell post hoc tests using the Real Statistics Data Analysis Tools add-in for MicrPercent frequency of occurrence (%F), number (%N), and volume (%V) of cane toad prey taxa were determined byi with equationA percent index of relative importance was calCompound indices such as IRI reduce potential bias associated with the component diet measures ,53. ExamMultivariate analyses were performed on cane toad dietary compositions using PRIMER v6 software . AmbiguoR is an absolute measure of the separation between two or more groups, typically ranging between 0 (no separation of groups) and 1 was used to contrast diet composition between sampling seasons, allowing for differences between toad sexes, and between sexes allowing for differences between seasons. The ANOSIM statistic aration; ). Unlikeificant; ). Two-wap = 0.002) among seasonal sampling events with smaller females collected during the early dry season in golf course Community A , big-headed ants (Pheidole spp.), and hunting billbugs (Sphenophorus venatus vestitus) were the most frequently consumed prey items and had the highest total numbers and/or volume with corresponding highest indices of relative importance (combined IRI of 74%) for all taxonomic categories.A total of 13,961 prey items in 180 taxonomic categories was identified from the stomachs of 239 cane toads . One of Labidura riparia) were also frequently consumed (62% F) during this season, but their lower contributions to prey volume and number resulted in lower relative importance (16% IRI). In contrast, yellow-banded millipedes were the dominant dry season prey in golf course Community B with much lower contributions to the diet measures by hunting billbugs and a corresponding low relative importance (7% IRI). Big-headed ants were the most important early wet season prey in both golf course communities (49% IRI), owing to the high frequency of occurrence and the highest contributions to number of prey items but with relatively low-volume contributions. Yellow-banded millipedes in both communities and lepidopterans, primarily caterpillars, in Community B were also frequently consumed during the wet season and both taxa had the highest prey volume contributions but much lower numbers and corresponding relative importance. Additionally, Cuban May beetles (Phyllophaga bruneri) and scavenger scarab beetles (Hybosorus illigeri) were only consumed during the wet season in both communities.After resolving ambiguous taxonomic categories, there were 109 unique prey taxa , and 14 of these unambiguous taxa had an IRI > 1% for at least one of the seasonal cane toad collections in either of the golf course communities in prey importance value percentages between sampling seasons. The low R value indicated moderate overlap with some separation in prey compositions. The SIMPER routine identified hunting billbugs as contributing the most to the seasonal diet dissimilarity in Community A with a much greater mean importance value percentage for this prey item in the early dry season (Camponotus floridanus) had higher mean percentages during the early wet season. Other distinctive prey items only consumed in the wet season included uneven billbugs and Cuban May beetles. The average similarity value for prey taxa consumed in the early dry season (26.4%) was higher than that of the early wet season (18.9%), but these relatively low similarity values also indicate considerable variability in prey consumed by toads during each season.For golf course Community A, there was a significant difference in prey importance value percentages between toad sexes in golf course Community A; however, the very low R value indicated strongly overlapping importance value compositions with little difference between sexes. Nonetheless, hunting billbugs were identified by the SIMPER routine as contributing the most to the dietary dissimilarity between toad sexes and males exhibited a greater mean Importance value percentage for this prey item in prey importance value percentages between sampling seasons and the low R value indicated moderate overlap with some differences in prey compositions. The SIMPER routine identified yellow-banded millipedes as contributing the most to the seasonal dissimilarity in Community B and this prey item had a substantially greater mean importance value percentage during the early dry season (Asiomorpha coarctata), and shore earwigs also had higher importance value percentages during the early dry season but contributed less to the seasonal dissimilarity. Big-headed ants and lepidopterans had higher mean importance value percentages during the early wet season. Other prey items with distinctive wet season differences included Cuban May beetles, scavenger scarab beetles, darkling beetles (Platydema), and rover ants (Brachymyrmex). Average similarities were higher in the early dry season (23.5%) compared to the early wet season (11.5%), but dietary variability was indicated by the relatively low values.For golf course Community B, there was a significant difference in prey importance value percentages between toad sexes in golf course Community B. The negligible R value indicated dietary compositions were barely separable with little if any differences in prey importance values between sexes. Furthermore, the borderline statistical significance should be interpreted cautiously owing to the relatively high number of replicates/permutations and their influence on significance levels. The SIMPER routine indicated some minor dietary differences by sex . Ideally, dietary investigations should employ at least one metric measuring amount (frequency and number), and one measuring the bulk of food items present in each sample [In addition to prey resolution, the choice of diet metrics may have influenced previous interpretations of cane toad diet. Most studies reported one or two diet metrics for prey taxa, such as frequency and/or number, and only a few measured the bulk (volume or mass) of food items . Only Pah sample . Reportih sample . As demoDespite individual variability and overlapping dietary compositions, cane toads exhibited significant seasonal differences in prey consumption in southwest Florida. Big-headed ants were the most important prey in both golf course communities during the early wet season and contributed the most to the differences for this season in both communities. Florida carpenter ants were also important wet-season prey in Community A. For regions with seasonal patterns of precipitation, cane toads ingested higher numbers of ants during the wet season in a coastal village of the Philippines and withPrey compositions during the early dry season differed significantly from those in the early wet season for both golf course communities, but the importance of dry-season prey types also differed between communities. Hunting billbugs were the most important dry-season prey in Community A, while yellow-banded millipedes were more important in Community B, and both prey items contributed the most to the seasonal differences in the respective communities. The golf course communities in our study were relatively proximal to one another so location does not appear to be a factor; however, different human activities may be affecting arthropod ecology, or our perception as such, within each community . HuntingYellow-banded millipedes, hunting billbug weevils, and bigheaded ants were the most important prey items for cane toads collected from golf course communities in southwest Florida. These arthropods are considered urban pests, but further studies are needed to determine whether cane toads provide any beneficial service with respect to the consumption of these nuisance taxa in the urban ecosystem. Our higher resolution for prey identification provided a better understanding of potential predator\u2013prey relationships and their inferred use of habitats in the anthropogenically altered landscape. Furthermore, using multiple dietary metrics revealed size bias with the prey , and applying compound indices provided a balance for interpretations of prey importance. There were significant seasonal differences in prey importance for cane toads, possibly related to the behavior of toads and the ants consumed during the wet season, and a locational difference in dry season prey importance that could have resulted from pest management practices in the golf course communities or unintentional bias during toad collections. We recognize the limited spatiotemporal scope of sampling effort in the current study and suggest a more rigorous, multiannual sampling design to address the potential effects of human activities and environmental variability on cane toad diet in urban ecosystems."}
{"text": "Wound healing is a complex and coordinated biological process easily influenced by various internal and external factors. Hydrogels have immense practical importance in wound nursing because of their environmental moisturising, pain-relieving, and cooling effects. As photo-crosslinkable biomaterials, gelatine methacryloyl (GelMA) hydrogels exhibit substantial potential for tissue repair and reconstruction because of their tunable and beneficial properties. GelMA hydrogels have been extensively investigated as scaffolds for cell growth and drug release in various biomedical applications. They also hold great significance in wound healing because of their similarity to the components of the extracellular matrix of the skin and their favourable physicochemical properties. These hydrogels can promote wound healing and tissue remodelling by reducing inflammation, facilitating vascularisation, and supporting cell growth. In this study, we reviewed the applications of GelMA hydrogels in wound healing, including skin tissue engineering, wound dressing, and transdermal drug delivery. We aim to inspire further exploration of their potential for wound healing. The skin is a multifunctional barrier organ that protects internal organs from potential environmental hazards . The proGelMA is a synthesised biomacromolecule with excellent biocompatibility and formability; it was first reported to be synthesised by Bulcke et al., in 2000 . Since tin situ photo-crosslinking properties make GelMA hydrogels particularly suitable for application in irregular wounds and hydroxyl (\u2013OH) groups on the side chains of gelatine are substituted by the methylacryloyl group . GelMA-dHAMMA hydrogels were found to promote fibroblast proliferation and \u03b1-smooth muscle actin expression. GelMA-dHAMMA has also been shown to promote wound collagen deposition and angiogenesis and accelerate tissue healing in rabbit full-thickness skin tissue defects are competitive candidates because of their excellent biological characteristics .in vivo vascularisation. In a previous study, epidermal stem cell\u2013derived EVs loaded with VH298 were encapsulated in GelMA hydrogels to enhance the angiogenic ability of diabetic wounds. GelMA hydrogels were shown to be convenient and adaptable delivery carriers for the sustained release of VH298-EVs, effectively promoting wound healing by locally improving blood supply and angiogenesis by increasing the HIF-1a level delivery (Microneedles are one of the transdermal drug delivery techniques that usually release loaded drugs directly into the deep layer of the skin through tiny holes formed by puncture . Hydrogedelivery . The micIn conclusion, GelMA hydrogels have been widely used in many applications, ranging from wound dressings to 3D printing skin tissue engineering. They provide an ideal multistratified anisotropic scaffold for the growth of various cells such as fibroblasts, endothelial cells, and keratinocytes. They can also be used to prepare personalised multifunctional dressings by combining small molecules, metal nanoparticles, and cellular EVs via physical binding or chemical reactions. Therefore, the application prospects of GelMA hydrogels for wound healing are significant. However, the biosafety of GelMA-based hydrogels remains a major obstacle to their clinical applications. The release of unreacted methacryloyl monomers after photo-crosslinking is a potential risk. Furthermore, photo-crosslinking under UV radiation may damage cellular DNA . Additio"}
{"text": "Impairments in cognitive and executive function of presumed cerebral microvascular origin are important and recently recognized neuropathological manifestations of vascular contributions to cognitive impairment and dementia (VCID) , 2. It hStudying WM continues to pose unique methodological and diagnostic challenges for aging research. WM is highly enriched in auto-fluorescent pigments that make rigorous immunohistochemical (IHC) approaches for mechanistic and diagnostic studies extremely challenging. Although astrocytes may degenerate in overt WM infarcts, the vulnerable glial subtypes in diffuse microvascular WM lesions remain essentially unknown. Admittedly, glial lineages are complex and relatively few specific markers are available. Furthermore, the expression of glial markers can change dramatically in regions of WM injury leading to nonspecific false positive staining . In addiTo provide rigorous access to human WM lesions, we recently developed a unique rapid autopsy brain procurement protocol using specimens donated by participants in the Adult Changes in Thought (ACT) study, a prospective, population-based study of aging and incident dementia among men and women in Seattle, Washington . This prA unique opportunity afforded by this rapid autopsy brain procurement protocol is access to fresh tissue samples for direct analysis of human penetrating microvessels. We have developed novel protocols to preserve these vessels for a wide range of physiological and molecular studies performed within 24 hours after procurement. Although cerebral microvascular disease is a common manifestation of aging, prior human and murine vascular and morphological studies were limited mostly to the middle cerebral artery and pial microvessels, and findings were extrapolated to WM penetrating microvessels. Moreover, despite growing interest in WM injury and MRI-defined WM hyperintensities in VCID and AD, vascular studies mostly lacked histopathological, neuroimaging or mechanistic correlation.We established the feasibility to study human penetrating WM arterioles in initial studies of aged human microvascular lesions with low ADNC . We founThe molecular mechanisms that mediate enhanced dysfunction of WM parenchymal arterioles when vascular dysfunction and ADNC coincide remain elusive. Analysis of human WM lesions and WM parenchymal arterioles , 7, as wTaken together WM injury and WM hyperintensities of presumed microvascular origin are of growing interest to aging and VCID researchers. A growing body of evidence supports that microvascular brain injury is accompanied by oxidative stress, astrogliosis, changes in the extracellular matrix , and quantitative MRI-defined abnormalities in prefrontal WM that involve disrupted integrity of axons and myelin. Mechanistic studies are needed to further define contributions of microvascular dysfunction to WM injury, particularly as it relates to the identities of the cell types and molecular signatures that could be harnessed to diagnostically discriminate among VCID, AD or mixed vascular/ADNC."}
{"text": "Cancer is the second most common fatal disease leading to death worldwide. Metastatic growth in distant organs is the main reason for increased cancer mortality . Cancer in vivo mouse models targeting cancer stem cells and their signaling pathways which are effective in treating pancreatic cancer. The article focuses on the mode of action of bioactive plant metabolites from TCM against various signaling pathways such as Wnt and Notch, which regulate cancer stem cells in pancreatic cancer. Zhang et al. explain the inhibition of cancer stem cell signaling pathways involved in epithelial to mesenchymal transition, migration, metastasis and apoptosis of pancreatic cancer cells by the plant metabolites.The exploration of plant derived drugs as potential therapeutic interventions against cancer stem cells and metastasis is an exciting area of research that complement existing cancer therapies and improve patient outcomes. Koklesova et al. describes how nanoparticles specifically designed to target cancer stem cells in tumor, serve as carriers for targeted delivery of plant-based drugs. Several Nano-drugs developed to target and treat the different types of cancer and their subsequent CSCs are discussed. Plant metabolite-based nanoparticles are modified to specifically target cancer stem cells, which helps in reducing the risk of tumor recurrence and the manifestation of metastases. Zhao et al. describe the anti-metastatic effect of thymoquinone in pancreatic cancer and its sensitivity to gemcitabine by regulating collagen. In pancreatic cancer cells, thymoquinone promotes apoptosis, inhibits tumor cell migration, invasion and metastasis, and sensitizes pancreatic cancer cells to gemcitabine. Furthermore, the study shows that thymoquinone stimulates cellular matrix production via TGF\u03b2/Smad pathways.Targeted therapies for the heterogeneous population of cancer tumors and multidrug resistance associated with cancer stem cells are still not effectively established. The review article by Mazurakova et al.). In the systemic review article, Mazurakova et al. detail the effect of flavonoids on breast cancer stem cells to combat therapy resistance and cancer proliferation. The accumulation of breast cancer stem cells (BCSCs) after chemotherapy, prevents further effective treatment of breast cancer patients. Therefore, it is also postulated that eradication of BCSCs in combination with standard cytotoxic drugs and flavonoids specifically targeting CSCs in breast cancer tumor is essential for successful treatment.Studies show that flavonoids have an anticancer effect against various types of cancer. Flavonoids can induce apoptosis and autophagic cell death of breast cancer cells, inhibit cancer proliferation and overcome drug resistance of cancer tumors (This Research Topic provides new data and detailed reviews on plant-derived compounds that target cancer stem cells and inhibit metastasis through various mechanisms of action by modulating self-renewal pathways, suppressing EMT, affecting the tumor microenvironment and disrupting signaling pathways essential for cancer cell migration, invasion and survival. Thus, plant metabolites are promising for developing innovative therapeutic strategies against cancer stem cells and metastasis. Prospective research is inevitable to successfully translate research findings into clinical trials by addressing challenges such as safety, bioavailability, formulation and standardization of herbal medicines. These findings and reviews demonstrate how phytomedicines targeting cancer stem cells significantly reduce metastasis and subsequent mortality. These prospective and innovative findings, if clinically established, are promising and can pave the way to new vistas for cancer therapy."}
{"text": "Advances and Challenges of Non-Invasive Brain Stimulation in Age-Related Neurodegenerative Diseases\u201d, highlighting the significance of aging as a risk factor for neurodegenerative diseases, the limited effectiveness of current treatments and the potential of non-invasive brain stimulation.This editorial summarizes the contributions of the Frontiers Research Topic \u201cAging is a major risk factor for neurodegenerative diseases. Neuronal losses during aging can lead to cognitive decline, particularly when combined with accumulation of toxic proteins. Treatment options for these conditions are limited. Noninvasive brain stimulation (NiBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (TCS), can modulate brain networks and enhance cognitive functions in both healthy individuals and neurodegenerative patients. The effects of NiBS can persist even after the stimulation ends. However, a comprehensive understanding of its biological mechanisms and clinical applications is still lacking, which poses challenges. This topic aims to explore NiBS as an innovative therapeutic tool, specifically discussing its advances and challenges in treating age-related neurodegeneration.He et al. promoted that spinal cord stimulation (SCS) is a promising treatment for disorders of consciousness (DoC). This study analyzed 66 DoC patients who received SCS treatment to investigate the association between postoperative cerebrospinal fluid (CSF) protein levels and consciousness improvement. Patients with permanent electrodes had higher CSF protein levels than those with temporary percutaneous electrodes. Moreover, elevated CSF protein levels were linked to reduced sagittal diameter and poor outcomes at 3 months. The findings propose that reducing the influence of electrode pads on anatomical changes may improve treatment outcomes. CSF protein levels could serve as potential biomarkers of postoperative outcomes and deserve further exploration.A study conducted by Ni et al.) evaluated the effects of various repetitive TMS (rTMS) stimulation procedures on upper limb function and brain functional network characteristics in stroke patients. The study involved 36 stroke patients who were assigned to either receive 1 Hz stimulation in the contralesional hemisphere and 10 Hz stimulation in the affected hemisphere, or solely 10 Hz stimulation in the affected hemisphere. The results demonstrated that rTMS treatment improved upper limb motor function, enhanced brain network connections, and reduced activation of isolated brain areas. Depending on the specific brain network states, optimal rTMS treatment plans could be suggested for precise rehabilitation.Another study explores the effects of continuous theta burst stimulation (cTBS) on enhancing language abilities in patients with aphasia. The researchers focused on targeting the right posterior superior temporal gyrus (pSTG), a region acknowledged for its critical role in semantic processing. This article presents findings from a randomized controlled trial involving 34 aphasic patients who underwent either cTBS or sham stimulation, followed by speech and language therapy. The study aimed to uncover whether cTBS applied to the right pSTG could promote language recovery and elucidate the underlying brain mechanisms. The results showed promising effects of cTBS, manifesting as improved language performance and modulation of brain activity and connectivity in specific regions. Overall, this research offers valuable insights into potential therapeutic interventions for language rehabilitation in individuals with aphasia.Another study investigates the effects of brain stimulation on two different age groups: middle-aged adults (40\u201360 years) and older adults (65 years and above). The researchers aimed to understand how tDCS impacts behavior and brain function differently in these two groups. Additionally, behavioral assessments and neurophysiological measurements were performed. This research provides valuable insights into age-specific brain stimulation effects and its potential applications for cognitive enhancement.One article explores the potential therapeutic effects of two brain stimulation techniques, median nerve stimulation (MNS) and rTMS, on patients with prolonged disorders of consciousness (pDOC). In a rigorously conducted trial, 75 eligible patients with pDOC were randomly assigned to one of three groups: (1) rTMS + sham-MNS; (2) MNS + sham-rTMS; or (3) MNS + rTMS. The primary outcome was the change in the Coma Recovery Scale-Revised (CRS-R) score after treatment. Findings showed that the combined MNS + rTMS intervention yielded significantly greater improvements in Glasgow Coma Scale (GCS) scores and somatosensory evoked potentials, compared to the other two groups. This research offers valuable insights into the potential benefits of combining brain stimulation modalities to enhance consciousness recovery in patients with pDOC.Another article and elderly adults (65\u201380 years). They aimed to measure the impact of stimulation on motor skills and cortex responsiveness. The study revealed significant age-related differences, indicating that ccPAS enhances action performance and corticomotor excitability more effectively in young adults compared to elderly adults. These findings offer valuable insights into the age-specific effects of brain stimulation and its potential applications for cognitive enhancement. By delving into this research, the researcher can gain deeper understanding of how brain stimulation techniques may differ in their outcomes based on age, contributing to advancements in neurostimulation and its implications for age-related cognitive functions.In a study conducted by Naparstek et al.) presents a comprehensive review of the potential uses of transcutaneous vagus nerve stimulation (tVNS), a non-invasive neuromodulation technique, in the context of cognitive aging. The authors have compiled a thorough review and provided valuable commentary on the existing literature, shedding light on the effectiveness of tVNS in enhancing various cognitive functions in older adults. Through this review, researchers can uncover the promising applications of tVNS for memory, attention, and executive functions in the aging population. This review not only synthesizes the current knowledge on tVNS but also suggests pathways for future research, offering new insights into innovative therapeutic approaches for addressing age-related cognitive decline.Another study (YG: Writing\u2014original draft. WW: Writing\u2014review and editing. JZ: Writing\u2014review and editing."}
{"text": "This cross-sectional study compares clinician and artificial intelligence (AI) chatbot responses to patient vignettes used to identify bias in medical decisions. This study aimed to evaluate AI chatbot responses to clinical questions previously tested in large samples of clinicians to examine established biases in medicine related to gender, race and ethnicity, and socioeconomic status (SES) through published vignettes.Artificial intelligence (AI) chatbots transformed how we access information provided by large language models. However, AI models may carry inherent bias, often mirroring the systematic inequalities present in our society.STROBE) reporting guideline. This study was deemed exempt from the institutional review board at Stanford University. Informed consent was waived because the study did not involve human participants. We selected 19 clinical vignettes in cardiology, emergency medicine, rheumatology, and dermatology. A full list of references can be found in the eReferences in This cross-sectional study followed the Strengthening the Reporting of Observational Studies in Epidemiology (The 4In this cross-sectional study, we observed that AI chatbots provided different recommendations based on a patient\u2019s gender, race and ethnicity, and SES in certain clinical scenarios. We found both overlapping and unique differences in responses among the AI chatbots and between the AI chatbots and physicians. The presence of bias among clinicians and clinical risk algorithms has historically caused disparities in clinical care and led to poorer health outcomes for some marginalized populations. While AI chatbots have shown proficiency in various medical tasks, including passing the United States Medical Licensing Examination, interpreting laboratory tests, and answering patient questions, neither chatbot is approved for medical applications.5 Differences in AI chatbot recommendations have not been fully explored, and their impact is unclear. These differences may be shown to propagate or counter biases that clinicians have, the impact of AI-based tools on health disparities may vary in different clinical situations. However, these tools are being adopted by patients and clinicians, making further research especially urgent.Limitations include a small number of vignettes tested and different assessment scales used per vignette following the original studies\u2019 approaches. Although AI chatbots are promising tools in medicine, our findings underscore the need for careful application of early adoption. Prior studies have suggested that using AI in medicine could contribute to treatment inequities in marginalized racial and ethnic groups."}
{"text": "Endoscopic ultrasound (EUS) has entered its golden age. The benefits of providing refined diagnosis and advanced therapeutic procedures by EUS are numerous and widely appreciated by clinicians worldwide \u20133.Just 20 years ago, EUS diagnosis was based mainly on radial mechanical echoendoscopes with no electronic image enhancement functions . On the Since then, EUS has gone through years of exciting and unrelenting scientific and technologic advancements. The biggest improvements were introduced by image enhancement techniques with ultrasound contrast agents and elastography allowing better detection and characterization of the lesions of interest.Frontiers in Medicine about advancements in the EUS diagnosis of pancreatobiliary diseases, image enhanced EUS for the diagnosis of gallbladder lesions is presented. Differential diagnosis between benign and malignant gallbladder tumors can be challenging in order to select the candidates for surgery. Contrast-enhanced harmonic EUS (CH-EUS) has been previously reported to be useful for the diagnosis of gallbladder tumors and accuracy (90%) . Data inThe usefulness of liquid-based cytology to increase the diagnostic yield of EUS-guided tissue acquisition is also discussed. Several techniques have been used in this regard, including fine needle biopsy with histology needles, rapid onsite cytopathology evaluation, and guidance by CH-EUS. A recent meta-analysis showed a pooled diagnostic sensitivity of 85% with CH-EUS-fine needle aspiration and 75% with standard EUS- fine needle aspiration . HoweverEUS is also a great tool for pancreatic cancer screening in conjunction with magnetic resonance imaging . InteresFinally yet importantly, bibliometric analysis of EUS publications is presented. Compared to previous EUS literature scans , an updaPF wrote the editorial. MT and YY reviewed the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version."}
{"text": "They validated their initial findings by targeted metabolomic analyses in two different cohorts with similarly increased cardiovascular risk, from the United States (n\u2009=\u20092149) and Europe (n\u2009=\u2009833) undergoing cardiac evaluation. This follow-up analysis strengthened their original findings by revealing that the association of erythritol not only remained significant but was independent of age, sex, and other established risk factors. This suggests the additional operation of other than metabolic mechanisms. Indeed both in vitro and in vivo studies in human whole blood and mice revealed an erythritol-elicited increase in platelet adhesion and clot formation (Fig. 1 Their subsequent pilot study showed that a single dose of 30\u2009g erythritol results in prolonged excessive plasma erythritol elevation for over 48\u2009h. The recorded concentrations remained well above the threshold, which increased platelet reactivity and thrombocyte reactivity in vitro,1 suggesting a prolonged thrombotic risk arising from exogenous erythritol.Abnormal vascular function and coagulation represent other central drivers of cardiovascular disease onset and development.3 At present, controlled trials did not detect detrimental effects of erythritol ingestion in healthy humans,5 but specific trials on vascular function and coagulation in healthy and diseased humans are lacking.While these studies support a novel conceptual framework of erythritol-induced promotion of thrombus formation leading to excess cardiovascular risk, several limitations need to be addressed. There is not only a lack of standardization of erythritol measurements but also of the preanalytical conditions. The observed prolonged elevation of erythritol upon dietary intake raises the question of whether simple overnight fasting conditions suffice for the interpretation of baseline concentrations; moreover, the kinetics of erythritol elimination might substantially differ between healthy and metabolically compromised people. Importantly, their in vitro procedures raised the platelet concentrations creating artificial experimental conditions. Also, the mice experiments showing enhanced clot formation upon erythritol injection do not necessarily mirror thrombosis risk in humans. Thus, a direct analysis of platelet activation in humans upon erythritol might better reflect real-life conditions. Further questions arise: to what extent do different conditions affect the relative contributions of exogenous versus endogenous sources to the total circulating erythritol concentration, particularly could people with increased cardiovascular risk produce more erythritol? One might speculate that altered hepatic metabolism in humans with type 2 diabetes, who are at higher risk of fatty liver disease, might at least contribute to the described effects. Of note, epidemiological and cohort studies cannot exclude reverse causality because people with an unfavorable metabolic profile are more prone to consume sugar-free meals to avoid weight gain or hyperglycemia, even before cardiovascular disease diagnosis.Taken together, Witkowski and colleagues shed light on one of the widely-used non-nutritive sweeteners and provide novel evidence for the potentially deleterious effects of erythritol on platelet function. At the same time, these findings raise new questions calling for sufficiently powered double-blind, randomized controlled trials addressing the safety as well as mechanistic studies examining the Janus-head-like features of erythritol. Importantly, the evidence derived from the current study should already suffice for the authorities to re-evaluate their policy statements regarding the cardiovascular and metabolic risks of artificial sweeteners."}
{"text": "Advanced Materials (2023) 10.1002/adma.202306834Owing to the absence of appropriate helical templates, circularly polarized organic ultralong room temperature phosphorescence with a high dissymmetry factor remains a formidable challenge in contemporary research. A team of Qiang Zhao and Yanqing Lu proposes an effective tactic to enable the high dissymmetry factor by employing a circularly polarized phosphorescent system composed of meticulously designed phosphorescent polymers and self-assembled chiral helical superstructures. Specifically, multiple interactions among polymer chains can strictly restrict molecular motions of phosphorescent molecules, thereby inhibiting the non-radiative relaxation pathways and resulting in the emission decay time of 735 ms. The self-organized periodic helical superstructures serve as an ideal medium for enhancing chirality, giving rise to the attained dissymmetry factor of 1.49 and surpassing previous records by two orders of magnitude. The creatively explored system displays remarkable photo-thermal stability and demonstrates the potential applications of photoprogramming photonics. These findings would create a brilliant outlook of the optical multiplexing-based information encryption, and establish the intimate connection between circularly polarized phosphorescent materials and the evolving field of optical information technologies toward the cutting-edge photonic applications and beyond."}
{"text": "Popular press coverage of the Medicare Part D coverage gap is based largely on research conducted using retrospective analyses of administrative claims data. These datasets are incomplete because they lack information about methods of obtaining medication that are commonly used by seniors, including free samples, generic drug discount programs, over-the-counter substitution, and patient assistance programs. As a result, evidence about the effects of 100% cost sharing on seniors is limited and suboptimal. Although the current deficit of information about the coverage gap is not entirely unexpected because the Medicare Part D program is relatively new, reliance on claims-based analyses to inform questions that claims data cannot possibly address accurately has tended to mislead and politicize rather than produce constructive policy guidance. Numerous important health policy questions remain unaddressed. These questions are becoming especially important as optimal approaches to providing health care to seniors are the subject of an increasingly vigorous debate."}
{"text": "Parents frequently purchase and inquire about smartwatch devices to monitor child behaviors and functioning. This pilot study examined the feasibility and accuracy of using smartwatch monitoring for the prediction of disruptive behaviors.N\u2009=\u200910) aged 7\u201310 years hospitalized for the treatment of disruptive behaviors. The study team completed continuous behavioral phenotyping during study participation. The machine learning protocol examined severe behavioral outbursts for preparing the training data. Supervised machine learning methods were trained with cross-validation to predict three behavior states\u2014calm, playful, and disruptive.The study enrolled children (The participants had a 90% adherence rate for per protocol smartwatch use. Decision trees derived conditional dependencies of heart rate, sleep, and motor activity to predict behavior. A cross-validation demonstrated 80.89% accuracy of predicting the child's behavior state using these conditional dependencies.This study demonstrated the feasibility of 7-day continuous smartwatch monitoring for children with severe disruptive behaviors. A machine learning approach characterized predictive biomarkers of impending disruptive behaviors. Future validation studies will examine smartwatch physiological biomarkers to enhance behavioral interventions, increase parental engagement in treatment, and demonstrate target engagement in clinical trials of pharmacological agents for young children. Evidence-based interventions such as parent\u2013child interaction therapy (PCIT) reduce behavioral and emotional symptoms in children by improving parent\u2013child relationships through the implementation of specific rules taught over a multiweek period the effectiveness of PCIT is contingent upon parents making a concerted effort to remember the rules imparted by a provider in engaging with their children and (2) families from rural areas and under-represented populations are less likely to have access to and utilize evidence-based therapies when it is available , there is an opportunity to improve access and effectiveness of behavioral interventions in children and adolescents, including PCIT. Smartwatches measure individual functioning in real time and provide opportunities to identify point-of-care smartwatch biomarkers in young children that can provide prompts for parents of child's impending behavioral outbursts. Accessible digital tools may have the promise of increasing parental engagement for improved outcomes.The growth in children's smartwatch market is largely driven by parental interest to track their child's functioning aged 7\u201310 years were enrolled in this IRB-approved study conducted during May 2020 through December 2020. Registered nurses (RNs) of the Mayo Clinic Child and Adolescent Psychiatry inpatient unit continuously assessed and annotated behavior for 24 hours daily during hospitalization , heart rate (beats per minute), and sleep (including duration and sequence of sleep stages) data through the Garmin Connect mobile application. The smartwatch minute-level data were aggregated and collected through Fitabase. Each participant and family had an abbreviated PCIT training intervention during hospitalization.Calm indicated that the child was sedentary while performing routine activities such as reading, lying down, watching movie, talking/interacting with others, or doing their daily homework. Playful indicated that the child was engaged in a nondisruptive activity of elevated heart rate such as exercising , playing a sport , or playing with other children .Inpatient RNs annotated behavior states as either calm, playful, or disruptive using the behavior code described in Disruptive (behavior codes 9\u201311) indicated that the child showed uncontrolled aggression/behavior warranting intensive behavioral interventions, time-outs, or restraint for safety. For each of the calm, playful, and disruptive phenotypic annotations on a given day, the corresponding average heart rate in the preceding 60 minutes and the durations of sleep stages from the previous night were captured with the smartwatches (see ches see .Decision trees were trained to use heart rate (60-minute average) and sleep data to predict calm, playful, or impending disruptive behaviors across the three behavior phenotypes. The Garmin vivosmart4 smartwatch provides three levels of intensity of motor activity . Notably, when participants were characterized as calm, there was no difference (p\u2009>\u20090.8) between the mean heart rate during the 60-minute calm period and the overall resting heart rate . However, the durations of REM, light, and deep sleep stages were different between participants who exhibited disruptive behavior versus those who did not if the duration of light sleep exceeded 4 hours, and there were no significant associations with the total sleep duration or duration of awake, deep, and REM sleep.The Garmin vivosmart4 watch provides the duration and sequence of sleep stages with an accuracy of 80.89%.Prior research has demonstrated parental acceptance -approved features are becoming ubiquitous across all ages for wellness monitoring and improved health-related outcomes. Cardiology practice has adopted the use of smartwatch devices for monitoring and assessment of remote cardiac monitoring are underway to establish benchmarks and the utility of wearable devices for monitoring, decision support, augmented interventions, and predictive models. Valid and accessible digital biomarkers will have great utility for future pharmacological trials for young children.This study has limitations. First, an inpatient monitoring study did not present specific behavioral triggers in outpatient settings . Biomarker thresholds and accuracies of predicted behavior states may vary between patients based on parents' perception of what constitutes disruptive behavior versus nearly homogeneous annotations of disruptive behavior marked by trained nurses. Second, only one smartwatch brand was used and additional studies with trackers from other vendors are needed. Third, the study used data from hours with complete measurements, hence the impact of time gaps in measurements is yet to be understood.Fourth, it is possible that more computationally intensive algorithms may outperform prediction performance of decision trees with larger sample sizes and duration of observation. Fifth, although the study psychiatrists and medical records did not identify any medication-related side effects in the sample, the potential impact of concurrent psychotropic medications on physiological measures (including sleep disturbances) is unknown as it is highly possible that the threshold of biomarkers varies with time and improves behavior states.Therefore, larger studies with longer duration of observation and treatment modalities are needed to further develop and refine time-series algorithms to predict impending disruptive behavior in children. Finally, digital biomarkers derived in this study need validation in an outpatient setting to guide the development of a technology-enhanced version of behavioral interventions such as PCIT.There is a critical societal need to better understand and leverage scalable remote technologies to foster healthy parenting practices within the framework of traditional evidence-based behavioral therapies such as PCIT. This feasibility study demonstrates the capability to introduce precision target-based technologies using smartwatch-derived biomarkers to improve effectiveness of psychosocial interventions in young children by predicting disruptive behavior in children before manifestation. Such biomarkers when successful could be utilized in delivering precision care to children and families through remote care capabilities\u2014thereby addressing barriers to accessing specialty pediatric behavior clinics."}
{"text": "Acculturation refers to the process of change that occurs when people of different cultural backgrounds are in enduring first-hand contact intersect to impact acculturation experiences in educational settings.While some papers focus on specific demographic groups, there is room for more research that considers Longitudinal studies could provide insights into how acculturation attitudes and experiences evolve over time, especially in relation to educational outcomes.Most of the papers employ cross-sectional designs. Comparative studies could provide insights into how cultural and national contexts influence acculturation processes in education.The papers focus on various geographical contexts. how educational policies impact acculturation processes. Future research could explore the role of policies in facilitating or hindering acculturation in schools.While the papers discuss individual and group experiences, there is a gap in the examination of technology in acculturation within educational settings remains underexplored. Research could focus on how digital platforms and online education impact acculturation experiences.In an increasingly digital world, the role of In summary, while the current Research Topic provides valuable insights into the relationship between acculturation and education, it also opens up multiple avenues for further exploration. These new directions could significantly enrich the academic discourse and have practical implications for educators, policymakers, and researchers alike.EM: Conceptualization, Writing\u2014original draft. NL: Writing\u2014review & editing. CW: Writing\u2014review & editing. DB: Writing\u2014review & editing."}
{"text": "Behavioral and emotional problems were showed to be associated with the prenatal environment. Changes in placental DNA methylation was identified as a relevant potential mechanism of such association.We aimed to explore the associations between placental DNA methylation and child behavior in order to explore pathways that could link prenatal exposures to child behavior.Data including 441 children of 3 years of age from the EDEN mother-child cohort. Child behavior assessed using the Strengths and Difficulties Questionnaire (SDQ). Both hypotheses-driven and exploratory analyses (including epigenome-wide association studies (EWAS) and differentially methylated regions (DMR) analyses) were conducted. The analyses were adjusted for confounding and technical factors and estimated placental cell composition. All the p-values were corrected using a false discovery rate (FDR) procedure for multiple tests.cg26703534 (AHRR), was significantly associated with emotional problems (pFDR = 0.03). In the exploratory analyses, cg09126090 (pFDR = 0.04) and cg10305789 were significantly associated with peer-relationship problems and 33 DMRs were significantly associated with at least one of the SDQ subscales. Placental DNA methylation showed more associations with internalizing than externalizing symptoms, especially among girls. DMRs tented to include highly methylated CpGs.In the hypothesis-driven analysis, This study investigated for the first time the associations between placental DNA methylation and internalizing and externalizing symptoms in preschoolers. Further analyses, such as consortium meta-analyses would be necessary to confirm and extend our results.None Declared"}
{"text": "This could be due to the primary surgical oncologist informed by MD-PALS members being able to better identify key EOL issues surrounding the patient and hence better equipped to conduct a quality GOC discussion during a surgical admission.We established a multidisciplinary palliative surgical intervention (MD-PALS) team comprising healthcare providers of various subspecialties involved in the care of these patients. We then performed a single-centre prospective cohort study recruiting advanced cancer patients who received palliative interventions, comparing the outcomes of those cared for under the newly established MD-PALS team and those who received usual care.6 Future research should delve deeper into investigating and validating the other potential benefits of MD-PALS teams. Robust and rigorous studies will be essential in refining team structures and processes, ensuring the model is optimized to cater to the unique needs of palliative surgical oncology patients.Our study highlights the positive impact of multidisciplinary specialist providers\u2019 involvement in the care of palliative surgical oncology patients, leading to enhanced GOC discussions. MD-PALS teams hold the potential to become the cornerstone of a \u2018Community of Practice\u2019, fostering interdisciplinary collaboration and seamless communication between team members, patients, and their families, ensuring the comprehensive and holistic management of the multifaceted challenges faced by these patients."}
{"text": "This editorial reports from seven international working groups from the US and Europe as follow-up of the Eight Kraepelin Symposium in Munich, LMU, recruiting former and recently recruited ones. It covers basic research investigating the consequences of genetic and environmental factors on psychosis in the translation in preventing psychosis in children of parents with severe mental illness. Secondary prevention aims to avoid further episodes having foci on translation of new mechanisms targeting family communication, patterns of cannabis use or targeting cognitive biases in metacognitive training. Translation in later phases of psychoses refer to translating the knowledge, its evidence and meta-analysis. Novel foci include psychoeducational groups for close relatives of patients with borderline personality disorder and lifestyle behaviors combined with metabolic disturbances in a transdiagnostic psychiatric sample. Recently, metacognitive training gained importance being an important addition to family therapy and cognitive behavioral therapy. Strategies that proved their effectiveness are to be implemented in standard treatment as well as strategies implemented to train professionals in effective crisis and family management.In the nineteenth century, Emil Krapelin pioneereThis special supplement related to the Eighth Kraepelin Symposium\u2014Translation in Psychiatry and Psychotherapy\u2014A Life-long Necessity covers tTranslation from mechanism to mental health practices covers basic research in psychological targets in trauma and its translation in mental health practices . TranslaThe vulnerability\u2013stress-coping model (2\u20133.5) is our conceptual framework guiding psychoeducational and family therapy focusing on the interaction between biological vulnerability, protective personal and environmental factors Garosi et al. and the real world FACE-SZ cohort investigWright et al. investigBighelli et al. investigNovel foci include psychoeducational groups for close relatives of patients with borderline personality (BPD). Pitschel-Walz et al. evaluateIn summary, the vulnerability-stress-coping model provides valuable targets for treatment stressing psychoeducation, family therapy and cognitive behavioral therapy (CBT) and recently MCT proved their effectiveness in meta-analysis. Psychoeducation, communication, and problem-solving skills are the main tools for relapse prevention. Novel trends refer to pioneering psychoeducational groups in borderline personality disorder, cannabis patterns in first episodes and predictive capability for weight gain during treatment in a transdiagnostic sample.Primary intervention is to focus on psychological targets in trauma in children of parents with PHSMI and there should be visiting and complex community programs, residential treatments and online help. Further research, as well as more training for professionals on effective crisis and family management seems necessary."}
{"text": "Case reports are vital components of scientific literature, providing essential insights into rare or unique medical conditions, diagnostic dilemmas, and therapeutic challenges . There hClinical case reports correspond to articles with the lowest level of evidence on the hierarchy of various research study types . HoweverMedical literature is often dominated by observational studies involving larger patient cohorts, leaving rare and unusual cases underrepresented. Case reports fill this gap by presenting detailed accounts of such unique situations that can be useful for other clinicians . Within The diverse range of respiratory diseases often presents diagnostic challenges due to overlapping clinical features. Case reports detailing unique diagnostic dilemmas and the strategies used to resolve them offer valuable learning opportunities for healthcare professionals . By sharCase reports can provide early evidence of the effectiveness of novel therapies or management strategies for different conditions . In instPneumocystis jiroveceii pneumonia, which exhibited a positive response to endobronchial Watanabe spigot and blood coagulation factor XIII supplementation . In the same way, others atipical respiratory infection are exposed in this Research Topic. Sun et al. described a chronic respiratory condition due to Fusobacterium nucleatum in pleural effusion associated with squamous cell carcinoma. Similarly, Yuan et al. presented a case with Actinomyces graevenitzii, Zhang et al. illustrated an abnormal Streptococcus pneumoniae thoracic image presentation, Peng et al. showed a hypervirulent Klebsiella pneumonia, and Liu and Gao described an infection with Chlamydia psittaci in severe pneumonia cases. All these cases had a positive clinical resolution after identification of the pathogen by molecular sequencing. Unfortunately, molecular diagnostics by next-generation sequencing is not a procedure accessible at the most respiratory centers in the world. In this context, these published cases are important to propose management of rare infection cases in respiratory field.For example, in this Research Topic, we present unusual cases that can provide valuable insights for clinicians facing similar challenges in their practice. One of the cases reported highlights a refractory pneumothorax secondary to human immunodeficiency virus -associated Zuccatosta et al.). The absence of cartilaginous support involvement allowed for successful bronchoscopic treatment, resulting in complete and permanent resolution of the stenosis . Other rare conditions are described in the biliobronchial fistula after cholecystectomy surgery case , a Kartagener s\u00edndrome with DNAH9 mutation case , an anomalous systemic arterial supply to the left lower lung lobe , an epithelioid hemangioendothelioma in main bronchus , and tracheal lobular capillary hemangioma . These reports offer important clinical knowledge and potential solutions for managing complex respiratory conditions.Another intriguing cases involved abnormalities in the thoracic anatomy. A post-COVID-19 tracheal stenosis with fibrotic bridges, leading to significant respiratory distress (Finally, this type of evidence serve as powerful teaching tools, especially in medical education . They prDespite representing the lowest level of evidence, clinical case reports continue to be among the most significant sources of knowledge in the biomedical field. They offer valuable insights into unusual disease presentations and the benefits of employing unconventional approaches in treatment . MoreoveRT-C: Writing \u2013 original draft, Writing \u2013 review & editing. ST: Writing \u2013 original draft, Writing \u2013 review & editing."}
{"text": "Pseudomonas aeruginosa PAO1 biofilm cell clusters. These P. aeruginosa cell clusters are in vitro models of the chronic P. aeruginosa infections found in adult cystic fibrosis patients, which display resistance to antibiotic treatments, leading to exacerbated morbidity and mortality. This resistance has been partially attributed to periphery sequestration, where antibiotics are unable to penetrate biofilm cell clusters. The underlying physical phenomena driving this periphery sequestration have not been definitively established. This paper introduces mathematical models to account for two proposed physical phenomena driving periphery sequestration: biofilm matrix attachment and volume-exclusion due to variable biofilm porosity. An antibiotic accumulation model which incorporated these phenomena was able to better fit observed periphery sequestration data compared to previous models.A spatiotemporal model for antibiotic accumulation in bacterial biofilm microcolonies which leverages heterogenous porosity and attachment site profiles replicated the periphery sequestration phenomena reported in prior experimental studies on To solve the time-dependent governing equations for dynamic concentration profiles, the method-of-lines technique was incorporated into the same solver system. Additionally, a variable liquid-interface concentration boundary replaced the constant concentration BC for this dynamic solver due to the observed dynamic BC in the literature data. Relative antibiotic concentrations were inferred from Tseng et al using WebPlotDigitizer (To solve the steady-state form of governing equations used in this paper for equilibrium concentration profiles, a finite-differences solver based on spatial discretization along with the Newton-Raphson technique for the resulting set of non-linear equations was implemented in python in the SPYDER IDE, with code available on Github (igitizer .Supplement 1"}
{"text": "Purpose: Competency assessment standards for Critical Care Ultrasonography (CCUS) for Graduate Medical Education (GME) trainees in pulmonary/critical care medicine (PCCM) fellowship programs are lacking. We sought to answer the following research questions: How are PCCM fellows and teaching faculty assessed for CCUS competency? Which CCUS teaching methods are perceived as most effective by program directors (PDs) and fellows. Methods: Cross-sectional, nationwide, electronic survey of PCCM PDs and fellows in accredited GME training programs. Results: PDs and fellows both reported the highest rates of fellow competence to use CCUS for invasive procedural guidance, but lower rates for assessment of deep vein thrombosis and abdominal organs. 54% and 90% of PDs reported never assessing fellows or teaching faculty for CCUS competency, respectively. PDs and fellows perceived hands-on workshops and directly supervised CCUS exams as more effective learning methods than unsupervised CCUS archival with subsequent review and self-directed learning. Conclusions: There is substantial variation in CCUS competency assessment among PCCM fellows and teaching faculty nationwide. The majority of training programs do not formally assess fellows or teaching faculty for CCUS competence. Guidelines are needed to formulate standardized competency assessment tools for PCCM fellowship programs. Goal-directed critical care ultrasound (CCUS) has become a necessary skill set for clinicians managing critically ill patients. The Accreditation Council for Graduate Medical Education (ACGME) includes CCUS among the core procedural requirements specifically for trainees in anesthesia and emergency medicine residencies Previous surveys of pulmonary and critical care medicine program directors demonstrated a heavy emphasis on informal bedside teaching of ultrasonography skills despite low reported levels of CCUS competency among faculty (i.e. PCCM attendings that routinely work and train fellows in the workplace setting) Better understanding of these gaps will allow for more transparency among pulmonary-critical care fellowship training programs regarding CCUS competency assessment of fellows and faculty, and allow for better standardization among programs nationwide. Our objectives were to investigate perceptions and methods utilized by fellows and teaching faculty in U.S. training programs to achieve and assess competency in CCUS.This study was approved by the New York University Grossman School of Medicine (NYUGSOM) Institutional Review Board (s18-00282). We conducted two cross-sectional surveys on CCUS competency from September to December of 2018: a survey of ACGME-accredited PCCM fellowship program directors or their designees, and a survey of PCCM fellows in ACGME-accredited programs. Surveys were designed through an iterative process of development that incorporated feedback from three groups at our institution: faculty experts in CCUS, PCCM fellowship program key clinical faculty, and senior PCCM fellows. The surveys were distributed via email to 148 PCCM fellowship program directors in the U.S. and Canada by the Association of Pulmonary and Critical Care Medicine Program Directors (APCCMPD). We asked PDs or their designee to complete the online PD survey, and forward a link to a second online survey to their fellows. We sent follow-up emails once a month for two months. The PD survey asked questions regarding methods used to teach CCUS to their fellows and their perceived effectiveness, perceived CCUS competency of their fellows and their teaching faculty that work with their fellows, and methods used to assess CCUS competency of their fellows and teaching faculty (see Appendix A for full PD survey). The Fellows survey asked questions regarding methods used to learn CCUS and their perceived effectiveness, their performance numbers of CCUS examinations, their perceived CCUS competency, and methods of CCUS competency assessment used by their programs (see Appendix B for full Fellows survey). Both surveys captured basic demographic information about respondents and training programs. Survey responses were anonymous and no personally identifiable information was collected. Survey study data was collected and managed using REDCap\u00ae (Research Electronic Data Capture) electronic data capture tools hosted at NYU Grossman School of Medicine Forty program directors completed the PD survey ; the total number of fellows that received survey invitations is unknown and a response rate cannot be definitively calculated but we estimated a response rate of 18%. Program and fellow demographics are described in Table 1. The vast majority were combined PCCM fellowship programs , academic , and moderately sized . Responding fellows represented a spectrum of training years .The majority of PDs thought the vast majority (76-100%) of their faculty were competent to perform US-guided vascular access (62%) and US-guided drainage catheter placement (64%). The majority of PDs (59%) felt that the majority or vast majority (51%-100%) were competent in lung/pleural US. However, only a minority of PDs believed that the majority or vast majority (51%-100%) of their faculty were competent in goal-directed cardiac echo (36% of PDs), abdominal/kidney US (23%), and lower extremity DVT studies (18%).We also performed a sub-analysis to explore if PD\u2019s perception of faculty CCUS competence correlated with their perception of fellow CCUS competence and the strength of that correlation. Spearman\u2019s rank correlation was computed to assess the relationship between PD\u2019s perception of faculty competence and fellow competence for the 5 different CCUS examinations. There was a statistically significant positive correlation for goal-directed echo, r(38) = [0.436], p=0.006; and DVT studies, r(38) = [0.624], p <0.001. It was not statistically significant for US-guided vascular access (p=0.05), US-guided drainage catheter placement (p=0.271), or lung/pleural US (p=0.089).Methods of teaching and learning CCUS and their perceived effectiveness are documented in Table 2. Utilized methods of teaching CCUS (PD survey) and methods of learning CCUS (Fellow survey) were similar for the two surveys--local lecture-based teaching , directly supervised bedside CCUS exams with feedback , local hands-on workshops , and self-directed learning . Slightly lesser use included regional/national courses , case-based didactics , and unsupervised archival of images with subsequent review for teaching . PD and Fellow perceptions of usefulness for these different teaching/learning methods were similar. Percentage of PDs and Fellows that perceived the different teaching/learning methods as \u201cvery\u201d or \u201cextremely useful\u201d on 5-point Likert scale were: hands-on local workshops , directly supervised bedside CCUS exams with feedback , regional/national courses , local lectures , local case-based conferences ; unsupervised CCUS with archival of images and subsequent review and self-directed learning were rated as less useful.Number of each CCUS examination performed by fellows over their fellowship is displayed in Figure 1. Percentage of fellows performing greater than 20 examinations varied by specific CCUS examination type: 90% for US-guided vascular access, 68% for US-guided drainage catheter placement, 69% for goal-directed echocardiography, 66% for lung/pleural US, 33% for abdominal US, and 19% for DVT studies.Program Director and Fellow Surveys: Methods of Assessing Fellow and Faculty CCUS Competency Methods of assessing fellows for CCUS competency are detailed in Table 3. The majority of PDs (54%) report never formally assessing fellows for CCUS competency, and the majority of fellows (67%) also reported never receiving formal competency assessment. Of the programs that do assess their fellows for CCUS competency, the most used method was global assessment by expert faculty . Half of PDs who engage in fellow CCUS assessments reported using formal review of archived real patient images, practical exam on real patients, and use of a standardized assessment tool. However, fellows report all methods other than global assessment by faculty to be used in the minority of their programs. Of the programs that do assess their fellows for CCUS competency, the specific CCUS exams being tested varied: procedural guidance 61% use on PD survey and 46% use on fellow survey; goal-directed Echo 78% and 62% respectively; lung/pleural US 67% and 59%; abdominal/kidney US 33% and 38%, and lower extremity DVT study 50% and 35% respectively.Ninety percent of PDs reported never assessing their teaching faculty for competence in performing CCUS examinations, and 8% did so only pre-employment. Given the very low prevalence of faculty competency assessment in general, data on methods of assessing faculty competence or specific examinations being assessed were deemed too small to draw conclusions and thus not reported.Regarding the documentation of CCUS competency, only 28% of PDs and 7% of fellows reported having a requirement for completion of a designated number of CCUS examinations prior to fellowship graduation, and only a small minority utilize an electronic portfolio to save their clips and images (18% per PDs and 6% per fellows).etails the percentage of fellows at a given fellowship program who attain competency to independently perform basic CCUS examinations by the end of fellowship training, as well as percentage of teaching pulmonary and/or critical care faculty at a given institution currently competent to perform these same CCUS exams. The percentage of PDs that believed the vast majority (76-100%) of their fellows attain competence varied by the specific CCUS examination type\u2014very high perceived percentage of competence for vascular access and drainage catheter placement (97% of PDs for both), moderately perceived percentage of competence for lung/pleural US (71%), and lesser perceived percentage of competence for goal-directed echocardiography (47%), lower extremity DVT study (37%), and abdominal/kidney US (26%). Fellows\u2019 perceptions generally agreed with PD competency perceptions for vascular access and drainage catheter placement, with fellows agreeing or strongly agreeing in their competence , as well as for lung/pleural exam (86% agreement with competence) and lesser perceived competence in DVT studies (50%) and abdominal/kidney US (44%). However, fellows perceived their competence higher for goal-directed echo (77% agree or strongly agree with competence) compared with PD perceptions. Breaking down fellow perceived competency by year of training, all years reported high perceived competency in US-guided vascular access and US-guided drainage catheter placement . A stepwise pattern of increasing perceived competency was seen for goal-directed Echo and lung/pleural US . However, rates of competence by year remained relatively flat/plateaued regardless of year of training for abdominal US and DVT study . CCUS is a complex skill that combines cognitive knowledge along with psychomotor image acquisition skills and affective attitudes, and has become essential in daily practice for intensivists at the bedside Prior surveys of PCCM faculty and trainees have demonstrated heterogeneous institutional practices and methodologies to assess competency Interestingly, these levels of perceived competence were mirrored by fellow-reported experience with the different CCUS examinations, as most fellows reported greater experience with US-guided placement of vascular access devices or drainage catheters , goal-directed echocardiography and lung/pleura assessment but less abdominal and DVT ultrasound experience. About half of fellows reported performing fewer than 10 abdominal or DVT ultrasounds. ACCP/SRLF expert consensus guidelines do not specify the number of each US examination type recommended for CCUS competence A survey of 67 surgical critical care fellowship program directors reported the following exams as \u201cvery important\u201d\u2014FAST exam (75%), central venous access (80%), transthoracic echo (47%), DVT study (3%), and abdominal US for biliary pathology (1.5%) Regarding CCUS competency assessment, we found in this study 54% of PDs and 67% of fellows reported that their programs never conduct formal competency assessments for CCUS. Among the programs that reported conducting formal assessments, a global assessment by expert faculty was the most common method cited by both PDs and fellows. Among those programs that do formally assess their fellows, the majority do not test specifically for competency in DVT studies or abdominal ultrasound. Additionally, there is a lack of use of archival review with feedback as well as development of ultrasound portfolios. Prior studies have documented the issue of poor faculty competence in CCUS as a barrier to training Given the lack of formal assessment of CCUS competency of faculty, it is uncertain what information or data PDs used to answer our survey questions on faculty competence\u2013 institutional delineation of privileges, direct observation, gestalt, or other. Of note, we saw a correlation with PD perception of faculty CCUS competency with their perception of fellow CCUS competency for goal-directed echo (moderate correlation) and DVT studies (strong correlation). This is of uncertain significance, as it could reflect causality , or could represent PD\u2019s inability to differentiate fellow from faculty competence due to lack of tangible metrics for the latter. Future studies to better understand the relationship between fellow and teaching faculty CCUS competency are warranted. PDs and fellows agreed on preferred methodologies for learning CCUS. Both groups reported that regional/national ultrasound courses, hands-on institutional workshops and directly supervised bedside CCUS exams were their most preferred approaches to learning CCUS, reinforcing concepts of learning through active processes. Regional CCUS courses including hands-on workshops with expert faculty have been found to be feasible and efficient in providing much needed hands-on training in CCUS Unsupervised CCUS exams, self-directed learning and lecture-based teaching were the least favored approaches to CCUS education. Brady et al. had determined through their 20-item survey of PCCM program directors that the most common method of learning CCUS was in fact unsupervised, independent bedside learning Our survey has several strengths and limitations. Unlike previous studies, our survey included perceptions of both program directors and fellows and found a general agreement on most topics. Our findings on the perceptions of program directors with respect to the competency of clinical teaching faculty to perform CCUS have not been described previously. The major limitation of our study was the small sample size compared to all PCCM training programs which could introduce selection bias and limit the overall generalizability to all current practices. However, the consistent data from both fellows and faculty does help with overall validity of the themes that emerged from the results, and the heterogeneous distribution of academic and affiliated hospitals improves the generalizability of the findings. However, given the small sample size of this study, we would caution that the results should be viewed as intriguing but ultimately hypothesis-generating and in need of future targeted studies to expand upon this work. Also, as this is a cross-sectional survey, there could be recall biases from the PD or fellow respondents. As stated above, it is uncertain what information PDs used particularly for faculty competence given the overall lack of faculty assessment. We also relied on PDs to forward a survey link to their fellows, introducing another element of potential sampling bias to fellow responses as there was a potential gatekeeper deciding to forward or not the survey to their fellows. Thus the assumption we made is that the responding PDs and fellows likely represent the same training programs, and thus the aggregate data is representative of the same training programs. This assumption is bolstered by the Demographic information detailed in Table 1 which shows very similar PD and Fellow survey demographics . However, as the data collected were anonymous, we expect the fellows to have been truthful and accurate in their responses. Lastly, given the anonymous nature of the data collection, we were able only to carry out analyses in aggregate, but unable to carry out detailed analyses of associations between PD and fellow responses from the same program.Our survey lays a foundation for future directions in the applicability and training of CCUS in clinical practice. Our exploratory analysis suggests that program director and fellow perspectives on CCUS competency overlap substantially; future surveys of PDs only might therefore be sufficient. It is also currently unknown how the COVID-19 pandemic may have impacted CCUS training despite high utilization of CCUS in intensive care units. This may help further improve our teaching practices and develop methodologies using advanced tools such as portable ultrasounds with remote access capabilities in the setting of contact precautions, virtual training and feedback sessions. It is currently unknown if CCUS training methodologies differ between CCM only programs vs PCCM programs and country-wide, survey-based studies are needed to include more CCM only programs.Our study highlights substantial heterogeneity in the CCUS teaching and competency assessment methods among ACGME-accredited PCCM programs in the United States. We found the perceptions of PDs and fellows were in general agreement with high levels of perceived competency to perform CCUS-guided procedures and lung/pleura assessment but deficiencies in the competent performance and interpretation of abdominal and lower extremity diagnostic venous ultrasonography. We also found that the majority and vast majority of programs do not assess their fellows and teaching faculty respectively for competence in CCUS, highlighting a major area of programmatic and curricular need. Our survey also demonstrates that active learning through regional and local hands-on workshops and directly supervised bedside CCUS exams were perceived as extremely useful, whereas, unsupervised CCUS exam, self-directed learning and lecture-based learning were perceived as less useful by both PDs and fellows. These findings suggest that further studies and guidelines are needed to formulate standardized competency assessment tools across all PCCM/CCM fellowship programs. MHA had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. MHA and DP contributed substantially to the study design, data analysis and interpretation. MHA, HD and DP contributed substantially to the writing of the manuscript. The authors have no relevant conflicts of interest to disclose.Appendix AAppendix A"}
{"text": "Biological events occurring in the human brain are elegantly tuned to impart diverse emotions and elaborate behavioral patterns. The role of signaling pathways often changes during the progression of CNS disorders, and there is remarkable spatial heterogeneity in cell types and molecular expression profiles over the brain. Therefore, a full temporal and spatial illustration of the pathological progression of CNS disorders would benefit the development of novel therapeutic strategies. In this Research Topic, 6 articles, including high-quality original research articles and comprehensive reviews, discuss the spatiotemporal regulation patterns of CNS disorders and emerging techniques in this field.Zou et al. explored the cell type-specific modulatory roles of dopamine receptor D1 (D1R)- and D2R-expressing medium spiny neurons in the nucleus accumbens shell in TLE. They found that cell-type-specific inhibition of either D1R-MSN or D2R-MSN alleviated TLE seizures by reducing the number of secondarily generalized seizures and improving seizure stages, without altering the onset time of focal seizures. The data of the aforementioned study along with other studies suggest that different brain areas and cell populations participate in seizure initiation, propagation and termination, thereby highlighting the necessity of demonstrating the spatial heterogeneity of pathological mechanisms of epilepsy.Temporal lobe epilepsy (TLE) is the most prevalent focal seizure, which is highly likely to progress to generalized seizures. Here, Zhou and Zhang. discussed the cell type-specific role of oligodendrocytes in various CNS disorders and delineated the contribution of myelin to neuronal activity. Interestingly, neuronal excitability can also affect myelin functions. The authors overviewed the potential strategies for myelin regeneration through the precise modulation of neuronal activity.Similarly, Yi et al. reviewed the temporal regulation of key biological events that occur during neurodevelopment after experiencing febrile seizures. Febrile seizures are quite common during early childhood (-4%) and receLai et al. examined the molecular mechanisms involved in the treatment of chronic pain using sinomenine, an active ingredient in the natural plant \u2018sinomenium acutum (Thunb.) Rehd. Et Wils\u2019, while focusing on its regulatory roles in distinct immune cell subpopulations. Sinomenine can regulate the interaction among different immune cells, immune cells and neurons and glial cells and neurons to confer immunosuppressive effects.The aforementioned studies dissect pathological mechanisms of CNS disorders from a spatiotemporal perspective. Similar research approaches can also be used to study the pharmacological mechanisms of drugs and other functional compounds. Wong et al. proposed a novel electrochemical localized oxygen scavenging system (eLOS) to induce hypoxia in vitro with spatiotemporal precision. Focal hypoxia is very common in multiple diseases such as ischemic stroke, cardiac arrest and dementia; however, the currently available experimental model of spatially restricted ischemia is limited. Using the eLOS platform, Wong et al. successfully induced axon-restricted hypoxic stress in human cortical neurons and found that localized axonal hypoxic stress induced neuronal death even when the somas remain in the normoxic culturing condition. These findings indicate the potential of the eLOS platform in studying cellular and subcellular changes in white matter after an injury and other hypoxic insults.Studies focusing on the spatiotemporal pathological mechanism of CNS disorders will benefit from the newly developed techniques providing spatiotemporal information. Ya et al. illustrated working principles and provided examples of the application of cutting-edge spatially resolved transcriptomic technologies in studying CNS disorders. The rapid development of these technologies will eventually provide a deeper understanding of the molecular mechanisms underlying CNS disorders.Furthermore, Overall, it has become inevitable to elucidate the pathological progression of CNS in high spatiotemporal resolution. We hope that this Research Topic will help readers understand CNS disorders from a highly spatiotemporally precise perspective."}
{"text": "We thank Drs. Sutt and Fraser for their insightful commentary on our publication. They open an important debate on tracheostomy timing and outcomes of interest.We concur that for decades, research has focused on \u201ctraditional\u201d outcomes such as mortality and length of stay (LOS). Additionally, focus on tracheostomy-specific outcomes including swallowing, and communication may aid efforts to improve recovery after intensive care unit (ICU) discharge.Our analysis of\u2009>\u200917,000 critically ill patients with severe stroke attempted to clarify whether tracheostomy timing is an important piece of the stroke management puzzle .We found that early tracheostomy does not impact neurological outcome (mRS). This was reflected in the SETPOINT2 trial, where 75% of patients in each group experienced poor neurological outcome despite active rehabilitation efforts (~\u200970% of patients were discharged to rehabilitation facilities) [We recognise that, strictly speaking, the timing of tracheostomy should not substantially impact neurological outcome. Studies often inadequately separate early and late groups . The phEvidence on patient-centric outcomes in this population is limited. Our work humbly sought to quell decades of debate on the impact of tracheostomy timing on mortality, neurological outcome (mRS), and LOS, in patients with severe stroke. Given our findings, we commend future efforts to protocolise reporting of additional patient-centred outcomes such as speech , swallowing and psyc"}
{"text": "Editorial on the Research TopicUrothelial carcinoma of renal pelvis and ureter, prognosis and recent advancesUrothelial carcinoma of the renal pelvis and ureter is a prevalent malignancy primarily affecting the elderly population . Its incZhanghuang et al.). The study revealed that non-UTUC deaths accounted for the majority of mortality among patients with localized disease. This highlights the importance of considering non-cancer causes in the management of UTUC survivors. Moreover, UTUC was found to be the leading cause of death in patients with regional and distant stages, emphasizing the need for improved therapeutic strategies targeting advanced disease while considering the increased risk of death from non-cancer causes survivors has provided valuable insights into mortality patterns. By utilizing the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, a large cohort of UTUC patients was examined and cancer-specific survival (CSS) in renal pelvic urothelial carcinoma (RPUC) patients. Using data from the SEER database, the study compared radical nephroureterectomy (NU) and inadvertent radical nephrectomy (RN). The results underscored the significance of accurate diagnosis and appropriate surgical intervention in RPUC patients. The study concluded that RN could lead to worse oncological outcomes compared to NU, emphasizing the importance of precise surgical planning and execution.Wu et al.).Another study emphasized the importance of distinguishing between radical nephroureterectomy (NU) and inadvertent radical nephrectomy (RN) in patients with renal pelvis urothelial carcinoma (RPUC). A retrospective analysis of data from the SEER database revealed that patients who underwent RN experienced worse overall survival (OS) compared to those who received NU. Furthermore, the study highlighted that the negative impact of RN on OS was more significant in patients with tumors larger than 4.2\u2005cm . While no significant differences were observed in surgical outcomes between the two approaches, the study identified various predictive factors associated with adverse oncological outcomes. Age over 70, positive lymph node metastasis, upper ureter tumor location, and male sex were identified as potential risk factors. Additionally, higher surgical volume showed trends toward favorable outcomes in terms of overall survival and cancer-specific survival.A study utilizing data from the Taiwan nationwide upper urinary tract urothelial carcinoma (UTUC) collaboration database evaluated the outcomes of transperitoneal hand-assisted laparoscopic nephroureterectomy (TP-HALNU) and transperitoneal pure laparoscopic nephroureterectomy (TP-LNU) . The findings indicate that patients who received chemotherapy (CT) combined with NU exhibited improved overall survival (OS) compared to those who received CT alone. This benefit was observed in both nonmetastatic and metastatic UTUC. The study emphasizes the potential advantages of NU in prolonging survival outcomes for patients with advanced-stage UTUC.A multicenter retrospective cohort study addressed the role of nephroureterectomy (NU) in stage IV upper tract urothelial carcinoma (UTUC) was shown to have a negative impact on overall survival (OS), particularly in patients with larger tumors. Furthermore, while the choice between surgical approaches may not significantly influence outcomes, other factors such as patient age, lymph node metastasis, tumor location, and surgical volume should be considered for prognostic evaluation. Finally, the role of nephroureterectomy (NU) in stage IV UTUC demonstrates potential benefits in terms of overall survival (OS) for both nonmetastatic and metastatic cases. These findings underscore the importance of precise diagnosis and treatment among patients with UTUC."}
{"text": "Three years since the onset of COVID-19, pandemic-related trends in child sexual abuse (CSA) remain poorly understood. Common administrative surveillance metrics may have underestimated abuse during the pandemic, given youths\u2019 limited access to mandatory reporters. Research using anonymous service-use data showed increased violence-related online help-seeking but overlooked youth-specific help-seeking for CSA during COVID-19. Understanding pandemic-related trends in CSA can inform abuse detection practices and mental health service provision for youth victims.The purpose of this study was to harness anonymous help-seeking data from the National Sexual Assault Online Hotline (NSAOH) to glean insights about CSA occurrence in the United States during the COVID-19 pandemic.We used an archival sample of victims who contacted NSAOH from 2016 to 2021 . We examined differences in the proportion of youth and adult victims contacting NSAOH during the first COVID-19 year (March 2020 to February 2021) compared to the prior year . Further, we compared key characteristics of hotline interactions among youth victims during the first COVID-19 year to the prior year (n=5913). Using joinpoint regression analysis, we examined linear trends in the number of monthly sampled youth and adult victims (excluding victims of unknown age) from 2016 to 2021 who discussed any victimization event and who discussed recent events .Most youth victims were abused by family members prior to and after the onset of COVID-19. The number of youth victims contacting NSAOH spiked in March 2020 and peaked in November 2020 for all youth and those discussing recent events . We observed a decline in youth victims into spring 2021 for all youth and those discussing recent events . The number of adult victims discussing any victimization event increased steadily from January 2018 through May 2021 and then declined . Trends were stable for adults discussing recent events.This study extends the use of hotline data to understand the implications of the pandemic on CSA. We observed increased youth help-seeking through the NSAOH coinciding with the onset of COVID-19. Trends persisted when limiting analyses to recent victimization events, suggesting increased help-seeking reflected increased CSA during COVID-19. These findings underscore the utility of anonymous online services for youth currently experiencing abuse. Further, the findings support calls for increased youth mental health services and efforts to incorporate online chat into youth-targeted services. As we approach a postpandemic world, understanding trends in child maltreatment during COVID-19 remains vital for informing practices to detect abuse and ameliorate the effects of trauma. Evidence of pandemic-related trends in child maltreatment is conflicting, resulting in part from limitations of traditional surveillance strategies. Apparent declines in child maltreatment reflected in emergency room visits may be aWhile youths\u2019 perspectives are often assessed through self-report survey methodologies, indicators of online help-seeking are potentially valuable. Prior to the pandemic, youth actively sought help for experiences of abuse via online and text-based hotlines ,8, whichRecent work has explored trends in violence-related online help-seeking during the pandemic. Google searches related to child maltreatment increased during the pandemic ,12 but mA study of multinational child helplines lacked cAmid these challenges, research on pandemic-related child maltreatment has largely overlooked child sexual abuse (CSA). However, concerns about victims\u2019 physical and social isolation and accessibility to perpetrators during stay-at-home orders are partWe advance knowledge by addressing limitations of previous work on 3 fronts. First, we examine online help-seeking for sexual violence among youth victims specifically. Second, we incorporate 5 years of observations (2016-2021), providing a broader picture of help-seeking patterns across the pre- and postpandemic onset time periods. Third, we delineate recent events to distinguish violence that occurred during the pandemic.The NSAOH is a US-based online hotline providing 24/7 anonymous crisis intervention services via desktop and mobile internet chat. RAINN , an anti\u2013sexual violence organization in the United States, created and has operated NSAOH since 2006 to serve victims of sexual violence.Data collection via an in-depth online assessment serves an integral role in hotline operations to identify areas for service improvement and staff training. Directly following the first chat session of their shift, staff record session information, such as event characteristics and topics discussed. Because information is not requested for the purpose of completing the assessment, data are often considered unknown . Staff receive instructions for assessment completion both within the assessment and through supplemental training.Data in this study represent a sample of all hotline chats in which the visitor discussed an experience of sexual or other interpersonal violence between January 2016 and December 2021 . Additional information about hotline procedures, the organizational context, and sample inclusion criteria are available in Data used in this study were originally collected as part of ongoing internal program evaluation; thus, informed consent was not required. Analysis of this archival data for the purposes of generating generalizable knowledge of online hotline users and sexual violence experiences was deemed exempt by the Advarra institutional review board under category 4 of the Revised Common Rule.We examined differences in the proportion of youth and adult (aged 18 years and older) victims during the first COVID-19 year (March 2020 through February 2021) compared to the year prior , with victims of unknown age excluded . Among youth (n=5913), we compared perpetrator type (family vs nonfamily), perpetrator living status (currently living with vs not currently living with the victim), event timeframe , and event frequency (repeated abuse vs single occurrence) during the first COVID-19 year compared to the year prior. These analyses used the chi-squared test with pairwise exclusion of missing data; analyses used SPSS .To contextualize trends in youth help-seeking, we used Joinpoint to examine linear trends in the number of monthly sampled victims by age group from 2016 to 2021 among all youth and adult victims . Among youth, we noted statistically significant but small shifts in the proportion of chats that involved family-perpetrated assaults , perpetrators currently living with the victim , recent assaults , and repeated assaults . Inflection points reveal variability in the strength or direction (or both) of trends in the number of victims by age in our sample . Prior tThis study is the first, to our knowledge, to reveal increases in youth help-seeking for sexual violence coinciding with the onset of COVID-19. These increases peaked in November 2020 and were present for all youth victims and for youth victims discussing recent events. Although the number of adult victims increased, this trend was more gradual, preceded the onset of COVID-19, and was not present for those discussing recent events. Our finding that trends were sustained for recent events suggests an increase in youth affected by sexual violence during the pandemic rather than increased help-seeking among all victims for current and past events due to limited alternative support options.While our findings seemingly conflict with declines in abuse-related hospital visits and official reports ,2, evideMost youth who contacted the NSAOH\u2014both prior to and during the pandemic\u2014discussed repeated experiences of violence perpetrated by family members or someone else living with them. During the pandemic, we observed small proportional increases in youths\u2019 chats that featured these characteristics, consistent with elevated violence driven by victims\u2019 increased accessibility to perpetrators in the home amid limited contact with trusted adults . Future work should examine to what extent increased youth help-seeking reflected increased frequency and severity of ongoing violence predating the pandemic or cases of violence that began during the pandemic.The number of chats from youth began to decrease after November 2020. This decline could relate to youth having a greater ability to avoid perpetrators or opportunities to disclose to alternative sources of support as schools reopened in the summer and fall of 2020. However, because reopening policies were variable across the United States, driven by state and local government, this trend should be interpreted with caution.While reported trends were transitory, the effects of sexual abuse are not. Our findings reflect increased help-seeking by youth during the pandemic, an indication of rising demand for mental health services to treat trauma and its sequelae among youth. Given the national shortage of child mental health providers that predates COVID-19 , there iJoinpoint regression analysis allowed us to identify changes in the linear trend of victims\u2019 hotline use from 2016 to 2021. While we interpreted the reason for some of these changes, their causes cannot be definitively ascertained from our analysis. We could not differentiate repeat hotline users from new users, which would help delineate new cases of abuse. Our data collection protocol prioritized the delivery of victim-centered services. We did not solicit information from visitors for assessment purposes, resulting in some missing data and limited demographic information. Future work could incorporate anonymous collection of demographics prior to service provision to enhance the utility of hotline data as a surveillance indicator of child maltreatment. Understanding the interplay of hotline supply and demand will also be useful because changes in staff availability could affect the accessibility and use of services.Our study demonstrates the utility of anonymous online hotline data as a complementary surveillance indicator for child maltreatment that is transferrable to other public health priority areas . Increased help-seeking amid decreased safety at home also speaks to the utility of online support options for youth experiencing abuse. Preparing for future public health emergencies necessitates consideration of additional online communication options that allow youth to privately disclose abuse to trusted adults. Future work should explore how to safely incorporate these communication options into existing services, such as online schooling or telemedicine platforms."}
{"text": "Remyelination biology and the therapeutic potential of restoring myelin sheaths to prevent neurodegeneration and disability in multiple sclerosis (MS) has made considerable gains over the past decade with many regeneration strategies undergoing tested in MS clinical trials. Animal models used to investigate oligodendroglial responses and regeneration of myelin vary considerably in the mechanism of demyelination, involvement of inflammatory cells, neurodegeneration and capacity for remyelination. The investigation of remyelination in the context of aging and an inflammatory environment are of considerable interest for the potential translation to progressive multiple sclerosis. Here we review how remyelination is assessed in mouse models of demyelination, differences and advantages of these models, therapeutic strategies that have emerged and current pro-remyelination clinical trials. Multiple sclerosis (MS) is a chronic demyelinating, inflammatory and neurodegenerative disease of the central nervous system (CNS). Remyelination is a regenerative process by which oligodendrocytes restore myelin sheaths to demyelinated axons. Evidence from animal models indicate that remyelination can restore neuronal conduction , 1981, pRemyelination is robust in many animal models that have been used to study remyelination, which is somewhat discordant with the heterogeneous patterns of oligodendrocyte loss, demyelination and remyelination in human pathology-based studies of MS tissue . The mecThe inflammatory environment can modulate oligodendroglial properties including oligodendroglial survival, migration, differentiation, axon engagement and remyelination . AdvanceIn animal models, aging influences oligodendroglial properties and prog14C has been used to investigate the age of oligodendroglia within MS lesions and this study indicated limited production of new oligodendrocytes within shadow plaques that may have undergone remyelination suggesting that mature surviving oligodendrocytes contribute to subsequent remyelination in human MS lesions (14C) prior to differentiation despite rodent studies indicating that OPCs can directly differentiate into mature oligodendrocytes without cell division is an endogenous lysophospholipid that can be used to generate a focal demyelinating lesion by injection into white matter tracts and demyelination results through disruption of oligodendroglial cell membranes leading In the lysolecithin model, myelin and extrEthidium bromide, a DNA-intercalating agent, injected into white matter tracts creates a focal demyelinating lesion with a larger area of demyelination compared to lysolecithin . EthidiuCombining X-irradiation with ethidium bromide injection has allowed for the investigation of transplanted progenitor cells in a lesion environment devoid of endogenous remyelination potential . NeonataAged animals exhibit slower remyelination after lysolecithin and ethidium bromide injection and agedCuprizone, bis-cyclohexanone-oxaldihydrazone, was first used as an animal model of demyelination in the 1960s . CuprizoMyelin loss occurs after several weeks of cuprizone ingestion and peaks at 4\u20135\u2009weeks . One of Manipulation of astrocyte and microglial responses after cuprizone-mediated demyelination can influence remyelination. Ablation of astrocytes after chronic cuprizone treatment results in improved oligodendrocyte density, remyelination and motor functional outcomes . AstrocyThe role of T cells in cuprizone-mediated demyelination is unclear. T cells are present in cuprizone ingestion and CD8 Toxin models have greatly facilitated the investigation of pathways involved in oligodendroglial proliferation, recruitment, differentiation and remyelination. Promising mechanisms that are under investigation in clinical trials for remyelination in MS that have emerged from investigation of remyelination in focal and systemic toxin models include LINGO-1 antagonism , Nogo-A The major advantages of toxin models are the robust remyelination response with stereotyped kinetics, separation of the demyelinating process from the regenerative process, minimal axonal degeneration, and decline of remyelination with aging that have allowed for discovery of targets that accelerate repair in an aged environment. While focal toxin models have these advantages, the short demyelinating insult and robust remyelination response are limitations. Diffuse CNS demyelination and white matter injury induced by cuprizone ingestion offers the advantage of an environment with prolonged oligodendroglial loss, neuronal stress and subsequent neurodegeneration, which may allow for the investigation of pathways that prevent neuronal degeneration and allow for the ability to assess motor and physExperimental autoimmune encephalomyelitis (EAE) models are one of the most commonly used models to investigate the immunopathogenesis of MS . Immuniz35\u201355 peptide and tranpt-mGFP) ,D. Signipt-mGFP) . Despitept-mGFP) , pharmacpt-mGFP) and K-oppt-mGFP) were abluprizone . Immunizl course . Remyelil course . The relon phase and whet35-55 EAE does not resemble the clinical course of relapsing remitting or progressive MS. The high degree of neurodegeneration and minimal remyelination after the acute EAE phase represent challenges for the utilization of these models in assessing remyelination strategies.Active immunization models have many features that differ from human MS pathobiology and clinical course. The robust inflammatory response and resulting secondary demyelination, early neurodegeneration , sparingEncephalitogenic T cells from CNS antigen immunized mice or myelin-specific T cells isolated from T cell receptor transgenic lines can be used to induce neuroinflammatory disease upon adoptive transfer into naive hosts . A majorAdoptive transfer of myelin-reactive Th17 cells after acute cuprizone ingestion has been used as a model to investigate oligodendroglial responses in the setting of T cell mediated inflammation and has Gfap-tTA) with tetracycline response element (TRE) upstream of IFN-\u03b3 sequence (TRE-IFN-\u03b3) in a double transgenic line allows for temporal regulation of CNS IFN-\u03b3 expression upon removal of doxycycline have been used to investigate demyelination and remyelination. Initial studies of transgenic mice with targeted expression of IFN-\u03b3 from the myelin basic protein (MBP) promotor and gliaycycline . CNS IFNlination . Prolonglination suggestiPlp-CreER\u2122) with a diphtheria toxin subunit A (DTA) floxed stop reporter line (ROSA26-eGFP-DTA) results in oligodendrocyte apoptosis upon exposure to tamoxifen results in oligodendrocyte death, widespread demyelination, microglia and macrophage reactivity, axonal damage and incomplete remyelination (Loss of function of transcription factor myelin gene regulatory factor (MYRF) that induces expression of mature myelin genes in maturlination . Subsequlination . While tChronic encephalomyelitis viral mouse models share pathogenic features similar to MS and may Theiler\u2019s murine encephalomyelitis virus (TMEV) is a single-stranded RNA picornavirus that causes flaccid myelitis in mice and can Mouse hepatitis virus (MHV) is a positive-strand RNA virus with neurotropic strains that can be used to induce a chronic demyelinating disease through intracranial or intranasal inoculation of susceptible mouse strains. An acute encephalomyelitis phase is followed by a secondary phase of demyelination and remyelination . MHV-spein vitro have been used to identify pathways with remyelination potential (High-throughput screens that evaluate the ability of compounds to promote oligodendrocyte differentiation otential . Many paotential .Assessment of remyelination in MS clinical trials has been challenging, with few validated clinical tools to assess remyelination in humans . MeasureAnimal models of MS with demonstrated remyelination capacity vary considerable in their mechanisms of demyelination, inflammatory infiltrates, degree of ongoing inflammatory activity, axonal loss and neurodegeneration and extent of remyelination. Focal toxin models offer the advantage of stereotyped remyelination after a short single demyelinating insult which has allowed for the investigation of factors that promote or inhibit this robust reparative response. A prolonged demyelinating insult predominated by corpus callosum and cortical demyelination and subsequent neurodegeneration and motor decline can be modelled with chronic cuprizone exposure and may share some features of the neurodegenerative process in progressive MS. Both cuprizone and EAE models induce inflammatory subsets of glia that are found in MS tissue and further investigation of how these subsets of glia contribute to ongoing inflammatory activity and promote or inhibit repair may offer insight into potential mechanisms to modulate remyelination in inflammatory settings. While no single animal model recapitulates the pathobiology of MS, considerations of the limitations and advantages of each model should be taken into account when investigating remyelination and translating animal model findings to human MS.DP and EH contributed to writing the manuscript. EF contributed to researching and generating the clinical trial table. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "Carotid web (CaW) and carotid free-floating thrombus (CFFT) are rare yet critical causes of ischemic stroke in young adults.A 54-year-old woman presented with a fluctuating right sensory-motor faciobrachial syndrome. A brain MRI scan revealed multiple small recent asynchronous cortico-subcortical ischemic foci in the vascular territory of the left internal carotid artery. A CT angiography identified a CFFT in the left internal carotid artery arising from an underlying CaW. The patient was treated with excellent clinical outcomes with carotid artery stenting and dual antiplatelet therapy.We provide a structured pathophysiological rationale connecting CaW and CFFT and highlight pivotal therapeutic implications. Further studies are needed to investigate this relationship and guide assessment and treatment. Etiological diagnosis of stroke in young adults is a challenging and critical aspect of neurovascular care. Indeed, patients affected by such devastating occurrences have an inherently longer time after the index event and can thus benefit most from adequate secondary prevention strategies . UnfortuCarotid web (CaW) and carotid free-floating thrombus (CFFT) are well-known yet often neglected causes of ischemic stroke in young adults. CaW defines a localized carotid intimal fibromuscular dysplasia presenting as a shelf\u00adlike projection into the lumen of the proximal internal carotid artery , 4. ConvHereby, we describe a case of ischemic stroke due to a CFFT originating from a contiguous CaW. We illustrate the diagnostic and therapeutic implications of these two rare conditions, as well as their possible pathophysiological relationship.A 54-year-old woman presented to the emergency department with a two-day history of fluctuating right sensory-motor faciobrachial syndrome. The patient was an active smoker without further major cardiovascular risk factors. Specifically, she had a normal body mass index and no medical history of hypertension, dyslipidemia, diabetes, neurological or cardiovascular events. Additionally, she was not using estrogen-containing oral contraceptives and her family history was unremarkable for cerebrovascular events. Neurological examination on admission revealed a right inferior facial palsy NIHSS\u2009=\u20092). Brain CT scan and blood tests were normal. A minor stroke was suspected, therefore, the patient initiated dual antiplatelet therapy (DAPT) and was admitted to our Stroke Unit. A brain MRI scan revealed multiple small recent asynchronous cortico-subcortical ischemic foci in the left middle cerebral artery and a subacute/chronic ischemic lesion in the left head of the caudate nucleus, a territory of the recurrent artery of Heubner Fig.\u00a0. Continu. Brain CWe report the case of an otherwise healthy young woman who presented with multi-embolic strokes caused by a CFFT stemming from an underlying CaW. The co-occurrence of these two conditions has been reported anecdotally, and the presence of thrombus superimposition on CaW was suggested to be a contributing factor to stroke recurrence \u201310. HoweRadiological differentials for CaW encompass atherosclerotic plaque with plaque rupture, carotid artery dissection, and fibromuscular dysplasia (FMD). However, the regular morphology of the filling defect, lack of calcium deposits and signs of intramural hemorrhage make atherosclerotic plaque unlikely in our patient. Furthermore, neither CTA nor DSA revealed the presence of an intimal flap, and no other stenotic segments were identified in our imaging studies, reducing the probability of carotid artery dissection and FMD.CTA has shown superior diagnostic accuracy compared to carotid US in diagnosing CaW . It is tAs a secondary prevention, our patient was successfully treated with CAS and transitory DAPT. Evidence of the best management is currently lacking in the literature. Indeed, secondary prevention strategies for CaW and CFFT are based on small case series and expert consensus, as no specific guidelines or clinical trials have been designed to date. Concerning CaW prevention, current strategies aim to avoid long-term complications arising from the high stroke recurrence rates. Although chronic pharmacologic management with anti-platelet agents would fall within current guidelines also antWe described a case of CFFT and CaW co-occurrence focusing on their possible pathophysiological connection as well as diagnostic and therapeutic implications. Meticulous evaluation of non-invasive or invasive vascular imaging tests aiming to detect an underlying CaW in unexplained CFTT should be required. Carotid artery stenting and, eventually, thrombectomy might be a safe and effective secondary prevention strategy to kill two birds with one stone unless underlying thrombophilic conditions requiring anticoagulation therapy are present. Future studies are needed to estimate the frequency and understand the underpinning biologics of the co-occurrence of these two conditions in order to inform assessment and treatment."}
{"text": "Since organizational psychology is a broad and evolving discipline, the topic editors are pleased to announce sixteen articles that highlight new insights into how leadership, collective intelligence, intellectual capital, innovation, job performance, satisfaction advance the tradition, nature, and research methods of organizational psychology. The articles showcase a global perspective of new insights in organizational psychology from Asia, Europe, Middle East, Africa, North America, and Oceania. The authors explored new insights in organizational psychology through conceptual analysis, qualitative and empirical research, a brief research report, and a systematic review.There is a continual focus to expand and provide new insights on leadership theory and research (Lord et al., van Niekerk highlights the importance of psychosocial factors and elevated stress levels that limit a flourishing multi-cultural environment, stakeholder engagement and leader-follower relationships. The author recommends that organizations should promote a multi-cultural team to counteract elevated stress and to better manage psychosocial factors in an organization. Zhao et al. extend the literature on authoritarian leadership by providing a new perspective for authoritarian leadership practice. In comparison to previous research studies, the authors findings indicate authoritarian leadership generates positive employee wellbeing and creativity. Haar and de Jong explored the dark side of leadership personality to provide new insights on how the dark side of leadership could benefit an organization's performance rather than decreasing organizational performance. Latent transition analysis is introduced by Zyberaj et al. for helping organizational psychology researchers to analyze longitudinal data through an applied example utilizing psychological capital and leader-member exchange. The author findings indicates psychological capital is more likely to occur when leader-member exchange is high rather than low. Therefore, high leader-member exchange works hand-in-hand with high psychological capital.Janssens et al. extends the collective intelligence literature and research through a conceptual analysis on the dynamic granular tensions between the needs of the environment with the collective team behaviors over time. The authors explored various methods to help organizational psychology researchers unpack micro-level team behavior. Senawi and Osmadi research study findings reveal that relational capital plays a significant role with intellectual capital for improving property tax reassessment activities. Overall, the attitudes of local government officials must align with relational capital and intellectual capital for successful property tax reassessment performance.Fan et al. research study findings extend self-determination theory to reveal employees' perceptions on organizational support has positive and profound effects on employees' proactive innovative behavior through the satisfaction of basic psychological needs such as autonomy, competence, and relatedness. Liu and Zhang focuses on employees' paradox mindset on innovative performance through role breadth self-efficacy. Employees with a paradox mindset intentionally make innovative things happen through their own actions. Moreover, role breadth self-efficacy and individual ambidexterity play an important role in understanding how employees manage a paradox mindset and innovative performance. Song et al. provide new insights on how employees should manage innovation performance under time pressure. The authors research study findings indicate time pressure significantly improves innovation performance. Therefore, employees operating under time pressures should receive significant leadership support for improving innovative performance.From a new Chinese perspective, Xu et al. investigated the interdependence of psychological capital, social capital and human capital, including the three capital's impact on job performance. The authors study findings discovered new insights on configuration and casual asymmetry from psychological capital, social capital and human capital that affect job performance. Consequently, Xu et al. challenged previous studies' symmetrical regression relationship findings and extended the relationship among psychological capital, social capital and human capital within intelligent career theory. Moreover, high psychological capital plays a key role in high job performance. Sanclemente et al. explored inconsistencies from previous research studies that predict workers' health levels in linear models. The authors research study focused on differences among service sub sectors through linear and non-linear relationships within task complexity, job autonomy, user contacts, time pressure, and psychological and physical symptoms of employees. Overall, Sanclemente et al. research study findings on non-linear relationships indicate medium levels of task complexity from job demands should not exceed greatly to mitigate increased negative impacts to foster service sector employees' physical and psychological well-being in job satisfaction and performance.Levitats et al. provides new insights on unexplored contexts of emotional intelligence in the literature. Specifically, the authors explore the role played by emotionally intelligence in an organization's culture combined with supervisors' emotionally intelligent behaviors. The two-study research findings reveal process links between emotionally intelligent values and practices, and job demands between supervisor emotional intelligence behaviors that affect employee exhaustion and engagement. Chen Y. et al. systematic review provides deeper understanding on the relationship between pay for performance and job performance by highlighting the research studies that examine pay for performance and job performance in real work settings. The results of the systematic review complements the positive effects of pay for performance and job performance in work settings through contextual performance and task performance. In addition, the authors introduce two mediating variables namely, intrinsic motivation and pressure that integrates the positive and negative effects of pay for performance and job performance into one framework.L\u00f3pez-Cabrera et al. research study is to explore potential factors that promote job satisfaction between volunteers and regular paid staff in non-profit organizations. The research study contributes to new understandings of the mechanism that promotes greater satisfaction from volunteer workers vs. regular paid staff through role ambiguity, role conflict and job performance. Chen C. et al. research study provides new insights on positive outcomes of customer incivility that could trigger employees' customer service behavior to challenge and extend the literature stream's focus on negative outcomes and customer incivility. The authors provide a more comprehensive understanding how customer incivility influences employees' behavior and the implications for revenge behavior and customer service behavior and performance in the work environment. Uzum et al. combine crab barrel syndrome and social comparison theory as a new approach for identifying precursors of crab barrel syndrome. The authors' research study findings indicate through social comparison theory that type A personality precedes crab barrel syndrome, especially when the work environment is highly competitive. Consequently, job performance for type A personalities requires strengthening the employee's self-esteem with group support to decrease crab barrel syndrome.The aim of In conclusion, the articles in this Research Topic provide examples of new insights that we find relevant and thought provoking for progressing further research into organizational psychology scholarship from multiple perspectives.MT: Writing\u2014original draft. DT: Writing\u2014review and editing. GG: Writing\u2014review and editing."}
{"text": "Impairments in decision-making processes are believed to play an important role in both substance use disorders and behavioral addictions. Clinical and pre-clinical experimental testing provide complimentary insights on the psychobiological mechanisms of decision-making. The IOWA Gambling Task (IGT) assesses decision-making under ambiguity and risk, in which individuals are faced with four card choices associated with varying monetary reinforcer/loss contingencies. The rat Gambling Task is a pre-clinical version using palatable reinforcers as wins and timeouts mimicking losses. However, studies with interspecies comparisons in these tasks are lacking, but important to facilitate translation of information that may help unravel the complex processes of decision-making and generate clinical advances.This study explores decision-making strategies among humans and rats performing the IGT and rGT.A total of 270 young human adults performed a computerized version of the IGT, and 72 adult outbread male Lister Hooded rats performed the rGT. Performance was assessed and explored by normative scoring approaches and subgroup formations based on individual choices.Results showed that most humans and rats learned to favor the advantageous choices, but the overall level of performance differed considerably. Humans displayed both exploration and learning as the task progressed, while rats showed relatively consistent pronounced preferences for the advantageous choices throughout the task. Nevertheless, variability in individual choice preferences during end performance were evident in both species.Results are discussed in relation to procedural differences impacting performance and potential to study different aspects of decision-making. This is a first attempt to provide formal evaluation of similarities and differences regarding decision-making processes in the IGT and rGT from an explorative perspective.None Declared"}
{"text": "Brain 2022).Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder affecting 1-2% of the population worldwide. Recent large-scale whole-exome sequencing (WES) studies identified hundreds of rare, highly penetrant genetic variations associated with ASD. Many of these genetic variations underlie particular genetic syndromes characterized by a variety of congenital anomalies in addition to the core ASD symptoms. Recently, we reported about certain ultrasonography fetal anomalies (UFAs) associated with later development of ASD who have both fetal ultrasound and WES data. We used an integrative in-house bioinformatics pipeline specifically designated to identify gene-disrupting variants (GDVs) in a panel of >1200 genes associated with ASD according to SFARI gene database. Then, we compared the prevalence of GDVs in these genes between children with and without UFAs. Finally, we applied the Gene Analytics tool to disrupted genes in children with specific fetal anomalies to identify biological pathways associated with both ASD and these fetal anomalies.children with UFAs were more likely to carry GDVs in ASD genes than their counterparts even after adjustment to the sex differences between the groups , and this association was the most prominent with GDVs in the most notable ASD genes . Also, the study shows higher prevalence of children with GDVs in most anatomical systems, with UFAs in fetal size and the head&brain being the most prominent . In addition, children with UFAs had significantly more co-occurring mutations, and the number of mutations in a single fetus was significantly correlated with the number of UFAs .Overall, 115 ASD children were included in this study, of which 49 (42.6%) of them had UFAs in their ultrasound scans . Children with and without UFAs did not differ in their sociodemographic and clinical characteristics except for a significantly lower proportion of males in the UFA group . Notably, Image:Image 2:Our findings suggest distinct genetic mechanisms for ASD subtypes that are characterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing. Our findings suggest distinct genetic mechanisms for ASD subtypes that arecharacterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing.None Declared"}
{"text": "Proteome stability is critical for proper cellular functionality and consequently organismal health and it is ensured by an extensive compartment-specific network of machineries known as the proteostasis network (PN) . Key comDeclined proteasome functionality is a hallmark of aging and a major risk factor for the development of many age-related diseases such as neurodegenerative disorders and cardiomyopathies . On the Drosophila experimental in vivo model we previously reported that flies exposed to therapeutic PIs display similar adverse effects with multiple myeloma patients treated with PIs, including both neurotoxicity and cardiac dysfunction [By exploiting the function . Recentlfunction ; these mfunction . Interesfunction ). In supfunction .Taken together, our findings provide mechanistic explanations for the heart-related adverse effects of therapeutic PIs, suggesting that proteasome dysfunction in the heart results in cardiotoxicity and systemic complications due to proteome instability, mitochondria disruption, redox imbalance and metabolic deregulation. Moreover, our therapeutically relevant finding that co-administration of autophagy inducers exert beneficial effects on heart functionality, provide preclinical insights for alleviating PIs-induced cardiac adverse effects and thus preventing anti-tumor therapy discontinuation."}
{"text": "The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.We identified two patients with transthyretin (ATTR) amyloid myopathy . Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on This was particularly pronounced in ATTRwt and ATTR-Val122Ile and could be confirmed histologically as ATTR amyloid myopathy in a small subset of patients with Perugini grade 3 on 99mTc-DPD scans.7ATTR amyloid myopathy, which is characterized by intramuscular interstitial amyloid deposits leading to weakness in the upper and/or lower extremities may contribute significantly to morbidity.We herein describe two cases of ATTR amyloidosis (ATTRv and ATTRwt) with clinical, imaging, and histological evidence of ATTR amyloid myopathy, which is probably often underappreciated and underrecognized in routine clinical practice Table .Table 1C99mTc-DPD whole-body planar imaging . There was no family history of amyloidosis. The patient\u2019s medical records were remarkable for bilateral carpal tunnel syndrome ten years and decompression for lumbar vertebral stenosis two years before diagnosis of ATTRv amyloidosis. Neurological examination at the time of diagnosis of ATTRv amyloidosis in 2015 revealed fatigue, paresthesia of the feet, and loss of Achilles tendon reflexes. Dyspnea, bilateral lower leg edema, muscle cramps, mild proximal muscle weakness, upper extremity paresthesia, and numbness in the upper and lower extremities developed over the following 1.5 years. In addition to heart failure treatment, the ATTR tetramer stabilizer tafamidis was started in 2017 when this substance was first available in Austria. Three years after the initial diagnosis, the patient underwent heart transplantation due to progressive heart failure. Tafamidis, which was paused perioperatively, was restarted seven weeks thereafter. On routine follow-up 12 and 19 months after successful heart transplantation, no evidence for recurrent cardiac amyloidosis was found on endomyocardial biopsy and 99mTc-DPD planar scintigraphy showed minor abnormalities with a mixed pattern of mild neurogenic and myogenic changes.Serum creatine kinase (CK) levels were within the normal range.Figure Reticular deposits of homogeneous eosinophilic material, representing amyloid, were mainly observed in the perimysial adipose tissue. Interstitial deposition of amyloid was also found in endomysium of skeletal muscle. Interestingly, the ATTR amyloid load was greater in the surrounding adipose tissue than in skeletal muscle. Immunohistochemistry showed amyloid deposits immunoreactive for transthyretin Figure E-G.99mTc-DPD scintigraphy and cardiac magnetic resonance imaging. No pathogenic mutation could be detected and treatment with tafamidis was initiated in 2019. 99mTc-DPD whole-body planar imaging after diagnosis of ATTRwt amyloidosis showing significant ATTR amyloid deposition initially presented with bilateral lower leg edema, vertigo, numbness in the pretibial area, lower extremity muscle weakness and muscle cramps. The latter had already started 1-2 years before and was initially considered as side effect of statin use. In the absence of monoclonal proteins, diagnosis of cardiac ATTR amyloidosis was obtained by A low-grade sensorimotor axonal polyneuropathy of lower extremities was revealed in 2019. Myopathic changes in the left gluteal muscle could be detected one year later by EMG.CK levels were within the normal range.Figure Hematoxylin and eosin staining showed slight variation of fiber size and increase of endomysial connective tissue. Necrotic fibers were not seen, although few regenerating fibers were present. Single atrophic fibers were vacuolated and contained amorphous sarcoplasmic deposits suspicious of amyloid. These amorphous deposits were clearly identified as green birefringent amyloid deposits on Congo red staining and were immunoreactive for transthyretin Figure A-D.TTR gene have been described to date, characterized by a wide phenotypic heterogeneity.2 The ATTR-Val40Ile variant, which was diagnosed in patient 8 A similar course was seen in patient 99mTc-DPD planar scintigraphy 19 months after heart transplantation revealed pronounced muscular tracer uptake in the shoulder and gluteal regions in the absence of cardiac tracer uptake in the transplanted heart. At the same time the patient complained of progressive muscle weakness and muscle cramps. Biopsy from the deltoid muscle confirmed significant ATTR amyloid deposition. As there was no evidence of progression of the previously diagnosed neuropathy in the follow-up examinations, it seems likely that the patient's complaints were due to increased amyloid deposits in the peripheral muscles after heart transplantation.In ATTRv more than 140 mutations in the 9One possible explanation for the development and clinical presentation of amyloid myopathy could be that ATTRv amyloid binds to pre-existing ATTRv amyloid deposits with high affinity. Therefore, after heart transplantation and release of ATTR amyloid cardiomyopathy, ATTRv amyloid may preferably deposit on pre-existing, formerly subclinical, ATTRv amyloid deposits in skeletal muscle, causing posttransplant amyloid myopathy in our patient. Similarly, it was reported that amyloid cardiomyopathy may develop after liver transplantation in ATTRv patients, due to binding of wild-type transthyretins, produced by the transplanted liver, on pre-existing ATTRv amyloid deposits in the myocardium.7 In this study bone uptake on 99mTc-DPD scintigraphy increased over the 3 h imaging period, whereas cardiac uptake and soft-tissue uptake (mainly muscle) decreased over time. This seems to be contradictory to the Perugini grading system, which is based on the reciprocal and relative decrease in bone uptake on planar imaging. The authors postulated that bone uptake particularly in patients with Perugini grade 3 on 99mTc-DPD scans may be obscured by tracer uptake in overlying skeletal muscles. Extensive soft-tissue uptake may even obscure visualization of cardiac tracer uptake on planar imaging.7 Conversely, it is conceivable that extensive cardiac tracer uptake may obscure visualization of muscular tracer uptake. It must therefore be considered that in our patient amyloid myopathy was already present before heart transplantation but was not noticed due to this phenomenon. However, increasing muscular complaints suggest an increase in amyloid load after heart transplantation.Hutt et al reported that most patients with cardiac ATTR amyloidosis, especially ATTRwt and ATTR-Val122Ile variant showed muscular tracer uptake on bone scintigraphy.Despite clinical improvement of muscular complaints under gene silencing therapy, a scintigraphic follow-up examination in November 2021 (40 months after heart transplantation) still showed a marked increase in muscular tracer uptake in shoulder and gluteal regions. Whether prolonging the duration of therapy will ultimately result in regression of muscular amyloid deposits remains to be seen.6Patient 2 (ATTRwt) complained about lower extremity muscle weakness and muscle cramps, which already started 1-2 years before cardiac manifestation. This was primarily attributed to a side effect of statin therapy. However, it is more likely that these complaints were already due to the subsequently confirmed amyloid myopathy. This is in concurrence with previous reports indicating that amyloid myopathy may precede cardiac manifestation in ATTRwt.It must be noted that ATTR amyloid myopathy is often difficult to distinguish from neuropathy in routine clinical practice. This is particularly because symptoms attributed to amyloid myopathy, such as weakness and cramps, are similar to symptoms of neuropathy, CK levels are mostly within the normal range and changes in EMG are often not very pronounced. This is due to interstitial amyloid localisation, whereas muscle fiber necrosis and muscle fiber alterations, causing changes in CK levels and EMG, are rarely present. Consequently, ATTR amyloid myopathy is likely to be frequently overlooked or mistaken as neuropathy.99mTc-DPD scintigraphy may ultimately be the more important diagnostic screening tool for diagnosis of ATTR amyloid myopathy than biopsy in future, given the current literature.7Histologically remarkable in this case report is the pronounced amyloid deposition in the adipose tissue in both patients, especially in patient 99mTc-labeled-pyrophosphat (99mTc-PYP) was minimal when assessed by qualitative and quantitative metrics. Thus, they conclude that the properties of 99mTc-PYP may be different from 99mTc-DPD in terms of non-cardiac uptake and that 99mTc-PYP cannot be used to image extracardiac ATTR deposition.10In a previous retrospective analysis of 57 patients with cardiac ATTR amyloidosis, Sperry et al noted that skeletal muscle uptake of 99mTc-DPD scintigraphy with high accuracy. As already shown in previous studies, myopathy can precede cardiac manifestation in ATTRwt amyloidosis.6 To date, amyloid myopathy has not been reported in the ATTR-Val40Ile variant and must be recognized as an important contributor to morbidity in these patients. In concurrence with previous reports, our findings from patient 1 (ATTRv) show that neuropathy and cardiomyopathy may precede the initial manifestation of myopathy.6 Whether this also applies to other patients with the ATTR-Val40Ile variant will be subject of future studies.In summary, muscular ATTR deposits can be visualized by 99mTc-DPD scintigraphy enables non-invasive diagnosis of ATTR amyloid myopathy with high accuracy, while invasive muscular biopsy is no longer obligatory. Due to the broad availability of 99mTc-DPD scintigraphy and the emergence of novel therapeutics it is of utmost importance to increase the awareness for the frequent concomitant occurrence of ATTR amyloid cardiomyopathy and myopathy, expanding the clinical spectrum of ATTR amyloidosis.Conclusively, we think that ATTR amyloid myopathy is still underappreciated and underrecognized, because accurate diagnosis in the past seemed difficult to achieve in routine clinical practice. As shown in this case report,"}
{"text": "Emotion regulation is crucial in individuals' cognitive ability to manage and express their emotions effectively. This Research Topic delves into the neural processes and reactions associated with emotion regulation using various neurophysiological techniques, including electroencephalogram (EEG), event-related potentials (ERPs), functional magnetic resonance imaging (fMRI), and transcranial electrical stimulation (tES). Furthermore, it investigates the impact of different stimulus types, aesthetic preferences, and mindfulness practices on emotion regulation. The findings contribute to a comprehensive understanding of emotion regulation strategies and provide insights for potential therapeutic interventions.Yang et al.) has proposed distinct roles for the P100, N170, and P250 neural generators. These generators are involved in encoding comprehensive frames of reference, maintaining structural cohesion, and adapting to internal representations of emotional expressions.Within this context, EEG and event-related potentials are valuable tools for investigating the neural processes and reactions related to emotion regulation. A piece of research component was examined using the mismatch negativity (MMN) in a group of young and middle-aged adults. They employed a modified oddball paradigm to compare responses to standard tones under fearful and neutral facial expressions. The results demonstrated that when exposed to fearful facial expressions, the amplitude of the N1 in response to classic techniques was smaller than in neutral facial expressions.In a study by Additionally, the amplitude was more negative in young adults than middle-aged adults. These findings suggest that the perception of negative emotions visually facilitates the processing of auditory features and enhances acoustic change detection in middle-aged adults. However, this effect cannot compensate for the age-related decline in MMN amplitude.Jamieson et al.).Emotions are interconnected with our social interactions as we navigate the social realm by interpreting and choosing between conflicting emotional cues. The effective face-word Stroop (AFWS) is an experimental method that can help uncover the fundamental neural processes that support crucial social and emotional abilities. Regarding the timing, location, and sequence of control processes involved in responding to emotional conflicts during the AFWS, a study determined that conflict control processes occur within the components of Visually evoked potentials (\u00c5sli and \u00d8vervoll) discovered that the interaction between emotional expressions and model gender influences the magnitude of startle responses. Specifically, greater startle responses were observed when participants viewed angry faces displayed by male models and happy expressions displayed by female models. Another study investigating emotional stimuli in individuals with spinal cord injury proposed an integrated explanation for emotional conflict resolution during response activation tasks. This study emphasized the influence of emotional arousal and primed approach or avoidance motivation. Furthermore, they discussed the role of arousal in individuals with spinal cord lesions, providing insights into the typical mechanisms involved in emotional conflict control. Understanding emotional conflict control is crucial for adaptive behavior and may have implications for therapeutic interventions.On the other hand, the role of other internal variables has also been addressed. A study utilizing electromyography . Moreover, a study conducted with patients suffering from mild traumatic brain injury examined negative frontal alpha asymmetry using EEG data and found greater right-sided frontal activity than healthy controls .Focusing on the clinical population, results from a study suggested that individuals with Authentic pride (AP) demonstrated greater success in down-regulating negative emotions through cognitive reappraisal, both in daily life and experimental settings, compared to individuals with hubristic pride . The amplitudes of the N400 brain wave component were correlated with participants' level of negative affect during the pre-contemplation stage. Another study revealed that post-error adjustments varied depending on the specific task context.Cognitive appraisal and associated emotional processes were also examined in motivational interviewing augmented mindfulness, suggesting that regular physical exercise before meditation can enhance early-stage mindfulness. Neurocognitive research indicates that physical exercise (such as aerobic exercises or yoga) and mindfulness impact similar pathways involved in stress regulation and cognitive control, supporting the idea of synergistic effects between physical exercise and mindfulness. Studies focusing on the psychophysiological impact of physical exercise have shown that it can lead to short-term neurocognitive changes that facilitate cognitive control and the attainment of mindful awareness.Mindfulness is another topic covered in this context. Despite the known benefits of mindfulness for mental health, drop-out rates among mindfulness practitioners can occur due to factors such as chronic stress, cognitive reactivity, and pathology. To address this issue, K\u00fc\u00e7\u00fckta\u015f and St. Jacques, the influence of visual perspective on the emotional aspects of autobiographical memory (AM) retrieval was examined. The review concluded that the impact of visual perspective depends on the emotional nature connected to the event.Lastly, in a review conducted by By investigating the neural correlates and strategies associated with emotion regulation, this research paper aims to advance our understanding of how individuals skillfully handle and display their emotions in various contexts. The multimodal approach provides valuable insights into the underlying processes involved in emotion regulation and informs potential interventions for improving emotional wellbeing and adaptive behavior.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "Background: Nonprescription antibiotic use includes taking an antibiotic without medical guidance . Nonprescription use contributes to antimicrobial resistance, adverse drug reactions, interactions, and superinfections such as Clostridioides difficile colitis. Qualitative studies exploring perspectives regarding nonprescription use among Hispanic patients are lacking. We used the Kilbourne Framework for Advancing Health Disparities Research to identify factors influencing Hispanic patients\u2019 nonprescription use and to organize our findings. Methods: Our study includes Hispanic primary-care clinic patients with different types of health coverage in the Houston metroplex who endorsed nonprescription use in a previous quantitative survey. Semistructured interviews explored the factors promoting nonprescription use in Hispanic adults. Interviews were conducted remotely, in English or Spanish, between May 2020 and October 2021. We used inductive coding and thematic analysis to identify the factors and motives for nonprescription use. Results: Of the 35 Hispanic participants surveyed, 69% were female and between the ages of 27 and 66. All participants had some form of healthcare coverage . Participants reported obtaining antibiotics from their own leftover prescriptions and through trusted persons , buying them under the counter in US markets, and purchasing them without a prescription outside the United States. Thematic analysis revealed the factors contributing to nonprescription use . Themes included beliefs that the \u2018doctor visit was unnecessary,\u2019 \u2018limited direct access to healthcare\u2019 in the United States , \u2018more open indirect access to healthcare\u2019 abroad and under the counter in the United States, and communication difficulties . Figure 2 shows representative quotes across thematic domains. Participants expressed having confidence in medical recommendations from pharmacists and trusted community members in their social networks. Conclusions: Antibiotic stewardship interventions that include pharmacist-driven patient education regarding appropriate antibiotic use may decrease nonprescription antibiotic use in Hispanic communities. Additionally, improving access to care while addressing communication barriers and cultural competency in clinics may improve primary care delivery and reduce potentially unsafe antibiotic use.Disclosure: None"}
{"text": "Multiple myeloma generally occurs in older adults, with the clonal proliferation of plasma cells and accumulation of monoclonal protein resulting in a broad range of clinical manifestations and complications, including hypercalcemia, renal dysfunction, anaemia, and bone destruction (termed CRAB features). A 64-year-old man with no history of malignancy presented with an enlarging precordial lump occurring three years post-sternotomy for uneventful coronary artery bypass grafting surgery. Initial investigations showed anaemia and impaired renal function. Multimodal imaging performed for further evaluation showcases the radio-pathological features which can be encountered in haematological malignancy. Subsequent percutaneous biopsy confirmed an underlying plasma cell neoplasm, and a diagnosis of multiple myeloma was achieved. The prompt resolution of the lesions upon the initiation of treatment highlights the importance of early diagnosis and treatment."}
{"text": "Aedes aegypti\u2013a primary vector of dengue, Zika, and chikungunya viruses. We then validated the use of our approach to generate experimental microcosms colonized by standardized lab- and field-derived bacterial communities. Our results overall reveal minimal effects of cryopreservation on the recovery of both lab- and field-derived bacteria when directly compared with isolation from non-cryopreserved fresh material. Our results also reveal improved reproducibility of bacterial communities in replicate microcosms generated using cryopreserved stocks over fresh material. Communities in replicate microcosms further captured the majority of total bacterial diversity present in both lab- and field-based larval environments, although the relative richness of recovered taxa as compared to non-recovered taxa was substantially lower in microcosms containing field-derived bacteria. Altogether, these results provide a critical next step toward the standardization of mosquito studies to include larval rearing environments colonized by defined microbial communities. They also lay the foundation for long-term studies of mosquito-microbe interactions and the identification and manipulation of taxa with potential to reduce mosquito vectorial capacity.Mosquitoes develop in a wide range of aquatic habitats containing highly diverse and variable bacterial communities that shape both larval and adult traits, including the capacity of adult females of some mosquito species to transmit disease-causing organisms to humans. However, while most mosquito studies control for host genotype and environmental conditions, the impact of microbiota variation on phenotypic outcomes of mosquitoes is often unaccounted for. The inability to conduct reproducible intra- and inter-laboratory studies of mosquito-microbiota interactions has also greatly limited our ability to identify microbial targets for mosquito-borne disease control. Here, we developed an approach to isolate and cryopreserve bacterial communities derived from lab and field-based larval rearing environments of the yellow fever mosquito i) facilitate the study of mosquito traits of interest in the absence of confounding effects of microbiota variation, and (ii) enable reproducible intra- and inter-laboratory studies of mosquito-microbiota interactions to identify microbial targets for disease control. Our results are also of broad interest to researchers in the fields of microbial ecology and host-microbe interactions because they demonstrate how tools commonly used to study microbiota assembly and function in mammals can be leveraged in other systems.Mosquitoes develop in the presence of diverse bacterial communities that shape their ability to transmit disease-causing pathogens. However, our current understanding of mosquito-microbiota interactions is largely based on studies of individuals colonized by low-diversity communities of bacteria that are not commonly associated with mosquitoes in the laboratory or field. In this study, we developed an approach to isolate and cryopreserve microbiota from mosquito larval rearing environments in the lab and field. We then demonstrated the successful use of this approach to produce experimental microcosms colonized by standardized microbial communities. Our results are of critical significance to the field of vector biology because they will directly ( The community of bacteria (hereafter referred to as \u2018microbiota\u2019) present in the aquatic environments where mosquito larvae develop can have profound impacts on mosquito biology by modulating larval growth and development and, consequently, adult survival, reproduction, and the competency of adult female mosquitoes to transmit human pathogens (reviewed in ). HoweveAedes aegypti and Culex quinquefasciatus mosquitoes that serve as primary vectors of arboviral infections and filariasis in humans .We initially sought to develop an approach to isolate and cryopreserve microbiota from conventional larval rearing pans in the laboratory for recapitulation in experimental microcosms. Multiplex sequencing of 16S rRNA gene amplicons for the resulting rearing pan- and microcosm-derived water samples generated a total of 2,669,979 quality-filtered reads with a median sequencing depth of 44,707 reads per sample . An unusi.e., those with a maximum relative abundance \u22641% in rearing pans), with significantly fewer rare ASVs being recovered in experimental microcosms generated using cryopreserved stocks of lower cell densities , even at 5 days post-incubation between any of the microcosms we generated of reads from these samples were assigned to ASVs belonging to one of eight bacterial families within the following phyla/classes: Alphaproteobacteria , Betaproteobacteria (Comamonadaceae), Gammaproteobacteria , and Bacteroidetes . A totalcubation . Howeverenerated .4, 105) . Differences in beta diversity, measured as average Bray-Curtis dissimilarity, were also overall higher between rearing pans and unprocessed controls than between rearing pans and experimental microcosms generated using material from cryopreserved stocks, regardless of cell density . Further= 0.001) , post-ho density .i.e., decreased in abundance) in response to cryopreservation .Finally, we performed ALDEx2 tests to identify rearing pan ASVs that significantly changed in relative abundance in response to cryopreservation and/or re-culturing under conventional mosquito rearing conditions Figs and S4. ion Figs and S4. Next we sought to validate the use of cryopreservation approaches developed above to generate experimental microcosms colonized by microbiota derived from a naturally occurring mosquito larval habitat in the field. Multiplex sequencing of 16S rRNA gene amplicons for the resulting habitat- and microcosm-derived water samples generated a total of 2,111,045 quality-filtered reads with a median sequencing depth of 43,541 reads per sample , with raP = 0.426).As expected, we identified a substantially higher diversity of bacteria (993 ASVs) across the field-derived water samples as compared to those derived from conventional larval rearing pans in the laboratory, with ~42% of reads being assigned to ASVs belonging to the eight bacterial families dominating communities in rearing pans and the remaining ~58% being assigned to ASVs belonging to one of 306 other families within 187 bacterial orders and 34 phyla/classes . A substP > 0.05).ALDEx2 tests identified a total of 110 of the 993 ASVs found in the habitat water samples we sequenced showing significantly different relative abundances in experimental microcosms, but only 12 of these ASVs, representing <6% of all habitat water sequences, were specifically negatively affected in response to cryopreservation Figs and S7. While our isolation and cryopreservation approaches resulted in the loss of some lab- and field-derived bacterial taxa and concurrent changes in the total alpha and beta diversity of microbiota within experimental microcosms as compared to the larval rearing pans and habitat water we originally sampled, we observed little variation among the bacterial communities present within replicate microcosms generated using the same cryopreserved stock, with the only exceptions being those generated using stocks of lower cell densities . On averMosquitoes live in close association with bacteria and other microorganisms that shape their ability to transmit pathogens . Howeveri) decouple the effects of sample processing and the cell density of cryopreserved stocks on the recovery and persistence of bacteria in microcosms from those of larvae, which are known to shape water pH, nutrient levels, and even bacterial metabolism [ii) better reflect natural microbiota exposure and acquisition processes in the field, whereby larvae hatch from eggs laid directly into (or adjacent to) water containing established bacterial communities [Ae. aegypti revealed a bacterial community comprised of ~100 unique bacterial taxa and dominated by members of the Proteobacteria, Bacteroidetes, and Firmicutes, consistent with sequencing studies of other laboratory colonies of mosquitoes [Paenarthrobacter, which were significantly reduced or absent in experimental microcosms and may represent taxa that are not readily amenable to centrifugation and/or cryopreservation using our methodology.In this study, we first developed an approach to isolate and cryopreserve microbiota from conventional larval rearing pans in the laboratory for recapitulation in experimental microcosms. We intentionally conducted our experiments in the absence of any larvae in order to: detected in laboratory rearing pans and commonly detected in field-collected mosquitoes \u201349,60\u201365The cell density of cryopreserved stocks also had a much larger impact on the recovery and persistence of field-derived taxa, with microcosms generated using stocks of lower cell densities exhibiting more variable bacterial communities that were overall lower in complexity that communities in microcosms generated using stocks of higher cell densities. This is consistent with results showing that small sampling volumes from aquatic and other high-complexity environments like soil often fail to adequately capture bacterial diversity \u201377, owine.g., immediately after a rainfall). Defined diets that support mosquito growth and development could also be developed to improve the reproducibility of field bacterial diversity between replicate microcosms, including the maintenance of rare taxa important for community assembly and stability [Overall, experimental microcosms generated using cryopreserved stocks containing lab-derived microbiota exhibited levels of reproducibility that were the same or better than those present under conventional rearing conditions in the laboratory, highlighting the value of our approach for intra-and inter-lab studies of mosquitoes in the presence of standardized microbial communities. Similar levels of reproducibility could also be replicated in microcosms generated using cryopreserved stocks of field-derived microbiota, although reproducibility significantly decreased with decreasing inoculum size\u2013consistent with our previous observation that variability among the bacterial communities present within replicate microcosms was significantly higher in those generated using cryopreserved stocks of lower cell densities. Future studies are warranted to establish best practices for field habitat sampling, though our results at minimum suggest that higher-volume samples are preferable, and that sampling should be avoided in situations where bacterial density is expected to be low . Unmodified bacteria that naturally inhibit pathogen colonization or mosquito fitness could also be disseminated to mosquito populations. The identification of suitable microbial candidates for pathogen or mosquito control will require a comprehensive understanding of the factors that influence the acquisition, maintenance, and transmission of mosquito microbiota and the mechanisms that underlie how individual microbial species and assemblages impact mosquito vectorial capacity. However, the dearth of tools to manipulate mosquito microbiota, including microbiota derived from naturally occurring mosquito habitats in the field, has greatly slowed progress in this area. In this way, the results reported here not only provide a critical first step toward the standardization of microbial inputs in mosquito studies, but also provide a critical first step toward the identification of taxonomic and functional profiles of bacteria associated with phenotypic traits of interest in mosquitoes. For example, a defined microbiota could be universally adopted by the community to conduct vector competence assays in the absence of confounding effects due to microbiota variation. Libraries of cryopreserved microbiota could also be screened to identify bacteria that improve or reduce mosquito fitness and/or pathogen susceptibility, or to predict the success of individual microbial candidates under variable microbial conditions. Similarly, the results reported here strongly support that our methods could immediately be leveraged to expand studies of mosquito-microbiota interactions to include microbial genotypes derived from the field, and thereby conduct lab-based mosquito experiments with field-relevant microbiota.Owing to their ability to impact numerous components of mosquito vectorial capacity, there is a growing interest in exploiting microbes for mosquito-borne disease control. For example, bacteria that naturally colonize the mosquito gut could be genetically modified to produce effector molecules that alter the mosquito\u2019s ability to become infected with and transmit pathogens, or that reduce mosquito fecundity or lifespan (S1 TableAsterisks (*) indicate samples that were removed from the dataset prior to downstream analyses.(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 FigReads from each water library were sampled starting at 1 sequence per step and increased in increments of 100 until the total number of reads per sample was reached. Lines are colored by sample source . Time of sampling of experimental microcosms is designated by line type .(TIF)Click here for additional data file.S2 FigP < 0.05).Proportion of rare (left) and abundant (right) ASVs found in at least one larval rearing pan that were detected in experimental microcosms containing unprocessed water or sterile water plus material from a given cryopreserved stock. An ASV was considered \u201crare\u201d if it had a maximum relative abundance \u22641% across the four larval rearing pans we sampled, while ASVs with a minimum relative abundance >1% were considered \u201cabundant\u201d. Asterisks (*) indicate significant differences between experimental microcosms generated using cryopreserved stocks relative to unprocessed controls as determined by paired Fisher\u2019s exact tests with Bonferroni correction ((TIF)Click here for additional data file.S3 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in samples from larval rearing pans. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across rearing pan samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing unprocessed water and experimental microcosms containing sterile water plus material from cryopreserved stocks see .(TIF)Click here for additional data file.S4 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in samples from larval rearing pans. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across rearing pan samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing sterile water plus material from cryopreserved stocks and experimental microcosms containing unprocessed water see .(TIF)Click here for additional data file.S5 FigReads from each water library were sampled starting at 1 sequence per step and increased in increments of 100 until the total number of reads per sample was reached. Lines are colored by sample source . Time of sampling of experimental microcosms is designated by line type .(TIF)Click here for additional data file.S6 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in habitat water samples. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across habitat water samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing unprocessed habitat water and experimental microcosms containing sterile water plus material from cryopreserved stocks see .(TIF)Click here for additional data file.S7 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in habitat water samples. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across habitat water samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing sterile water plus material from cryopreserved stocks and experimental microcosms containing unprocessed water see .(TIF)Click here for additional data file."}
{"text": "Simulation is a key component of surgical training, enabling trainees to develop their skills in a safe environment. With simulators broadly grouped into physical models and virtual-reality (VR) simulators, it is important to evaluate the comparative effectiveness of the simulator types in terms of validity as well as cost. The review aims to compare the benefits and drawbacks of novel VR and physical simulators within the broader themes of endourology, laparoscopic and robotic operations, and other urological procedures.Key benefits of bench models include their comparatively lower cost, easy access and provision of haptic feedback, whereas VR simulators are generally self-sufficient, reusable and enable skills of haemostasis to be practised. The advent of perfused 3D printed simulators across a range of urological procedures may replace cadavers as the traditional gold-standard simulation modality.Although possessing differing strengths and downsides, VR and physical simulators when used together can have an additive effect due to skill transferability across the platforms. Further comparative studies are required to directly quantify the differences between physical models and VR simulators in terms of performance metrics and cost-effectiveness. There is lack of validated VR simulators for open and reconstructive procedures. Simulation is an integral part of surgical training enabling trainees to hone their technical skills away from actual patients until they achieve a safe level of competency . This isEndourological procedures include ureteroscopy, cystoscopy and transurethral resections of the bladder and prostate. The SIMULATE international prospective trial examined3D model simulators have been recently developed in the field of cystoscopy such as the \u2018FlexBlad\u2019 and \u2018Bla\u25aa\u25aa] examining simulation training in transurethral resection and laser vaporisation procedures of the prostate. The review findings pointed towards VR simulators uniquely possessing data capture and performance evaluation features but that alongside their typically poor haptic feedback, their simulation of bleeding is generally poor for TURP and laser vaporisation. Physical simulators such as bench-top tissue and food-based models also inadequately simulate bleeding for these procedures and carry hygiene risks, but are lower cost and beneficial in that they use real instruments. In the context of laser-based procedures, cadavers demonstrate content validity for holmium laser AEEP training [The European Section of Uro-Technology (ESUT) undertook a systematic review \u25aa\u25aa examintraining with suptraining , VR simutraining \u25aa,16 and PCNL is another endourological procedure for which simulators have been validated. One study used participant ratings and performance data to compare three simulators ; a porciAlthough cadavers are considered the gold-standard simulation modality, artificial perfusion of cadavers is limited by high cost, positive viral profiles and difficulty clearing the vascular tree. One low-cost, nonbiohazardous physical model for robot-assisted partial nephrectomy (RAPN) directlyLive animal models such as porcine models pose ethical challenges not associated with other simulators. One study aimed toVR simulation performance for robot-assisted radical prostatectomy (RARP) has crucially been shown to correlate with live surgical performance in the real operative environment thereby increasing its validity as a training modality. One study of 20 suWith VR, simulation is moving beyond just basic isolated skills training to full procedural simulation. This has been demonstrated for RARP with supFor laparoscopic pyeloplasty, various physical simulators exist with advantages over VR simulators such as significantly lower cost and easy access whilst maintaining anatomical realism. As with aforementioned procedures, 3D printed models for pyeloplasty have been produced demonstrFor the management of urological emergencies such as priapism and testicular torsion, there is an absence of validated VR simulators to develop the skills necessary for the therapeutic interventions these conditions require. There is therefore a reliance on physical simulators to facilitate skill acquisition and these have been incorporated effectively into training curricula. For example, a urological emergency simulation curriculum was devised for military surgeons utilisinFor penile fracture repair, the first validated simulation model was recently created , based oReconstructive urology is another field in which validated VR training is absent. Instead high-fidelity, 3D-printed penile models have been produced for the simulation of plaque incision and graft (PIG) as indicated for the treatment of Peyronie's disease , achieviTo conclude, physical models are generally superior with regard to cost-effectiveness, the provision of haptic feedback and ease of access, while VR simulators are self-sufficient, reusable and avoid the ethical and infection concerns associated with animal models. Although cadavers have long been considered the gold-standard simulation modality, these may soon be superseded by the advent of highly realistic, perfused 3D printed models capable of procedural simulation incorporating anatomical variation and intraoperative complications at a subThe authors received no source of funding and have no conflicts of interest.None.Baldev Chahal, Abdullatif Aydin and Kamran Ahmed have no conflicts of interest or financial ties to disclose."}
{"text": "Watermelon stomach, also known as gastric antral vascular ectasia (GAVE), is a rarely seen cause of acute upper gastrointestinal bleeding or chronic iron deficient anemia, revealed when gastroscopy is performed. GAVE affects predominantly women of advanced aged and is usually associated with certain underlying co-morbidities including liver cirrhosis, autoimmune diseases and chronic kidney disease. Based on the above, we report the case of a 75-year-old woman under hemodialysis for six consecutive years due to end-stage renal disease attributable to hypertensive nephrosclerosis. The patient also suffered from chronic ischemic heart disease, severe peripheral artery disease and an unidentified connective tissue-disease characterized by high levels of anti-nuclear antibodies and clinical symptoms restrained in flares of non-erosive polyarthritis. Six months prior, she developed hyporesponsiveness to recombinant human erythropoietin (rEPO) due to iron deficiency despite the administration of the appropriate dose of intravenous iron as well as the exclusion of other co-existing causes of resistance, namely inadequate hemodialysis, inflammation, malnutrition, severe hyperparathyroidism and underlying hematologic disorders. Surprisingly, the patient experienced a sudden episode of severe upper gastrointestinal bleeding characterized by hemodynamic instability, hemoglobin fall and melena that required blood transfusions. Once hemodynamic stabilization was achieved, an upper endoscopic exam was performed showing the pathognomonic extensive vascular ectasias and patchy erythematosus lesions at the distal antrum. Thus, GAVE should be considered in the differential diagnosis of chronic kidney disease patients who present not only with acute blood loss but also with resistance to rEPO due to inadequate iron stores."}
{"text": "Many cattle and sheep do not produce enough colostrum for their offspring.Prepartum nutrient intake is an accessible strategy for producers to influence colostrum production.Greater prepartum starch intake can influence colostrum composition and increase colostrum yield for beef cattle and ewes.Colostrogenesis is sensitive to fat intake, dependent on the dietary fatty acid composition: greater linoleic acid intake often increases colostrum antibody concentration.Colostral bioactive compounds are frequently altered by a prepartum diet without changes in overall colostrum composition. Prepartum nutrient intake could be strategically used to maximize beneficial compounds for the newborn.IgG), macronutrients, and bioactive compounds that promote physiological maturation and support the immune system or protein (MP) intake, or dietary components such as starch, neutral detergent fiber (NDF), or fat.Most research evaluating how prepartum nutrient intake affects colostrum production has mainly focused on global nutrient under- or over-provision prior to parturition. Imposing mid to late-gestation nutrient restriction reduced first-milking colostrum yield in beef cattle without NE]). This is additionally complicated by using either empirical or mechanistic models to predict energy requirements and dietary sufficiency and which coefficients of energetic efficiency are used for the conversion of ME to NE for pregnancy or maintenance. Thus, utilization of either system can impose a bias on colostrum production responses between studies. Research evaluating carbohydrate consumption prior to parturition is shown in Carbohydrates proportionally contribute the greatest amount of dietary energy in ruminant rations and, as such, relative starch and NDF substitutions have consequences for dietary energy intake that often confound colostrum production responses. Furthermore, studies that manipulate dietary starch and NDF content to achieve specific energy intakes differ in which energy partition they target and MP intake not always being balanced across treatments increased colostrum yield by 80% in Simmental-Angus crossbred beef cattle . These cIn accordance with beef cattle, increasing dietary starch and energy intake in sheep consistently increased colostrum yield . Bancher1 and total IgG concentrations in colostrum ; thus, this factor should be considered when comparing colostral IgG concentrations between studies using different dietary starch sources. Nonetheless, IgG concentration in first-milking colostrum collected within 1 to 12 h after calving has been reduced by greater dietary starch inclusion or ME intake precalving while suppressing the synthesis of de novo FA relative to cows fed a ration that targets 125% or 150% predicted ME requirements prior to calving are substantial but transient and, as such, presumed negligible relative to pregnancy and maintenance requirements. Regardless, numerous studies .Models that evaluate the sufficiency of prepartum shown in have evashown in and 2. Wiso-nitrogenous and iso-energetic rations; Apart from substituting sunflower meal for cottonseed meal as a protein source wherein the authors observed that greater sunflower meal increases first-milking colostrum yield increases colostrum yield . HoweverAs with colostrum yield, colostrum IgG concentration, as measured by radial immunodiffusion or estimThere are limited data regarding how prepartum protein intake affects colostrum macronutrient composition and yield in cattle. That said, from what is available, colostral fat, protein, and lactose concentrations are unaffected , nor areComparatively, colostrum protein concentration has been reported to increase with protein supplementation in some studies with ewes , but notRations typically have 2%DM dietary fat and, generally, dietary fat should not exceed 6% to 7%DM to avoid detrimental impacts on ruminal fermentation. However, greater dietary fat provision can also improve ration palatability, control dust and fines, and alleviate heat stress due to its lesser heat increment respective to proteins and carbohydrates. Increasing prepartum dietary fat intake can concurrently increase energy intake without providing excessive dietary starch. Consequently, prepartum fat intake may have utility for prepartum rations and studies in cattle and ewesLate-gestation fat inclusion rate and source have not been shown to affect first-milking colostrum production in dairy cattle, either when NE concentration was maintained or when \u0251-linolenic) in late-gestation rations could be beneficial for increasing ewe colostrum yield. Currently, it is unclear why this response occurs.First-milking colostrum yield in ewes appears to be more responsive to dietary fat content than cattle, but results across studies remain inconsistent. Some authors have found that specific fat sources can decrease first-milking half-udder colostrum yield collected within an hour and betwInterestingly, colostral IgG concentration, as measured by ELISA or estimated using Brix, appears to be responsive to dietary fat inclusion and source in both dairy and beefAlthough fewer data are available for ewes, their colostral IgG concentration does not appear to respond to fat intake and source as in cattle . Though,Colostral macronutrient concentrations are usually unaltered by dietary fat content and source for cattle . NotablyThe colostral FA profile is the most reported bioactive component among research evaluating prepartum dietary fat intake and source. For both cattle and sheep, colostrum FA composition ubiquitously varies across all reported studies when the dietary fat inclusion rate or source is altered in such a way that coincides with dietary FA intake and maternal plasma FA profile. With respect to other bioactive components and micronutrients, Prepartum nutrient intake has the capacity to influence colostrogenesis in bovine and ovine species and impact colostrum yield and composition. Although ewes are generally more sensitive to ration composition than cattle, there is evidence to suggest that prepartum nutrition can be used strategically to promote colostrum production in both species. Dietary starch and fat content and source appear to exert influence on colostrum IgG concentration, with data indicating that starch:NDF substitutions affects colostrum yield in beef but not dairy cattle. Current data suggest that cattle are irresponsive to dietary protein content, whereas ewe colostrum production responds to dietary protein source and intake. Further work needs to differentiate between carbohydrate, protein, and fat sources, accounting for total IgG and macronutrient yield, to characterize mammogenic capacity under differing nutritional regimens, particularly in relation to the feeding duration and timing of supplementation relative to the onset of colostrogenesis. In addition, there is a need to detail the colostral bioactive profiles, as this constituent often responds to prepartum nutrient intake without changes in the gross composition of colostrum. Colostral bioactive components are inherently important for neonatal development and, as such, prepartum nutrient intake might be used strategically to benefit the offspring."}
{"text": "Psychiatric disorders are complex clinical conditions with large heterogeneity and overlap in symptoms, genetic liability and brain imaging abnormalities. Building on a dimensional conceptualization of mental health, previous studies have reported genetic overlap between psychiatric disorders and population-level mental health, and between psychiatric disorders and brain functional connectivity. Here, in 30,701 participants aged 45\u201382 from the UK Biobank we map the genetic associations between self-reported mental health and resting-state fMRI-based measures of brain network function. Multivariate Omnibus Statistical Test revealed 10 genetic loci associated with population-level mental symptoms. Next, conjunctional FDR identified 23 shared genetic variants between these symptom profiles and fMRI-based brain network measures. Functional annotation implicated genes involved in brain structure and function, in particular related to synaptic processes such as axonal growth (e.g. NGFR and RHOA). These findings provide further genetic evidence of an association between brain function and mental health traits in the population.The online version contains supplementary material available at 10.1186/s12888-023-04905-7. Psychiatric disorders are complex, with a polygenic architecture, and large degree of overlapping symptoms and risk factors. Both imaging and genetics studies have shown numerous but small associations between brain phenotypes, psychiatric disorders, and genetics, such as schizophrenia (SCZ) \u20133, bipolWe have recently deployed a multivariate analysis to study the genetic architecture of brain functional connectivity, revealing genetic variants associated with functional brain connectivity as well as variance in brain activity over time . The resPrevious studies have shown widespread phenotypic and genetic overlap between psychiatric disorders \u201318. In aHere, we aimed to uncover the genetic architecture of mental symptoms and identify shared genetic loci with neurobiological processes related to brain function. Using multivariate analysis , we geneWe utilized data from the UK Biobank with perThe processing pipeline for imaging data used for the multivariate GWAS is described in Roelfs et al. . In shorIn this study we applied MOSTest to the phenotypic data from the ICA decomposition described in Roelfs et al. . MOSTestIn order to quantify the degree of genetic overlap and identify shared genetic loci between the mental health profiles and the imaging features we deployed the pleiotropy-informed conjunctional false discovery rate (conjFDR) through the pleioFDR toolbox . We usedADH1B and ADH5 (chromosome 4) and CRHR1 (chromosome 17).MOSTest revealed 10 significant (P\u2009<\u20095e-8) loci across the 13 previously identified profiles of mental health , bipolarNext, we explored the genetic overlap between the mental health profiles and the psychiatric disorders through the conjunctional false discovery rate (conjFDR) , 36 whicWe then calculated the number of shared genetic loci between the multivariate genome-wide association statistics for mental health profiles and the two multivariate measures of the brain functional connectome using conjFDR. The GWAS summary statistics from our previous study of brain function . In shorIn this study we identified a number of loci associated with multivariate genome-wide association statistics for mental health profiles and found overlapping loci with the measures of brain function and psychiatric disorders. Using MOSTest we were able to leverage the phenotypic overlap between different mental health profiles to identify new loci associated with a multivariate measure of mental health. Genes associated with these loci showed regional expression in different parts of the brain .Our analysis using conjFDR revealed a number of shared loci and genes between the multivariate genome-wide association statistics and the psychiatric disorders. This demonstrates the shared genetics between psychiatric symptoms regardless of clinical diagnosis, emphasizes the utility of using population-level phenotypes to investigate variance in mental health profiles, and highlights the advantage in leveraging pleiotropy between complex phenotypes to boost discovery. We found shared genes with all but two case-control GWAS , which also had the two smallest sample sizes, which may reflect insufficient power to detect an effect , or may We also identified a number of overlapping loci between mental health profiles and fMRI measures of brain function, including 18 shared loci with functional connectivity and 5 shared loci with node variance. The higher number of shared loci for functional connectivity might be partially explained by the number of phenotypes in each composite measure. While the functional connectivity GWAS comprises 210 measures, i.e. partial correlations between 21 brain nodes, the node variance GWAS encompasses only the temporal variance in each node. It is possible that the number of phenotypes included in the multivariate analysis can affect the discovery . Both thThe two conjunctional analyses with fMRI measures and the multivariate genome-wide association statistics for mental health each showed a number of overlapping loci. Not all shared loci were unique, this can be partially explained by the definition of the brain networks in our analyses. The functional connectivity and the node variance measures use the same 21 nodes, and, ultimately, the two measures reflect different properties of the same time series. We found that the number of overlapping loci between the multivariate genome-wide association statistics for mental health and the brain functional connectome was generally larger than findings from our previous study highlighting shared genetic loci between psychiatric disorders and the brain functional connectome. This may partly be due to the larger sample size of the multivariate measure of mental health, but it could also reflect that the multivariate genome-wide association statistics capture genetic variance more generally related to the brain functional connectome. We found little direct overlap between loci of these two GWAS\u2019 separately, which highlights the discovery boost advantage of using conjFDR in phenotypes with generally low heritability.The main implication from our findings is that we can identify shared genetic variants between a multifactorial measure of mental health in an undiagnosed population sample and fMRI-based measures of brain functional connectivity. Several limitations should be considered. First, the data were obtained from a middle-aged and older White British population, which limits the generalizability of the findings. Further, the mental health questionnaires are self-administered, so the data is vulnerable to various response and self-selection biases . We exclIn conclusion, our multivariate GWAS on 13 mental health symptom profiles showed a number of shared genetic loci with two fMRI-measures reflecting brain function and connectivity. This research shows that genetic overlap between mental health symptom profiles and brain functional connectivity can be linked to, among other processes, axonal growth regulation (through NGFR and RHOA) and regulation of MECP2 transcription factors (through MEF2C). This provides further genetic evidence of an association between brain function and mental health traits in the population.Below is the link to the electronic supplementary material.Supplementary Material 1: Supplementary Figures and Tables"}
{"text": "Editorial on the Research TopicMolecular pathogenesis and novel treatments for inherited cardiomyopathiesInherited cardiomyopathies have diverse genetic etiologies, but together are major contributors to cardiac disease that affect patients of all ages, typically with early onset in childhood or adolescence. While inherited cardiomyopathies are currently classified according to functional and morphologic features, finer resolution of these categories has been made possible with the aid of modern genetics. However, despite the identification of many disease-causing variants, effective therapies for the majority of inherited cardiomyopathies remains scarce. In this issue, a collection of original research and review articles unveil and summarize the pathogenic mechanisms and gene expression signatures of various inherited cardiomyopathies as well as novel and extant therapeutic strategies in treating selected subsets of inherited cardiomyopathies.Hilal et al. which discusses in detail how mutations in RAS genes underlie phenotypically diverse cardiomyopathies in addition to distinct systemic syndromology. Notably, one must cautiously distinguish cardiomyocyte-intrinsic from extrinsic effects of RAS hyperactivation. While several in vitro studies demonstrated that ectopic RAS activation results in cardiomyocyte hypertrophy, cardiomyocyte-specific expression of gain-of-function RAS variants did not result in HCM despite cardiomyocyte hypertrophy seen in neonatal mice carrying the same germline mutation in the RAS gene , represents a major co-morbidity of genetic hemochromatosis as well as secondary iron overload. A recent clinical trial demonstrated that amlodipine and chelation combination therapy significantly lowers intracardiomyocyte iron deposition. Mechanistically, amlodipine appears to block the L-type calcium channel, which otherwise provides a major route for iron entry into the cardiomyocyte. Over the past decades, the identification of genes in which pathogenic variants are associated with inherited cardiomyopathies has raised expectations for new therapies. Advances in genomic editing technology hold promise for directly targeting pathogenic variants, and have the potential for shifting the paradigm for treatment in genetic medicine. Other approaches harnessing natural genetic modifying mechanisms that suppress the penetrance of pathogenic variants may also be useful. While the incomplete penetrance of inherited cardiomyopathies often complicates the genetic evaluations of families with cardiomyopathies, the observation that many mutation carriers remain disease free in fact provides paradoxical hope that disease-modifying therapeutics may be achievable. Future omics studies comparing transcriptome and proteome between clinically active and silent mutation carriers may thus uncover novel therapeutic approaches to delaying disease onset. In parallel, development of additional genetic animal models that approximate human cardiomyopathies will enable rigorous mechanistic studies that potentiate development of therapeutic agents."}
{"text": "Structural valve deterioration is commonly defined as an intrinsic permanent change of the bioprosthesis due to leaflet calcification, thickening, pannus formation, tear, or disruption. The resulting deterioration leads to stenosis and/or intra-prosthetic regurgitation. Here we present the case of a 75-year-old patient who underwent aortic valve replacement with a bioprosthetic valve. Predischarge transthoracic echocardiography revealed an aortic prosthesis with normal gradients. Three years later, the patient reported exertional dyspnea. Transthoracic echocardiography was performed and showed a high transvalvular pressure gradient of 80 mmhg with restricted mobility of the leaflet caused by subprosthetic tissue. Redo aortic valve replacement was planned and surgical resection was performed showing pannus ingrowth in both aortic and ventricular side of the bioprosthesis."}
{"text": "We also do not understand how suicide and suicidal ideation changed for different Hispanic immigrant populations since 2015, coinciding with a rise in anti-immigrant political sentiment and policymaking. Without action to either improve public health surveillance or leverage existing data sources with immigration status information to better understand the burden of suicide death and suicide risks among Hispanic immigrants, we may fail to prevent unnecessary loss of life.,,Anti-immigrant attitudes are not a new phenomenon in the U.S.,A key example of these policies was the administration's highly publicized public charge rule changes, which built upon the public charge standard developed through the Illegal Immigration Reform and Immigrant Responsibility Act.,Unfavorable immigration policy has been linked to greater perceived health problems among adults and children.,Despite these risks, deportation fears and the chilling effects of anti-immigrant attitudes and policies likely discouraged enrollment into health insurance programs ,Avoiding care while facing discrimination or psychological trauma can be problematic for suicide prevention. Discrimination is a risk factor for mental health problems among Hispanic persons.In response, public health researchers have an opportunity to increase their understanding of the burden of suicide among Hispanic immigrant populations in relation to the rise of anti-immigrant sentiment. This remains a challenging task when national mental health and suicide statistics do not take immigration status into account, when commonly available data sources restrict access to information about visa status, and when data from the Centers for Disease Control and Prevention do not distinguish between immigrants and U.S.-born Hispanics.Many researchers have attempted to account for immigration status in their studies\u2015cutting across multiple disciplines\u2015although these attempts have been discordant, resulting in different definitions and experiences of unauthorized legal status.Specific actions can be taken while being mindful of stigma-related implementation concerns. First, rather than actively seeking information from Hispanic immigrants, we can prioritize efforts to report deceased immigrants\u2019 citizenship status on either the U.S. Standard Certificate of Death or equivalent state-level forms. Specifically, citizenship status, available by contacting Citizenship and Immigration Services, could feasibly be collected by the medical certifier or funeral director when collecting demographic data required for the death certificate. This information would then be reported into state violent death report systems, which already aggregate deidentified information on country of birth and other sensitive characteristics for suicide decedents.Second, additional initiatives could include collecting citizenship information for immigrants participating in large health surveys. Previous studies suggest that unauthorized immigrants are interested in and willing to discuss legal status in research. To ease the impact of the deportation-related concerns on unauthorized immigrant participation, surveyors should build rapport before presenting legal status questionsThird, the research community can use existing data in creative ways to better understand suicide-related risks experienced by Hispanic immigrants. Data sources collecting citizenship or country of birth information, such as the National Health Interview Survey or Hispanic Community Health/Study of Latinos, respectively, can be used to estimate the relationships between immigration status and important suicide risk factors for Hispanic populations since 2015. Existing data sources can also give us guidance on how to estimate the impact of recent immigration policies on suicide risk factors such as mental health outcomes.We do not fully understand the burden of suicide or recent changes in suicidal ideation among Hispanic immigrant populations in the U.S. However, we hypothesize that increasingly acrimonious immigration attitudes and policies likely worsened suicide-related outcomes for many Hispanic immigrants, authorized and unauthorized. The coronavirus disease 2019 (COVID-19) pandemic is likely intensifying suicide-related risks, given the harmful impacts the pandemic has imposed on Hispanic communities."}
{"text": "The United States Department of Health and Human Services (HHS) pledged $90 million to help reduce health disparities with data-driven solutions. The funds are being distributed to 1400 community health centers, serving over 30 million Americans. Given these developments, our piece examines the reasons behind the delayed adoption of big data for healthcare equity, recent efforts embracing big data tools, and methods to maximize potential without overburdening physicians. We additionally propose a public database for anonymized patient data, introducing diverse metrics and equitable data collection strategies, providing valuable insights for policymakers and health systems to better serve communities. This sum is planned to be distributed to 1400 community health centers (CHCs) serving over 30 million Americans1. Specifically, this pledge will allow health centers to expand analytics and reporting capabilities to enhance healthcare services while supporting patient-level UDS+ data submissions to collect more precise data on health disparities2. We herein propose a national public database featuring voluntarily self-disclosed and deidentified patient data to increase the granularity of health disparities metrics, and propose how this project can incorporate diverse metrics and equitable data collection procedures.In April 2022, Health and Human Services (HHS) pledged 90 million USD to the American Rescue Plan Uniform Data System Patient-Level Submission (ARP-UDS+) funding award in support of new data-driven efforts for Health Resources and Services Administration (HRSA) Health Center Programs to identify and reduce health disparities3. The NHQR is a comprehensive review of American healthcare comparing health outcomes across both state and national levels4. This report revealed that, although communities of color have enjoyed increased healthcare access since 2000, racial inequity persisted in 2021 due to lack of focused interventions addressing disparities3. While CHCs disproportionately serve marginalized populations, their lack of granular data collection is likely leading to underestimations of health disparities in areas requiring the greatest resource support4.Big data has already been proposed to promote health equity at the federal level. For instance, in 2021, the Agency for Healthcare Research and Quality (AHRQ) released the National Healthcare Quality and Disparities Report (NHQR)4. For instance, the Community Health Needs Assessment (CHNA) in the Patient Protection and Affordable Care Act (ACA) requires CHCs to investigate the biggest health-related challenges in their communities and outline solutions5. However, CHNAs often lack subjective data like medical trust and are only collected periodically, producing an unnecessary lag time between when systemic health issues arise and when healthcare providers can identify and respond to them.Big data has impacted patient care for decades by helping health insurance companies incentivize preventative care among patients and physicians, ultimately decreasing the use of costly acute care and improving care equity4. This platform can also be used to monitor medications while empowering CHCs to pinpoint and respond to systemic issues more quickly. Although the database may be skewed towards higher-income individuals with more time to self-report, the resource can help compare assess healthcare quality without overburdening physicians, ultimately improving equity interventions.Given these challenges with current healthcare metrics, the Centers for Medicare and Medicaid Services (CMS) should develop a national database like the CDC\u2019s Vaccine Adverse Event Reporting System (VAERS), which collects self-reported issues with vaccine reactions, to regularly collect self-reported data on symptoms, diseases, adverse reactions, medical trust, and perceptions of health equity through metrics like transportation time or food insecurity6. These metrics were only introduced to eight of these measurements, and that only in 20226. HEDIS also does not stratify metrics by other determinants of health like food insecurity or employment status6. Metrics for further development could also include language access, transportation barriers, and health literacy.Although the data would be self-reported, the requested data should include many new metrics. For instance, the National Committee for Quality Assurance (NCQA) Healthcare Effectiveness Data and Information Set (HEDIS), the basis for many equity measurement systems, HEDIS was inaugurated in 1991 and continued for 31 years without race or ethnicity included in its nearly one hundred performance measures7. CHCs can also assess the readability of patient education materials and track the effectiveness of health literacy interventions like counseling, visual aids, staff training on health literacy communication, and simplified language in educational pamphlets through validated health literacy screening tools like REALM-SF (Rapid Estimate of Adult Literacy in Medicine - Short Form)8. REALM-SF examines abilities to read aloud medical terminology and is available free for download on the National Center for Education Statistics (NCES) website9.Healthcare organizations can better understand language barriers by offering patient surveys after each visit. Depending on the extent of the issue, Community Health Centers (CHCs) can then adopt interpreter services and track its effectiveness through surveys. To address transportation barriers, patients can opt to disclose transportation service use and reasons for missed appointments. CHCs can then partner with transportation providers like Uber WAV (Wheelchair Accessible Vehicles) and Uber Health to improve patient accessibility and cover for deficiencies in available wheelchair-accessible vehicles11.To ensure that the system captures data from marginalized populations, we propose CHCs invest in technology infrastructure and staff training to prepare for more comprehensive data collection by, for instance, leveraging telehealth services to provide care management while streamlining data collection through remote patient monitoring and automated post-checkup surveys. Then, outside partnerships with research organizations can help CHCs analyze this data and devise tailored solutions through partnerships with relevant nonprofits like the National Partnership for Women and Families, which has developed best practices for patient engagement in healthcare, and Leapfrog, which helps analyze data to promote healthcare safety and qualityFurthermore, to promote interoperability with electronic health records, we suggest following the technical standards developed by organizations such as the Office of the National Coordinator for Health Information Technology (ONC) and the Health Level Seven International (HL7) organization. These standards ensure that data can be exchanged seamlessly between different healthcare systems while safeguarding self-reported data. We also recommend consulting with the ONC\u2019s Trusted Exchange Framework and Common Agreement (TEFCA) to help establish policies for securely exchanging health information across organizations.However, marginalized groups must be involved in the design of this database. They could provide input on how to create a user-friendly interface with icons instead of words on buttons to accommodate those with low literacy or limited technological proficiency. The database should also collect data on the widest possible range of demographic factors; provide technical support through online tutorials or help desks staffed by technical support personnel; establish robust privacy policies like strict data access controls, encryption protocols, and other technical safeguards; and implement data quality controls, like automated data validation checks; and seamlessly deliver the data to researchers and policymakers through data dashboards.As big data revolutionizes the world, we must not forget its potential impact on improving health outcomes and disparities. By investing funds into health centers and hospitals for patient-driven reporting and data collection on race and ethnicity and developing minimum standards for health equity metrics collection and reporting across states, public discourse and media then draw on subsequent patient data analyses to bring greater attention to regional and national healthcare inequities, leading lawmakers to prioritize health equity initiatives and healthcare systems to have a clearer picture of the communities they serve.Further information on research design is available in the Reporting Summary"}
{"text": "In recent years, the advancement in biotechnology has enabled much improvement in quality and outcomes of medicine. These innovations have also drawn great attention in dental research fields. Regenerative medicine such as tissue (bone and tooth) engineering has been a hot topic in oral and craniofacial research for a few decades. Cells, signaling molecules and scaffold materials are three key components of tissue engineering approaches. Almost everyday new bioengineering approaches are proposed and tested for various diseases and treatment in dentistry.Liu et al.). EVs secreted by human gingival MSCs (hGMSC-derived EVs) were shown to promote osteogenesis and neovascularization in vitro and in vivo . The roles of stem cell-derived EVs and non-stem cell-derived EVs in bone tissue regeneration are reviewed . Engineering modified EVs may play important roles in future cell free EV-based bone tissue engineering therapies.Stem cells such as mesenchymal stem cells (MSCs) are multipotent and may differentiate into different cell types for tissue repair and regeneration. However technical issues including phenotype consistency, host immune response and potential tumorigenicity are still not completely resolved. Extracellular vesicles (EVs) originate from cellular endosomes and contain bioactive molecules to target cells by paracrine. It is known that these EVs are one of the major mediators of stem cells leading to their biological effects. MSC-derived EVs (MSC-EVs), instead of MSCs, may be potentially used in tissue repair and regeneration. The current status and future therapeutic applications of MCS-EVs in oral and craniofacial tissue regeneration are discussed in a review . Similarly, nanofibrous scaffold material can be modified to provide better coordinated regenerative endodontic treatment when pulp connective-tissue, dentin formation, revascularization and reinnervation need to be well orchestrated . Silk fibroin nanoparticles were coated with genetically engineered cell membrane overexpressing toll-like receptor 4 and loaded with minocycline hydrochloride. These biomimetic nanoparticles demonstrated excellent targeted antibacterial and immunoregulatory effects in vitro and in vivo (ligature-induced periodontitis mouse model) .A new generation of scaffold materials has been developed for tissue engineering. A multifunctional structurally optimized hydrogel scaffold was designed by integrating polyvinyl alcohol, gelatin, and sodium alginate with aspirin and nano-hydroxyapatite (nHAP). The osteogenic of nHAP and anti-inflammatory function of aspirin were successfully synergized . Targeted delivery of antitumor drugs has been recognized as a promising therapeutic modality to improve treatment efficacy, reduce toxic side effects and inhibit tumor recurrence. A controlled-release of an anti-tumor drug (apatinib) from supramolecular nanovalve-modified mesoporous silica was designed for targeted inhibition of osteosarcoma . This in vitro study showed efficient release of antitumor drug and promising results for future osteosarcoma treatment. Enamel white spot lesions do not have effective yet conservative treatment methods. Synergistic remineralization of enamel white spot lesions was achieved by using mesoporous bioactive glasses loaded with amorphous calcium phosphate, which implies great potential for clinical application .Other advancements in oral disease therapies are also made in recent years. Eldecalcitol, a novel active vitamin D3 analog, was shown to be effective on preventing alveolar bone loss in diabetes-associated periodontitis . Understanding the composition and differences between supragingival plaque biofilm microbes on the surface of fixed prostheses and natural crowns can provide patients with targeted guidance to focus on oral hygiene habits, reduce the risk of periodontal diseases and improve the success rate of fixed prostheses.The microbial composition and structural diversity of supragingival plaque on the surface of fixed prostheses were found to differ from that of normal natural crowns, with relatively high levels of periodontally related pathogens and higher microbial metabolism. The microflora on the surface of all-ceramic crowns was more similar to that of natural crowns than to that of porcelain-fused-to-metal crowns . Through the use of AM technology, personalized implant treatment for individual patients can be achieved.In addition to biotechnology, digital technology has also been applied in oral disease treatment, such as implant therapy. Additive manufacturing (AM) can enable the direct fabrication of customized physical objects with complex shapes, based on computer-aided designs. The applications of AM technologies in oral implantology, including implant surgery and restorative products, was reviewed (With the quick advancement of therapeutic approaches, biotechnology, and bioactive materials, it will not be too long before precision and personalized dentistry become reality."}
{"text": "Background: Older people living in residential aged care facilities frequently experience medicines-related harm. Evidence regarding the perception and practices towards reducing these harms may facilitate the development of customised educational programs for pharmacists providing services in RACFs.Objective: To explore Australian pharmacists\u2019 opinions and practices towards reducing the risk of medicines-related harm in aged care residents.Methods: An online survey was developed based on a literature review, expert opinion, and feedback from pharmacists providing services in RACFs. A web link for the survey was shared via professional pharmacy organisations and social media groups with Australian pharmacists providing services in RACFs.Results: A total of 209 pharmacists participated in the survey. Of these, 76% (n = 158) were residential medication management review embedded pharmacists, and 24% (n = 51) were supply pharmacists for RACFs. Most pharmacists believed that medicines-related harm is common in residents , yet few agreed that pharmacists have enough time to participate in medicines-related harm reduction services . There was a high level of agreement regarding the key risk factors and potential strategies for reducing medicines-related harm in residents.Conclusion: Pharmacists agreed that older residents often experience medicines-related harm, but they did not frequently participate in medicines-related harm reduction services. Initiatives to engage pharmacists in team-based harm reduction services and educate aged care staff regarding safe medication management may improve residents\u2019 safety and health outcomes. Medicines play an integral role in disease management, yet can be associated with significant problems, especially in vulnerable older people . Older pPharmacists are recognised as experts in pharmacotherapy and could potentially prevent medicines-related harm in older people . A pharmPrevious studies in Australian RACFs focused on determining pharmacists\u2019 views towards antibiotic prescribing and moniA cross-sectional national survey was conducted between February 2022 and August 2022. Pharmacists across Australia providing clinical or supply services to RACFs were the target population.An initial draft of the survey was generated based on a literature review, expert opinion, and feedback collected from pharmacists providing services to RACFs. The survey comprised questions on demographics, pharmacists\u2019 extent of agreement with statements regarding medicines-related issues and practice considerations, and perceptions towards risk factors for medicines-related harm and potential strategies for reducing medicines-related harm in aged care residents. Question types included Likert scales and free-text boxes. The face and content validity of the draft questionnaire was determined through a pilot sample of 10 registered pharmacists. Based on feedback, the questionnaire was reviewed to ensure it was easy to understand and complete. It was designed to be completed within 15\u00a0min.\u00ae was shared with pharmacists via Australian pharmacy organisations , Pharmacy Daily (an online publication), and social media groups . An information sheet was on the cover page of the survey to provide general information to the potential study participant, including eligibility such as providing any type of services to RACFs. Completion of the survey was deemed as implied consent. We opted for the \u201cOff\u201d setting under multiple responses in SurveyMonkey\u00ae portal, which prevents the survey from being taken multiple times from the same device. Further, we added an additional note \u201cIf you have already taken this survey, then you do not need to submit it again\u201d on the cover page of the survey to prevent multiple responses from the same pharmacist. All participants who completed the survey were entered in a draw to receive one of two AUD$100 gift cards. All returned questionnaires were reviewed for eligibility and completion.In 2020, the total number of RACFs in Australia was 3,300 . An assuU test for non-parametric numerical variables, were used to compare responses between the RMMR/embedded and supply pharmacists. Many supply pharmacists also provide services as RMMR pharmacist after receiving case-related training and accreditation from the Australian Association of Consultant Pharmacists. The purpose of comparing these groups was to assess the differences in their perceptions and practices towards reducing medicines-related harm among aged care residents. A p-value of <0.05 was used as the level of significance in all analyses.Data analysis was carried out using SPSS and Microsoft Office Excel 2019. The mean \u00b1 standard deviation was used to present normally distributed continuous data. Ordinal or skewed data were presented using the median [interquartile range (IQR)], and frequency (percentage) was used to report categorical variables. The study questionnaire was comprised of four main sections: Perception (13 items), Practices (6 items), Risk Factors (11 items) and Strategies (7 items), and a 5-point Likert scale (1 = Strongly disagree to 5 = Strongly agree) was used. Inferential statistics, such as a chi-square test for categorical and Mann-Whitney Approval was obtained from the Tasmanian Human Research Ethics Committee (Reference: H0026755). We followed the reporting guidelines of the STROBE statement for observational studies .From February to August 2022, 209 pharmacists completed the survey. One hundred and forty-six were RMMR pharmacists and twelve were embedded pharmacists within RACFs; we combined these groups as their roles are relatively similar and distinct from supply pharmacists. The demographics of the pharmacists are detailed in n = 174, 83%) and only half believed that safe medication management is usually practiced in RACFs . Almost all pharmacists agreed regarding the risk factors for medicines-related harm in aged care residents, such as polypharmacy, PIMs, dementia, recent drug changes, shortage of aged care staff, transitions of care, renal impairment, and specific drug use . A minority of respondents agreed that antibiotics and antipsychotics are usually prescribed in appropriate circumstances in older residents.n = 199, 95%). Most pharmacists also agreed that RMMRs prevent medicines-related harm , although only 62% of the RMMR/embedded pharmacists believed that their recommendations during RMMRs were typically accepted by general practitioners. Most pharmacists, particularly within the RMMR/embedded pharmacist group, agreed that aged care management personnel consider pharmacists\u2019 suggestions for reducing medicines-related harm in residents , but few agreed that pharmacists have enough time to participate in medicines-related harm reduction services .As with risk factors, the pharmacists displayed high agreement regarding potential strategies for reducing medicines-related harm in aged care residents. Enhancing collaboration between pharmacists and aged care staff was acknowledged by almost all pharmacists as a key strategy to reduce this harm in older residents ; this was lower for supply pharmacists (29%) relative to the RMMR/embedded pharmacists (60%). Also, a significantly lower proportion of the supply pharmacists reported that they were familiar with medication appropriateness tools and routinely utilised these tools. Overall, very few supply pharmacists participated in harm reduction services, reported adverse drug reactions to the Australian Therapeutic Goods Administration, and utilised tools to predict the risk of medicines-related harm. There was a large difference in the proportions of supply and RMMR/embedded pharmacists who agreed that supply pharmacists detect medicines-related harms whilst supplying medicines. Most pharmacists indicated that they routinely recommend deprescribing interventions ; this was lower for supply pharmacists (47%) relative to the RMMR/embedded pharmacists (92%).Only half of the pharmacists indicated that they routinely participate in harm reduction services (The role of pharmacists in aged care is evolving globally and may be critical in reducing the incidence of medicines-related injury in aged care residents . KnowingMost pharmacists agreed that medicines-related harm is highly prevalent in residents. Aged care residents take many medicines for their multiple morbidities, and it is a responsibility of all stakeholders involved in managing older residents to ensure the safe medication management . All staPharmacists believed that older residents frequently experience medicines-related harm due to factors such as polypharmacy, PIMs, anticholinergic drug use and multi-morbidity. They believed increased collaboration between pharmacists and aged care staff would reduce these harms. The 2021 Australian Aged Care Royal Commission report recommended increased communication and collaboration between aged care staff and other healthcare professionals, such as general practitioners and pharmacists providing services in RACFs . In New Relatively few pharmacists in our study agreed that antibiotics and antipsychotics are frequently prescribed in appropriate circumstances in Australian aged care residents. The RedUSe intervention, comprising multidisciplinary case review, provision of education to the staff, and audit and feedback, has recently been introduced in RACFs to reduce inappropriate antipsychotic prescribing . AntibioMost RMMR/embedded pharmacists believed that supply pharmacists do not usually identify medicines-related injury whilst supplying medicines. Many supply pharmacists in our study were not familiar with tools, such as the Beers criteria and anticholinergic drug burden scale, to predict the risk of medicines-related harm in aged care residents. In addition, very few supply pharmacists regularly utilised these tools or routinely engaged in harm reduction services. Similarly, a Malaysian study reported that only 27% of community pharmacists were familiar with Beers criteria and 17% frequently used this tool in practice . Educativia supplying medicines and consultancy, and these roles are executed remotely or in a visiting capacity (In Australia, pharmacists usually provide services in RACFs capacity . There icapacity . Embeddecapacity . In 2023capacity . A recencapacity .This study is the first of its kind that explored the perceptions and practices of Australian pharmacists providing services in RACFs towards reducing the risk of medicines-related injury in residents. One of the key study limitations was that the recommended sample size was not reached, indicating that these findings may not be representative of the entire group of Australian pharmacists providing services for aged care residents.Pharmacists agreed that aged care residents frequently experience medicines-related harm, but their involvement in medicines-related harm reduction services was relatively limited. Initiatives to engage pharmacists in harm reduction services and educate aged care staff regarding safe medication management may improve residents\u2019 health outcomes. Medicines use in aged care residents can be optimised by the presence of embedded pharmacists in a team environment, provision of education to aged care personnel, and collaborative medication reviews with general practitioners. Ideally, supply pharmacists would also play a greater role in accepting responsibility for the risks posed by the medicines they provide to RACFs. Future research is needed to assess the impact of educating aged care staff about safe medication management on residents\u2019 health outcomes."}
{"text": "Elevated peripheral inflammation is common in psychosis. Impairments in general cognition were linked to elevated C-reactive protein (CRP) and other inflammatory markers in patients with psychotic disorders. Whether there is a subgroup of persons with elevated peripheral inflammation demonstrating deficits in specific cognitive domains remains unclear. While molecular underpinnings of altered inflammation in psychosis are hypothesized, genetic contributions to relationships of psychosis, inflammation, and cognition have not been clarified. Thirteen peripheral inflammatory markers and 17 neurobehavioral tasks were quantified in a subset of participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Principal component analysis resulted in 5 inflammation factors across inflammatory markers. Three latent cognitive domains were characterized based on the neurobehavioral battery. Hierarchical clustering identified a psychosis subgroup with elevated inflammation and worse cognitive performance. Genetic predispositions to schizophrenia and cognition were explored in relation to inflammation. Among persons with psychosis, higher inflammation indices were associated with impairments of Inhibitory Control and Visual Sensorimotor function. Greater deficits in Inhibitory Control were observed in a high inflammation patient subgroup. Consistent with previous studies, global genetic correlations of schizophrenia, CRP, and cognition were observed. Significant bivariate local genetic correlations of CRP with schizophrenia or cognition across 22 loci with several genes in 1 locus on chromosome 3 suggested pleiotropic mechanisms for inflammatory relationships with cognition and psychosis. Specific neurobehavioral domains may be more sensitive to inflammation dysregulation in psychosis as compared to general cognitive function, particularly performance on tasks requiring ongoing behavioral monitoring and control. These, along with evidence of genetic correlations of CRP, psychosis, and cognition, provide further supporting evidence that inflammation dysregulation is an important underlying mechanistic contributor to the disruption of cognition in psychosis. Targeting this dysregulation may be an avenue for novel therapeutics to improve cognitive outcomes in these patients.None Declared"}
{"text": "Migraine is a primary headache disorder recognized by the World Health Organization as one of the most poorly understood and debilitating neurological conditions impacting global disability. Chronic pain disorders are more frequently diagnosed among cisgender women than men, suggesting that female sex hormones could be responsible for mediating chronic pain, including migraine and/or that androgens can be protective. This review discusses the major gonadal hormones, estrogens, progesterone, and testosterone in the context of molecular mechanisms by which they play a role in migraine pathophysiology. In addition, the literature to date describing roles of minor sex hormones including prolactin, luteinizing hormone, follicular stimulating hormone, and gonadotropin releasing hormone in migraine are presented. Because transgender and gender non-conforming (trans*) individuals are an underserved patient population in which gender-affirming sex hormone replacement therapy (HRT) is often medically necessary to align biological sex with gender identity, results from cisgender patient populations are discussed in the context of these major and minor sex hormones on migraine incidence and management in trans* patients. Migraine headaches are diagnosed based upon attack frequency and aura. When headache symptoms are present for at least three months, episodic migraine is defined as 0\u201314 headache days per month while chronic migraine requires 15 or more headache days . The phy1.2.Cortical spreading depression is defined as the spreading of a slowly propagating wave of cellular depolarization and inhibition within neuronal and glial cells across the cerebral cortex. A large change in the concentration gradient between extracellular potassium and intracellular sodium/calcium ions produces a depression of electrocortical signals that travels anteriorly at a rate of 3\u20136\u2005mm/min , 6. In aPreliminary research on the possible involvement of CGRP in migraine found that patients experienced elevated CGRP levels during the interictal phase when headache symptoms were absent ; furtherGiven that trigeminovascular neurons have intrinsic projections to the cerebrovascular system, cortical hyperexcitability induced within central neurons activates and amplifies the underlying vascular processes that sustain migraine headache. The current neurovascular understanding of migraine suggests that neurological processes are necessary to alter trigeminal activity . Clinica1.3.Migraine is more commonly diagnosed with a higher rate of disability in cisgender women than men , 21. AltResearch on sex differences usually refers to the hormonal differences between female sex hormones and male sex hormones , but the correlation between migraine and menstrual sex hormone fluctuations reveals that the physiological concentration as well as the type of sex hormone is critical for headache pain. The human menstrual cycle typically lasts 28 days and is divided into two stages: the follicular and luteal phase. In the follicular phase, progesterone levels remain low while estradiol steadily increases. Ovulation then triggers a sharp decline in estradiol simultaneous with rising progesterone levels; when progesterone peaks halfway through the luteal phase, estradiol remains slightly elevated until both hormones drop back down to baseline , Figure\u00a0Sex hormones are lipid signaling messengers that can enact long-lasting effects on neurovascular structure and function. To provide more comprehensive treatment for cisgender women/men and to expand the much-needed area of research on chronic conditions within transgender/gender non-conforming (shortened to trans* as a gender-inclusive umbrella term) patients who receive gender-affirming sex hormone replacement therapy (HRT), a comprehensive analysis on the impact of hormonal fluctuations in migraine-related pathological processes and on nociceptive processing is required. This review will first examine pre-existing, chronic pain-related health disparities among trans* patients to determine current healthcare needs regarding pain management and migraine headache. The medical necessity of gender-affirming treatment and current barriers to healthcare access will then be integrated to emphasize that gender affirmation is critical to reestablish important health measures\u2014such as patient self-efficacy and trust in the healthcare system\u2014that will grant trans* patients with the necessary skills needed to improve pain outcomes. Due to the significant knowledge gap between gender-affirming care and physical health disparities, research on sex hormone activity in migraine pathology will be summarized through cisgender patient data as it pertains to ovarian HRT (estrogen/progesterone) and androgen HRT (testosterone). Further gaps in knowledge and future research directions will be identified as needed to improve healthcare practice and to continue gender-affirming healthcare for LGBTQ\u2009+\u2009patients.2.2.1.When explicitly examining sex differences in primary headache, cisgender women report a higher migraine prevalence of 18% compared to 6% among men , whereas2.2.Estrogen is categorized as a \u201cfemale\u201d sex hormone synthesized within the ovaries to induce female sexual maturity; however, this simplification fails to consider the role of estrogen in male physiology as well as on other biological systems in cisgender women. Estrogen incorporates three hormones that have different functions based on the stage of female reproduction: estradiol is the main hormone that is sustained over a woman's lifespan while estrone and estriol are weaker forms that become dominant during menopause and pregnancy, respectively . EstrogeThe high prevalence of disabling migraine features among cisgender women implies that fluctuating levels of estrogen are critical for migraine development, but assumptions based on female physiology and the effects of hormonal signaling currently restrain the understanding of migraine to a system primed for estrogen. The difference in prevalence between migraine with aura during high estrogen and migraine without aura during estrogen withdrawal suggests that in addition to promoting migraine mechanisms, higher levels of estrogen increase CSD susceptibility and encourage significant headache-related disability through neurovascular dysfunction. Headache studies conducted using animal models demonstrated that female mice have intrinsically lower CSD thresholds than male mice , but wheGiven that CSD could be an initiating mechanism of migraine in patients, increased CSD susceptibility from female hormones indicates that estrogen has a critical role in triggering migraine wherein higher hormonal concentrations correlate to worse pain outcomes. However, clinical data from both cisgender and trans* patients differentiate the effectiveness of estrogen on male and female physiology. The introduction of estradiol to male physiology enables rapid CSD and central sensitization induction since low levels of pre-existing estrogen are insufficient to dominate testosterone activity, but for patients with female physiology, the developmental role of estrogen for sexual reproduction could require hormones that exceed healthy estradiol concentrations to propagate migraine mechanisms. During Tanner stage IV which occurs after puberty onset, patients with female physiology report estradiol levels between 15 and 85\u2005pg/ml while male patients report a maximum of 38\u2005pg/ml. In adulthood, female patients experience fluctuating levels of estradiol within the range of 15\u2013350\u2005pg/ml that varies according to the menstrual cycle ; during B receptors from the G-protein-coupled receptor attached to potassium ion channels; this suppression of neuronal hyperpolarization lowers activation thresholds because hyperpolarization is necessary to return neuronal activity back to baseline pathway contains several metabolites vital to regulating excitatory and inhibitory signaling in the central nervous system. Kynurenic acid (KYNA) is a competitive antagonist that binds to the glycine site of the GluN1 subunit of NMDA receptors while other metabolites\u2014such as quinolinic acid (QUINA) and xanthurenic acid (XA)\u2014increase cortical excitability as orthosteric agonists that bind to the GluN2A-D subunit of NMDA receptors. QUINA and XA also activate type-2 metabotropic glutamate receptors . MigrainCentral sensitization consists of two critical components: cortical hyperexcitability facilitated through increased glutamate expression and enhanced synaptic efficiency through long-term potentiation; therefore, revealing the contributions of estrogen signaling on both aspects will improve headache pain relief. Clinical studies on migraine sex differences reported that in addition to elevated CGRP, cisgender women also experience fluctuating CGRP expressions within the central and peripheral nervous systems that correspond to estradiol concentrations across the menstrual cycle . EvidencEstradiol signaling seems to have a minimal role in directly perpetuating cerebral vasodilation since a significant portion of endothelial dysfunction and oxidative stress is proportional to the sensitized strength of trigeminal neurotransmission. However, research on the vascular contributions to migraine with sex hormones is still needed to elucidate the full impact of estrogen. In a study that compared plasma concentrations of nitric oxide among cisgender women with either menstrual migraine, non-menstrual migraine, or non-headache controls, enhanced activation of the nitric oxide pathway during the luteal phase leads to increased nitric oxide synthesis that aligns with reports of oxidative stress markers peaking during the late follicular and early luteal phases . EstrogeEstrogen-mediated disruptions in essential biomolecules bolster the efficiency of trigeminal neurotransmission at the cost of regulatory processes that are necessary to prevent excessive cortical hyperexcitability and cerebral vasodilation; therefore, since migraineurs demonstrate higher levels of serotonin (5-HT) during the ictal phase of headache but lower levels during the interictal phase, estrogen could influence the synthesis of neurotransmitters like serotonin . AlthougIn addition to generating intermediate metabolites that destabilize excitatory and inhibitory cortical signaling, the KYN pathway also reduces serum 5-HT levels in migraineurs by metabolizing the amino acid tryptophan into KYN metabolites at the expense of serotonin synthesis. Michael et al. demonstrAn overview of the current understanding of estrogen signaling on neurovascular migraine mechanisms is summarized in 2.3.Although estrogen hormones are incredibly efficient at accumulating dysfunction within the trigeminovascular system, the role of fluctuating progestin hormones with estradiol signaling could clarify gaps in understanding between migraine headache, hormonal states, and pain symptomology. Progesterone has two receptors: progesterone receptor alpha (PR\u03b1) and progesterone receptor beta (PR\u03b2). Although murine models demonstrate higher expressions of one receptor isoform over the other, human cells contain equivalent amounts of PR\u03b1 and PR\u03b2, which suggests that the PR\u03b1-PR\u03b2 heterodimer is the dominant molecular species for humans . Therefo2.4A receptor activity within neurons of the trigeminal nucleus caudalis gene on chromosome 5 encodes three different isoforms: long (PRL-L), intermediate, and short (PRL-S), but only PRL-L and PRL-S will be considered since unlike humans and rats, mice lack intermediate PRL receptors . PRL-L ae models .Prolactin-induced sensitization imitates estradiol neurogenic inflammation by proliferating CGRP release from sensory neurons via the excessive activation of sensitized TRP channels. Although sensory neurons lack PRL, application of TRP channel activators to cultured female sensory neurons pretreated with prolactin resulted in amplified trigeminal neurotransmission due to enhanced calcium ion influx. Within male physiology, prolactin sensitization might require abnormally high concentrations to further support estrogen-mediated sensitization since males have lower PRL-L and PRL-S expressions in the dorsal root ganglion . PRL-S sWhen prolactin is considered alongside androgen and ovarian hormones, pronociceptive headache states fueled by estrogen can recruit prolactin-induced sensitization to further advance chronic pain since estrogen increases PRL receptor expression. Conversely, testosterone suppresses PRL expression to mitigate central sensitization, but since the molecular pathway defining this androgen-mediated phenomenon has yet to be explored, only coinciding interactions between estrogen and prolactin will be discussed. High concentrations of endogenous estrogen within female migraineurs correlate to an increase in PRL receptor mRNA in dorsal root ganglion neurons; however, because equal expressions of PRL-S and PRL-L were retained in both sexes regardless of estradiol concentrations, estrogen upregulation of PRL expression occurs independently from receptor isoform translation . ApplicaCRE mice to deduce sex differences in migraine. Prior to experimentation, murine models expressed KORCRE neurons in the dorsomedial/ventromedial hypothalamic nuclei and ARC as well as within tyrosine-hydroxylase-positive cells that were quantified as 80% for female and 70% for male mice. In response to RS, enhanced serum prolactin produced allodynia from latent sensitization in both male and female mice, although females experienced an intrinsically greater increase. When the KOR antagonist nor-binaltorphimine dihydrochloride was applied to the right ARC, serum prolactin was reduced likely due to the synchronized TIDA network axis and reduced efficacy of the kappa-opioid receptor (KOR) system to alleviate trigeminal nociception. Previous clinical studies reported that stress activates the hypothalamus of migraineurs to increase cortisol levels, resulting in a positive correlation between stress-induced priming and chronic headache frequency. Since stress increases prolactin and the endogenous KOR agonist dynorphin, central sensitization could decrease the analgesic efficiency of the KOR signaling pathway such that chronic stress would hinder endogenous recovery from headache . Watanab network . Combinehibition , 81. Furhibition . Howeverhibition . Therefohibition . The mec2.6.2.Luteinizing (LH) and follicle-stimulating (FSH) hormones are synthesized from gonadotropin cells in the anterior pituitary to amplify estrogen synthesis during the menstrual cycle . Several2.6.3.Although the majority of gender-affirming healthcare focuses on medical interventions for trans* adults, trans* youth who wish to postpone the puberty of their assigned sex might receive puberty blockers\u2014which are gonadotropin-releasing hormone (GnRH) agonists such as goserelin, leuprolide, and histrelin\u2014to delay the development of secondary sex characteristics and prevent gender dysphoria\u2014which is defined in the DSM-5 as the \u201cpsychological distress that results from an incongruence between one's sex assigned at birth and one's gender identity\u201d , 89. SexGnRH is synthesized within hypothalamic neurons to regulate LH and FSH concentrations throughout the menstrual cycle; the activation of GnRH G-protein-coupled type I receptors on gonadotrophin cells in the anterior pituitary generates GnRH pulse frequencies wherein low pulses stimulate FSH and high pulses promote LH. Although female migraineurs demonstrated normal FSH/LH levels, dysfunction of the hypothalamic-pituitary-adrenal axis could cause abnormal GnRH pulse frequencies. Research demonstrated that persistent GnRH stimulation produces elevated LH:FSH ratios\u2014amplifying the ovarian synthesis of androgen hormones\u2014while minimal stimulation and abnormal GnRH serum levels were associated with hypothalamic amenorrhea . Despite3.Despite the growing number of trans* patients, healthcare practices have yet to move beyond the perspective that this patient population only engages with the healthcare system to receive gender-affirming medical treatment. Research examining pre-existing health disparities among LGBTQ\u2009+\u2009patients has been recognized as a crucial gap in knowledge ; howeverWhile the exact number of trans* individuals with migraine is unknown, there are an estimated 1.4 million transgender adults and 39 million individuals with migraine in the United States . Based oAlthough this risk of headache could be detrimental for the physical and mental wellbeing of an already vulnerable population, transgender men and gender non-conforming individuals who receive androgen HRT might experience some relief from migraine. Yalinay Dikmen et al. investigFrom the available evidence, estrogen HRT is associated with an increased risk for acquired migraine in transgender women while testosterone HRT could potentially provide some pain relief for transgender men with a pre-existing primary headache disorder. Although data from cisgender migraineurs has supported the role of estrogen in promoting migraine mechanisms, gaps in knowledge remain on the minimum physiological concentration of estrogen required to propagate chronic pain states; given that migraine has been observed during states of estrogen withdrawal and elevation , determining physiological hormone concentrations can clarify the association of sex hormones and migraine symptoms. Consenting trans* patients represent the ideal clinical population to investigate this theory as the natural diversity in gender identity and use of gender-affirming hormones allows researchers to clarify the issue of sex hormone functionality without subjecting cisgender patients to potential unwanted side effects. These individuals are also ideal in furthering progress for LGBTQ\u2009+\u2009health outcomes beyond mental health disorders and sexual diseases because current debates regarding the legality of gender-affirming care already establish the immediate need for improved LGBTQ\u2009+\u2009healthcare and better understanding on the long-term effects of HRT. Treatment of headache for cisgender patients can also be improved through trans* data by reframing the consideration of health with gender identity; notably, by replacing binary sex as a health factor with measures of serum sex hormone levels, mechanisms involved in chronic pain pathology can improve the accuracy of disease diagnosis and treatment as well as support pain outcomes hindered by sexist gender stereotypes.4.Despite limited data in trans* individuals with migraine, cisgender data suggests that femininizing estradiol HRT increases the risk for acquired headache and chronic pain while masculinizing testosterone HRT is associated with improved pain relief for patients with a pre-existing headache disorder. Future studies are needed to directly evaluate the risk between gender-affirming HRT and migraine. Ovarian hormones like estrogen and progesterone promote migraine headache via CSD and central sensitization within the trigeminal nociceptive network through reactive species, CGRP, and an imbalance of excitatory/inhibitory neurotransmission while androgens like testosterone attempt to reduce excessive cortical hyperexcitability by bolstering neuroprotective and analgesic qualities. When the effects of sex hormones in cisgender and trans* patients are examined together, rapid sex hormone fluctuations create vulnerabilities through which heightened estrogen induces pronociceptive states and reduced testosterone fails to adequately establish trigeminal neuroprotection. Since many trans* individuals begin HRT when patients are already well into adulthood, pubertal hormones likely establish migraine susceptibility that can be aggravated further by estrogen HRT, thus putting transgender women at the most risk. Susceptibility could be curtailed through pubertal suppression and treatment with puberty blockers, but the same limitations currently impacting adult gender-affirming care also affect trans* youth, maybe even more so due to debates on parental rights to oversee the healthcare decisions of their children. Given the changing landscape of trans* patients seeking gender-affirming healthcare, more investigation into sex hormones on migraine pathology is warranted to determine the impact of gender-affirming HRT and potential chronic pain risk.Research on LGBTQ\u2009+\u2009healthcare has largely focused on educating medical providers about the appropriate terminology to improve interpersonal interactions between patients and providers , 99. How"}
{"text": "Antibiotic resistance stands as one of the most significant public health challenges in recent decades. FEM proteins are responsible for the synthesisof pentaglycine cross-bridge, a primary constituent of bacterial peptidoglycan polymer crosslinking during cell wall biosynthesis. Since they are necessaryfor bacterial survival and antibiotic resistance, they were considered as significant antibacterial targets. We report herein, the virtual screening andselection of FDA-approved drugs and their potent similar molecules as FEM protein inhibitors and analyzed for inhibiting affinity and their ADMET pharmacokineticproperties. This data provide a foundation for the development and optimization of structurally innovative antimicrobial drugs. Staphylococcus aureus causes a wide spectrum of common ailments that can be acquired from the community and in hospitals. Due tolower responsiveness to commercially available drugs, the rise of Methicillin-resistant Staphylococcus aureus (MRSA) clinical isolateshas increased and evolved into various multi-drug resistant strains making the treatment difficult. The foreign expression of altered PBP2a performs the host PBPfunction and governs the strategy of \u03b2-lactam antibiotic resistance in methicillin-resistant S. aureus (MRSA)amino]-3-methylpyridin-2-yl]benzoic acid (PubChem ID: 90080139) against FemX with highest binding energy of -137.66 among all by forming a Pi-sulfur and Pi-alkylinteraction with TYR320, 377 and MET196. The whole complex has involved many hydrogen bonding with several residues listed in active site amino acids of theFemX receptor .In addiinvitro evaluations.For the first time this manuscript reported the FemB inhibitors from FDA approved drug molecules, which can be possibly repurposed.An overview of selected chemical molecules and clinical features with pharmacokinetic properties were analyzed using the pkCSM webserver and labeled ininvitro results. In this work, we virtually examined a library of FDA-authorized drugs from ZINC15 and DrugBank databases againstS. aureus FEM proteins. Three lead molecules were shortlisted based on their docking scores and prioritized based on their minimum bindingenergy and active interactions with the FEM proteins. In this study, we also evaluated the molecules solubility and toxicity properties.The limited therapeutic spectrum against MRSA necessitates an urgent development of antibiotics and medications to enhance the current antibiotic efficacyand drugs to enhance the existing antibiotic efficacy. We report the optimal binding features of structure-based FDA-approved drugs repurposed to treat MRSApathogenic infections. It helps to cross the emergence by following certain time limit management in collaboration with certain existingThe authors declare that they have no known competing interests (or) personal relationships that could have appeared to influence the work reported in thismanuscript. The research leading to these results received funding from the DST-SERB-ECR grant under file no: ECR/2017/003381."}
{"text": "Pain generator-based lumbar spinal decompression surgery is the backbone of modern spine care. In contrast to traditional image-based medical necessity criteria for spinal surgery, assessing the severity of neural element encroachment, instability, and deformity, staged management of common painful degenerative lumbar spine conditions is likely to be more durable and cost-effective. Targeting validated pain generators can be accomplished with simplified decompression procedures associated with lower perioperative complications and long-term revision rates. In this perspective article, the authors summarize the current concepts of successful management of spinal stenosis patients with modern transforaminal endoscopic and translaminar minimally invasive spinal surgery techniques. They represent the consensus statements of 14 international surgeon societies, who have worked in collaborative teams in an open peer-review model based on a systematic review of the existing literature and grading the strength of its clinical evidence. The authors found that personalized clinical care protocols for lumbar spinal stenosis rooted in validated pain generators can successfully treat most patients with sciatica-type back and leg pain including those who fail to meet traditional image-based medical necessity criteria for surgery since nearly half of the surgically treated pain generators are not shown on the preoperative MRI scan. Common pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte and cyst, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte. The position of the key opinion authors of the perspective article is that further clinical research will continue to validate pain generator-based treatment protocols for lumbar spinal stenosis. The endoscopic technology platform enables spine surgeons to directly visualize pain generators, forming the basis for more simplified targeted surgical pain management therapies. Limitations of this care model are dictated by appropriate patient selection and mastering the learning curve of modern MIS procedures. Decompensated deformity and instability will likely continue to be treated with open corrective surgery. Vertically integrated outpatient spine care programs are the most suitable setting for executing such pain generator-focused programs. Lumbar spinal stenosis (LSS) is defined as a narrowing of the lumbar spinal canal caused by age-related degeneration of the spinal motion segment. It causes encroachment of neural elements and may contribute to back and leg pain. It is a leading cause of disability from lack of mobility due to neurogenic claudication worldwide . Spinal Spondylolisthesis and decoIn this review perspective article, the authors take a fresh, consensus look at the available evidence including their own professional expertise and experiences on using minimally invasive and endoscopic lumbar decompression techniques in a more targeted and personalized care model. 14 professional societies reviewed recent articles on the topic and through their related committees and subcommittees express their professional position. This perspective paper is coordinated by the Interamerican Society For Minimally Invasive Spine Surgery\u2013La Sociedad Interamericana de Cirug\u00eda de Columna M\u00ednimamente Invasiva (SICCMI) and the Spine Subcommittee of the Society For Brain Mapping & Therapeutics (SBMT), and endorsed by the International Society For Minimal Intervention In Spinal Surgery (ISMISS), the Korean Minimally Invasive Spine Society (KOMISS), the Minimally Invasive Surgery Section of the Chinese Orthopaedic Association (COA-MIS SECTION), The Colombian Spine Society, the Bolivian Spine Association, the Iberolatinoamerican Spine Society\u2013La Sociedad Iberolatinoamericana de Columna (SILACO), the Mexican Association of Spinal Surgeons\u2013Associacion Mexicana de Cirujanos de Columna (AMCICO), the Federation of Latinamerican Neurosurgical Societies\u2013Federaci\u00f3n Latino-Americana de Sociedades de Neurocirug\u00eda (FLANC), the Latin American Society of Neurosurgeons of USA & Canada (SLANC), the Brazilian Spine Society\u2013Sociedade Brasiliiera de Columna (SBC), the Brazilian Society For Thoracic Surgery\u2014Sociedade Brasileira de Cirurgia Tor\u00e1cica (SBCT), and the International Intradiscal Therapy Society (IITS).The annual incidence of adult spine disease is estimated at 266 million people globally . The higIn the 2010 Global Burden of Disease (GBD) Study ,23, LBP Most contemporary medical necessity criteria for spinal decompression are based on analyzing advanced imaging studies such as MRI or CT. Using these image-based criteria reserves decompression surgery only for patients with progressive disease ,38,39,40Whoever does not fit these medical necessity criteria is often committed to repetitive cycles of spinal injections, physical therapy, and non-steroidal anti-inflammatory treatments. Those who are so disabled that they cannot even participate in these programs in a meaningful way or have poorly controlled co-morbidities which preclude medical management often cannot get much help. An exemplary summary of traditional Review Clinical Guidelines For Spinal Stenosis affecting coverage decisions is shown in In this perspective paper, SICCMI, in collaboration with 12 other international surgeons\u2019 societies, is confronting the increased scrutiny on the appropriateness of spine care spending by payers, government, and patients in an attempt to deliver on simplified, innovative, less costly, more effective, and more durable treatments for common degenerative and painful spine conditions associated with lower complication and revision rates. Resolution to these problems is needed to meet the increasing demand by the aging baby-boomer population for such simplified treatments.The treatment of the painful degenerative disease process of the spinal motion segment with traditional open spine surgery is dictated by the application of MRI and CT image criteria of spinal stenosis, instability, and deformity. The clinical decision-making for surgery focuses on treating the end-stage of the disease, leaving many patients without timely treatment or no treatment at all. With the backdrop of recent clinical studies describing the limited utility of the lumbar MRI scan and its reporting suffering from relatively low sensitivity and specificity to diagnose the painful spine condition , key opiTraditional open spine surgery in the lumbar spine includes laminectomy. A translaminar decompression is performed by removing the posterior spinal elements, including the spinous process, the lamina, and part of the bilateral facet joints. The benefit of lumbar decompression for symptomatic herniated disc and spinal stenosis has been demonstrated in several prospective randomized clinical trials, including the original study by Weber , the MaiMinimally invasive surgery (MIS) for the treatment of common degenerative conditions of the spine is increasingly practiced. It encompasses a portfolio of surgical techniques that are aimed to alleviate patients\u2019 pain via reduced surgical access resulting in less blood loss and reduced peri- and postoperative problems including pain, nausea, and vomiting. The introduction of tubular retractors and microsurgical dissection techniques simplified the very nature of spine surgery by transforming it through the implementation of less burdensome and more simplified protocols. Over the last 40 years, open spine surgery has established a track record that is interpreted by most patients, employers, and payers as aggressive and too costly due to high out-of-work complications and reoperation rates.Quality of life and cost-effectiveness of minimally invasive surgery (MIS) for spinal stenosis in patients with degenerative lumbar spondylolisthesis (DLS) has been calculated relative to failed medical management and compared to the cost-effectiveness of hip and knee arthroplasty for matched cohorts of patients with osteoarthritis . IncremeSelect pain generators in the lumbar spine are not diagnosed on routine lumbar MRI scan . A recenCommon pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte, and many others examples, as shown in One example is highlighted by the INTRACEPT prospective, open-label, 1:1 randomized controlled trial. This trial tests the efficacy of basivertebral nerve (BVN) ablation technology compared to a standard care control treatment of vertebrogenic chronic low back pain . ConceptThe authors take the position that direct visualization and treatment of pain generators is the foundation for surgical pain management of the lumbar spine. Spinal endoscopy enables the surgeon to diagnose and treat the painful condition during the same operation ,66,67,68Objective measurements of the foraminal or lateral canal dimensions are rarely given. Surgical stenosis classifications use measurable parameters such as height and width of the posterior disc, lateral recess, or neuroforamen to stratify patients for the most appropriate MIS approach and technique . The lacTreating pain generators involves identifying those structural problems in the lumbar spine that cause the majority of the patient\u2019s symptoms as implicated in the symptoms by history and physical examination or by advanced imaging studies such as MRI or CT scan. Most patients have unilateral or mono-segmental radiculopathy symptoms. When confirmed with diagnostic selective nerve root blocks, these clinical observations highlight that many structural changes in a degenerative spine are multilevel but may not be painful, even if the MRI or CT scan suggests a similar degree of stenosis as within the symptomatic spinal motion segment. For example, exiting and traversing nerve root pain syndromes may or may not exist within the same lumbar motion segment simultaneously. However, when they do, the surgeon can easily be confused with patients whose MRI suggests multilevel disease. Identifying the correct source level of axial facet joint pain in multilevel degeneration may even be more difficult without a radicular component. The staged management concept is the central element of the clinical spine care model. It implies treating validated symptomatic pain generators and ignoring all degenerative changes or injuries that do not hurt.While it is easier to rely on MRI-based criteria of compression, instability, and deformity when deducting a plan of surgical care\u2014certainly within the mainstream of traditionally trained surgeons, and perhaps a coincidence between the radiologist\u2019s confirmation of compressive pathology and the surgical plan of care invites less scrutiny during the health insurance preauthorization process for surgery\u2014identifying the predominant pain generator can be a daunting task. Recommending a targeted surgical treatment plan to a patient in pain is as much of an art as it is a science and relies heavily on judgment and clinical experience. Less aggressive treatment recommendations are often sufficient to substantially reduce pain, all while ignoring traditional decompression and lumbar fusion criteria.What to treat and, more importantly, what to ignore requires attention to detail and utilization of preoperative diagnostic tools of high positive predictive value. For the endoscopic spine surgeon, the plan of care is derived from identifying those pain generators that impair the patient the most. Minimizing the risk-taking and maximizing the benefit, all while managing patients\u2019 expectations about the desired outcome, are the key to achieving high patient satisfaction . The staA new subspecialty is emerging: \u201cSurgical Pain Management.\u201d The term implies a blend of diagnostic and patient management strategies employed by interventional pain physicians comprised of physiatrists, anesthesiologists, and spine surgeons consisting of orthopedic and neurosurgeons. This new emerging subspeciality is a grassroots development driven by enthusiast physicians who invested their careers into a more personalized approach to spine care. Thus, surgical pain management integrates needle-based non-visualized interventions into MIS and endoscopic surgical procedures by tailoring the treatment based on the individual patient\u2019s symptoms and the functional context when the spine care is delivered. Examples of this development include the integration of radiofrequency and laser into endoscopic surgeries. The continued use of rule-based medical necessity criteria for lumbar spine care seems increasingly inappropriate. It invites the delivery of costly, ineffective therapies and treatments which ultimately do not lower the societal burden of spine care. Ignoring individual pain generators stemming from the underlying disease causing cumulative disability does not address the root cause and precludes the patient from definitive care or leads to patient entrapment in repetitive yet ineffective treatment cycles. In the opinion of the KOL authors of this lead perspective article in the JPM special issue \u201cThe Path To Personalized Pain Management,\u201d the staged approach to surgical pain management is poised to lower disability and the direct and indirect costs with all of its hidden unintended consequences of repetitive treatments. Its implementation has the potential for diminishing the burden of failed medical pain management and opioid addiction, delayed returned to work, and disrupted social reintegration. While the authors do not suggest abandoning traditional open spine surgery, we propose integrating staged surgical pain management of directly visualized pain generators early in the disease process into existing spine care programs.The authors of this perspective paper arrived at the consensus statement on the indications for surgical treatment for symptomatic lumbar spinal stenosis based on validated pain generators rather than traditional image-based medical necessity criteria. This approach to treating patients with claudication and sciatica-type low back and leg symptoms represents the authors\u2019 views and their respective surgeon societies. The most published individuals on this team of authors are accomplished and passionate endoscopic spinal surgeons. In experienced hands, approximately 80% of patients with painful degenerative spine conditions may be treated successfully with a targeted outpatient MIS or endoscopic decompression procedure ,82,83. WJudiciously and skillfully executed modern targeted MIS surgeries can provide more cost-effective and less burdensome spine care with shorter treatment cycles as the underlying structural correlate for the patient\u2019s pain is treated causally. Lateral recess and foraminal stenosis are the most common clinically relevant indications for primary surgery and revision surgery after decompression in the lumbar spine. The personalized clinical protocols for treating lumbar spinal stenosis based on validated pain generators are a break with traditional population management protocols that employ image-based medical necessity criteria for intervention since nearly half of the surgically treated pain generators are not shown on the preoperative MRI scan. Common pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte. It is the authors position, that further clinical research will continue to validate pain generator-based treatment protocols for lumbar spinal stenosis. The endoscopic technology platform enables spine surgeons to directly visualize pain generators, forming the basis for more simplified targeted surgical pain management therapies. Clinical judgment of appropriate patient selection and mastering the learning curve of modern MIS procedures will likely lead to a broadening of the accepted indications for such a pain generator-based approach to patient care. Limitations of this care model are dictated by decompensated deformity and instability, for which open corrective surgery will likely continue to be the treatment of choice. Vertically integrated outpatient spine care programs are probably the most suitable setting for executing such a pain generator focused program since physicians who have complete custody of their patients can minimize protocol breaches by other providers who are not invested in the personalized care model proposed by the authors."}
{"text": "Epidemics in the Pacific Islands noted flu-like symptoms and complications following human ZIKV infection. However, after a severe outbreak in 2015, Latin American studies reported fetal birth defects with maternal infection but reports in other developing countries where outbreaks occurred were not fully characterized. This study aims to review current reports on birth outcomes associated with maternal ZIKV infection .Zika Virus became an emerging health threat in the early 21This narrative review evaluated birth outcomes of Zika positive pregnant women. Research articles were found using Google Scholar, PubMed, and MEDLINE. The inclusion criteria were publication between 2012 to 2022, availability as full text in English, categorization as original research, meta-analyses or case reports. Exclusion criteria were studies that were part of a book chapter or encyclopedia and studies that cited results from developed nations. The articles were studied and 20 methodologically sound studies were selected for review, and the data was classified in themes based on birth outcomes.18 studies reported that infants born to some laboratory-confirmed zika-positive mothers had abnormal birth outcomes after delivery including microcephaly, stillbirth, neurological abnormalities and hearing loss. Maternal ZIKV infection is associated with an increased risk of abnormal birth outcomes in newborns in developing countries. In the countries of studies that did not report abnormal outcomes there may have been a protective factor from previous maternal Dengue Virus (DENV) infection adding protection for their infants.Overall, there appears a difference in birth outcomes of infants born to mothers infected with ZIKV, however more research is needed on environmental factors and prior arboviral infection as additional factors contributing to these outcomes.All Authors: No reported disclosures"}
{"text": "Spinal cord injury (SCI) disrupts the structural and functional connectivity between the higher center and the spinal cord, resulting in severe motor, sensory, and autonomic dysfunction with a variety of complications. The pathophysiology of SCI is complicated and multifaceted, and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after SCI. Combinatory strategies targeting multiple aspects of SCI pathology have achieved greater beneficial effects than individual therapy alone. Although many problems and challenges remain, the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat SCI. In this review, we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following SCI at both the acute and chronic stages. In addition, we analyze the current status, remaining problems, and realistic challenges towards clinical translation. Finally, we consider the future of SCI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice. Going forward, clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeutic benefit in humans with SCI. Spinal cord injury (SCI) leads to long-term dysfunction and lifelong disability. There are hundreds of thousands of new patients suffering an SCI each year worldwide, and ninety percent of these SCIs are caused by traumatic events, including traffic accidents, falling, sports injuries, violence, etc. . SCI intThe pathophysiology of SCI involves primary injury and secondary injury. The primary injury is caused by acute mechanical trauma and results in vascular disruption, blood\u2013spinal cord barrier rupture, cell death , and interruption of neural fiber tracts in the spinal cord. The secondary injury references the consecutive pathological events triggered by the primary injury, such as hemorrhage, excitotoxicity, neuroinflammation, demyelination, astrogliosis and extracellular matrix (ECM) remodeling, which aggravate tissue damage, and compromise neuroplasticity . The curIn this review, we provide an overview of recent advances and challenges in SCI research and treatment. We summarize the recent progress regarding interventions after SCI in preclinical rodent and non-human primate models as well as in the clinical settings. We then discuss the current status and challenges with respect to clinical translation, prospect the future of SCI repair, and we highlight combinatory approaches and multidisciplinary cooperation are imperative to optimize clinical outcomes after SCI. This review provides an update of current strategies following SCI and provide researchers with new insights to develop more effective and targeted interventions to facilitate clinically meaningful recovery after SCI.The originally narrow concept of regeneration referred to the regrowth of transected axons across the lesion core to form functional synapses with their original pre-injury targets after SCI. The broad definition of regeneration now encompasses multiple forms of axon growth, including long-distance axon regrowth, compensatory sprouting of injured and spared supraspinal axons as well as propriospinal neurons, synapse remodeling, and circuit reorganization Fig. 1)Fig. 1). Axon outgrowth is driven by the growth cone, a motile structure located at the tip of the growing axon. Growth cone motility and axon growth are determined by the neuronal cytoskeleton, which includes microtubule and actin filament (F-actin) . MicrotuCytoskeletal dynamics and rearrangements are mainly modulated by two intracellular signaling pathways: glycogen synthase kinase 3\u03b2 (GSK3\u03b2) and Rho GTPases. GSK3\u03b2 is downstream of PI3K signaling and is inactivated through serine-9 phosphorylation within its amino-terminal region upon activation of the PI3K pathway. GSK3\u03b2 has been shown to be a crucial negative regulator of microtubule dynamics by phosphorylating multiple microtubule binding proteins (MBPs), such as collapsin response mediator protein 2 (CRMP-2), adenomatous polyposis coli (APC), and microtubule-associated protein-1B (MAP1B) . InhibitEnhancing cytoskeletal dynamics in the growth cone supports axon growth, whereas aberrant cytoskeletal dynamics following injury represents a major obstacle to axon regeneration. Therefore, manipulations targeting cytoskeletal dynamics may be potential strategies to induce axon regeneration of adult neurons following injury.Socs3 in adult retinal ganglion cells magnified JAK/STAT signaling, thereby inducing axon regeneration after optic nerve injury axons in the mouse spinal cord (Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is involved in regulating axon regeneration and cell survival. JAK is activated by growth factors and cytokines ) and then phosphorylates STATs, which transduce the signals to the nucleus and promote transcription of regeneration-associated genes (RAGs). Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of the JAK/STAT pathway. Ablation of e injury . Activatnal cord .Pten promotes mTOR activation and positively modulates regeneration of facial nerve and CST axons pathway plays a crucial role in regulating fundamental cell processes, including cell growth and metabolism, gene transcription, protein synthesis, and cytoskeletal remodeling . mTOR fuST axons . Activatneration .dlk-1 is sufficient to enhance regrowth capacity of injured axons in C. elegans , a highly conserved mitogen-activated protein kinase kinase kinase (MAP3K), plays a vital role in injury response, apoptosis, axon transport, and regeneration following injury both in the peripheral nervous system (PNS) and in the central nervous system (CNS) . Upon ax elegans . Germina elegans .Klfs), Sox11, Stat3, cAMP-response element binding protein (Creb), and hypoxia inducible factor-1a (Hif-1a) , which initiate pro-regenerative transcriptional programs and enable the reacquisition of regenerative potential. Previous studies have identified multiple pro-regenerative TFs, such as Kr\u00fcppel-like factors ((Hif-1a) . ManipulEpigenetic modifications, which include histone acetylation, DNA demethylation and hydroxymethylation, as well as modification of non-coding RNAs, facilitate access to gene regulatory regions by TFs, thus enabling active transcription of genomic regions and RAG expression. Epigenetic modifications play a key role in embryonic and adult neurogenesis . In receIt is difficult to achieve frank regeneration of injured axons beyond the lesion site in the adult mammalian CNS. Apart from limited intrinsic regenerative competence, multiple extrinsic barriers contribute to the axon regeneration failure. Among these, myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) represent the major inhibitors to axon regeneration following SCI. Nogo A, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) are three prototypical myelin-associated inhibitory molecules that exert inhibition on axon regeneration after injury in the adult CNS. These MAIs initiate intracellular Rho and ROCK signaling pathways through multiple receptors and eventually lead to growth cone collapse and prevent neurite extension . CSPGs aSpinal cord injury interrupts the connectivity of the spinal cord and leads to devastating neurological deficits. In addition, concomitant complications, including respiratory and urinary infections, gastrointestinal disorders, muscle atrophy, and chronic pain exacerbate clinical outcomes. Numerous novel approaches have been emerged to ameliorate SCI outcomes that can be divided into two parts: (i) relieving secondary damage via neuroprotection and (ii) fostering neuroplasticity and axon regeneration by triggering intrinsic regenerative mechanisms, ameliorating the extrinsic environment, and applying cell transplantation and neuromodulation technologies . Each ofThe primary mechanical injury to the spinal cord triggers a cascade of complex biological processes, termed the secondary injury, which cause further damage to the spared tissue and exacerbate neurological impairment and regeneration failure. Therefore, interventions that confer neuroprotection during the acute phase are crucial to suppress the spread of the secondary injury and to protect the spinal cord tissue from further damage. Several strategies have been deployed to attenuate the secondary damage. Pharmacological agents like methylprednisolone, minocycline, and cyclosporine A have been used to in patients with SCI to suppress secondary damage . HoweverIn recent years, a large number of novel neuroprotective approaches have emerged designed to counteract the progression of secondary injury. These therapies have demonstrated neuroprotective effects in preclinical studies and provide new perspectives for the treatment of clinical SCI. Oxidative stress following SCI leads to excess release of reactive oxygen species (ROS), which exacerbates secondary injury and results in axon degeneration and permanent neurological dysfunction. Antioxidant enzymes encapsulated in biodegradable nanoparticles have been shown to significantly reduce ROS activity and neuronal cell apoptosis, attenuate mitochondrial dysfunction, and improve locomotor recovery following severe contusive SCI in rats . In a moOveractivation of microglia after SCI exacerbates the inflammatory response and results in loss of neurons, gliosis, and synaptic damage. Inhibition of microglia proliferation by oral administration of the CSF1R inhibitor, GW2580, reduced neuroinflammation and improved locomotor function in mice and non-human primates following lateral spinal cord hemisection . MicroglWhile self-repair spontaneously occurs after injury in the adult mammalian PNS, mature neurons in the CNS fail to regain regenerative competence after SCI. Axon regeneration failure is mostly attributed to the poor intrinsic growth competence of the adult CNS neurons. Axon growth capacity sharply declines with age and is switched off upon maturation. However, over the last few decades, accumulating evidence suggests that axon regeneration and remodeling of neural circuits are possible via pharmacological, molecular, or genetic manipulations in the adult mammalian CNS . SubstanMicrotubule destabilization and actin disassembly following SCI lead to growth cone collapse and retraction bulb formation. The reformation of a growth cone-like structure from severed axon stumps is the first step in axon regeneration. Most manipulations aiming to augment axon regenerative ability eventually converge on cytoskeletal dynamics and remodeling within the growth cone.Rhoa knockdown was shown to enhance axon regeneration and reduce apoptosis, cavity formation, and astrogliosis in a rat compression SCI model , which is mainly produced in the mitochondria. SCI-induced mitochondrial dysfunction and energy deficits exacerbate axon regeneration failure. Syntaphilin (Snph) is a static anchor protein that holds axonal mitochondria stationary on microtubules via its microtubule-binding domain. Enhancing mitochondrial transport by in mice . The mit in mice .Intracellular signaling pathways, such as mTOR, JAK/STAT/SOCS3 and DLK regulate neuronal survival and axon growth. Accumulating evidence suggests that manipulating these pathways could enhance intrinsic growth competence and neuroplasticity after SCI.Socs3 triggered collateral sprouting of intact CST axons to the denervated spinal cord after unilateral pyramidotomy. Moreover, co-deletion of Pten and Socs3 further enhanced CST sprouting with significant restoration of skilled locomotion function, suggesting the reformation of functional circuits mediated by sprouting axons concentration by extruding Cl\u2212 from the cytosol. KCC2 has important roles in synaptic inhibition as well as in neuronal development and plasticity directly modulate transcription of RAGs and initiate the switch from the resting state to the robust regrowth state in damaged neurons. TFs have been shown to be an important determinant controlling axon growth potential in the mature CNS. Over the past decades, researchers have identified several candidate TFs that potentiate the regenerative capacity of injured axons after SCI.Klf6 or Klf7 promoted sprouting and regeneration of CST axons in adult mice promoted histone 3 Lys 9 acetylation (H3K9ac) following peripheral injury, and nal cord . Recent nal cord . These rnal cord . This stIn addition to limited intrinsic growth ability, the hostile microenvironment is another obstacle to axon regeneration after SCI. Indeed, extrinsic growth-inhibitory factors and the deficiency of neurotrophic factors further hamper neuroplasticity and axon regeneration. Therefore, removing inhibitory molecules and augmenting neurotrophic support contribute to render a more permissive environment and promote functional recovery following SCI.The presence of inhibitory factors surrounding the lesion site appears to be the major environmental obstacle to axon growth that prevents the injured axons from real regeneration. Removal of extrinsic inhibitory components by enzymatic degradation, receptor blocking, or antibody neutralization has demonstrated positive effects on axon regeneration and neurological restoration.Chabc gene expression was shown to promote recovery of skilled reaching and ladder walking performance as well as sensory axon conduction following cervical contusion injury in adult rats to specifically modulate PTP\u03c3 released the inhibitory effect of CSPGs on axon growth and markedly fostered functional recovery of sensory, locomotor, and urinary systems after contusive SCI in rats . InhibitAttenuating MAI-mediated inhibition can be achieved by antibody neutralization, receptor antagonists, and genetic inhibition. Anti-Nogo A treatment ameliorated lower urinary tract dysfunction and restored bladder function in rats with severe SCI . The firLotus overexpression has been proved to enhance axon regeneration of the raphespinal tract and reticulospinal tract fibers, suppress axonal dieback of CST fibers, and promote motor recovery in a mouse contusive SCI model into neurons and oligodendrocytes, and transplantation of Lingo-1 shRNA-treated NSPCs facilitated locomotor recovery in mice with contusive SCI are a family of proteins that direct neuronal survival, synaptic function, and axonal growth within the adult nervous system . NFs areBdnf vector into the lesion significantly enhanced sprouting of 5-HT+ axons and increased their synaptic connections with phrenic motor neurons (PhMNs), and contributed to recovery of diaphragm function following cervical SCI is a secreted protein that fosters neuron survival and synaptic plasticity. Delivery of BDNF mRNA with cationic polymers resulted in improved motor function recovery in a mouse model of contusive SCI . Intraspical SCI . Retrogrical SCI . Sustainical SCI . In addiical SCI . Insulin pathway . Igf-1 o in mice . Subcuta in mice . In addi in mice . Vascula in mice . VEGF wa in mice .The substantial loss of neurons and oligodendrocytes following SCI leads to disruption of neural network and signal transduction. Cell transplantation exhibits multitherapeutic capacities, such as replacement of damaged tissue, formation of relay neural circuits, immunomodulation, neuroprotection, and myelin regeneration, thus emerging as a more promising intervention to promote functional improvement following SCI . A varieNeural stem cells/neural progenitor cells (NSCs/NPCs) are self-renewing cells and can differentiate into specific neurons or glial cells to replace damaged spinal cord tissue. Implantation of NPCs/NSCs has shown great therapeutic potential in axon regeneration and functional restoration after SCI in rodents and primates . The obsMSCs are ideal candidate for cell-based therapies. MSCs raise no ethical concerns and can be acquired from diverse tissue sources like bone marrow, placenta, umbilical cord, and adipose tissue. Therefore, MSC transplantation is one of the most promising candidates for SCI repair. The therapeutic effects MSC transplantation after SCI are primarily due to their paracrine activity and trophic support: MSC-secreted factors modulate the immune response and induce neuroprotection, angiogenesis, and fiber regeneration in the injured spinal cord . In the SCs are another potential candidate for transplantation in patients with SCI. SCs have been shown to promote spinal cord repair through multiple mechanisms; they myelinate axons, reduce tissue injury, enhance neuroprotection, and maintain axonal plasticity. SCs are easily acquired from autologous nerve, thus alleviating the risk of immune rejections and avoiding the need for immunosuppression. SCs have demonstrated potential therapeutic effects in rodent SCI models, and their safety and potential efficacy have also been confirmed in clinical trials. A phase I clinical trial in humans with subacute SCI suggested that autologous human Schwann cell (ahSC) transplantation injected into the epicenter of the spinal lesion was safe and feasible. No serious adverse events or neurological complications were detected within in one year after transplantation . AnotherLike ahSCs, iPSCs derived from somatic cells avoid ethical concerns and immune rejection, and they can be reprogrammed to NPCs/NSCs, supporting human iPSC-derived NSC/NPC transplantation as a viable approach to treat SCI. Transplantation of human iPSC-derived NSCs facilitated axon growth and functional neural circuit reconstruction as well as motor function restoration after cervical spinal cord hemisection in rats . SimilarCollectively, the multiple observed therapeutic benefits associated with cell transplantation makes cell-based therapy an attractive approach that could substantially improve outcomes for patients with SCI. However, some remaining issues may limit their clinical practice, including ethical controversy, cell source, intervention time, uncontrolled cell proliferation, and long-term safety. Continued efforts to resolve these issues and concerns could make cell transplantation a feasible clinical option.The descending motor pathways are severely interrupted after SCI. Although the spinal neural circuits below the injury level remain intact, the absence of supraspinal descending commands leads to the circuits functionally dormant and loss of motor function. Neuromodulation is a bioengineering approach that utilizes electrical or magnetic stimulation, pharmacological agents, optogenetics, and chemogenetics to modulate neuronal activity. Neuromodulation has been successfully applied in a variety of neurological diseases. Neuromodulatory technologies applied for SCI aim to reactivate the spinal intrinsic motor circuits below the lesion and ultimately restore the basic motor function and/or voluntary movements. These neuromodulatory inventions primarily include spinal cord stimulation, brain stimulation, and brain\u2013machine interface.Spinal cord stimulation is emerging as a potential therapy to alleviate neurological deficits and promote functional recovery following SCI. Epidural electrical stimulation (EES), transcutaneous spinal cord stimulation (tcSCS) and intraspinal microstimulation (ISMS) are the three forms of spinal cord stimulation that designed to facilitate functional restoration after SCI.Epidural electrical stimulation (EES) applied to the lumbosacral spinal segments has been shown to substantially restore locomotion and motor control after SCI both in preclinical and clinical studies. Paralyzed rats treated with EES were able to perform continuous stepping, walking, and even climbing staircases . Co-deliContinuous EES may abolish proprioceptive information in humans and restrict locomotion recovery. In contrast, spatiotemporal EES enhanced the active control of motor neurons while preserving the interaction between antagonistic muscles to ensure coordination and stability of lower limb movement . SpatiottcSCS is another well-developed form of spinal cord stimulation and has been demonstrated to restore motor, sensory, and autonomic function when used alone or combined with other interventions . tcSCS iPrevious studies have indicated that even clinically complete SCI spares some descending nerve fibers, but they are dormant and insufficient to trigger movement. Brain stimulation has been used to engage the residual motor circuits to restore voluntary limb movement after SCI. The brain stimulation strategies mainly include deep brain stimulation (DBS), transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS).DBS is a well-established technique that activates neural activity of the target brain region via implanted electrode. Motor cortex electrical stimulation was shown to promote CST axon sprouting, and the combination of motor cortex stimulation and transcutaneous spinal direct stimulation (tsDCS) further augmented CST axon plasticity and restored forelimb motor function after rat spinal cord contusion . This coBrain\u2013machine interface (BMI) has emerged as a novel technique that combines engineering, computer science, and neurophysiology to restore sensorimotor functions in patients with severe neurological disability . BMI recA participant with quadriplegia from cervical SCI regained cortical control of dexterous hand movements using BMI. The participant\u2019s forearm muscles were reactivated and controlled by the intracortically recorded signals, ultimately enabling complete functional movement task like grasping, manipulating, and releasing objects . An indiThe wireless brain\u2013spine interface was employed to directly link the intended motor states decoded from leg motor cortex activity to spatiotemporal EES over the lumbosacral segment to re-establish voluntary control of leg activity. This approach alleviated gait deficits and enabled weight-bearing locomotion on a treadmill and overground in rhesus monkeys with unilateral corticospinal tract lesion during the first week post-injury . As obseNeuromodulation therapies have achieved unexpected efficacy in restoring locomotion and volitional control in both SCI animal models and individuals with SCI. Therefore, these neuromodulatory technologies might be the most promising approach to achieve meaningful functional recovery following SCI.Individual treatments are insufficient to restore meaningful locomotion due to the complex pathological responses after SCI. Therefore, combinatory approaches targeting diverse aspects of SCI pathology are warranted to facilitate functional recovery in humans with SCI. Biomaterials serve as physical and structural supports to guide axon outgrowth and have been widely applied in the treatment of SCI. Meanwhile, biomaterials act as a key component of combinatorial approaches, as they provide temporary storage substrates for the long-term release of drugs, bioactive molecules, and transplanted cells to modulate inflammation, neural plasticity, axon regeneration, and cell survival .Combined delivery of multiple growth factors and chemokines released from hydrogel depots elicited robust propriospinal axon regrowth after complete SCI in both mice and rats. The regenerating propriospinal axons formed synapse-like contacts with neurons below the lesion site and restored electrophysiological conduction across lesions . The supLycium barbarum oligosaccharide (LBO) promoted microglia towards M2 polarization. Combination of LBO, nasal mucosa-derived mesenchymal stem cells, and fibronectin hydrogel synergistically enhanced the M2 polarization of microglia and promoted axon remyelination and recovery of hind limb movement after complete spinal cord transection in rats was shown to promote functional recovery in rodent models of SCI, and its safety and feasibility were confirmed in preliminary phase I/IIa clinical trial. However, the phase 3 clinical trial failed to show significant benefit of G-CSF in the primary end point . A few oAlthough encouraging results have been achieved in SCI animal models, interventions that are effective preclinically demonstrate little efficacy to produce functional improvements when translated into clinical trials. Therefore, the beneficial outcomes from rodent models are not always reproduced in clinical practice. One possible reason is the limitation of rodent models for predicting efficacy in human SCI. The anatomy and size of the spinal cord vary greatly between rodents and primates. For instance, the anatomical characteristics and function of descending pathways involved in motor control demonstrates pronounced interspecies differences between rodents and primates. In rodents, the CST fibers mostly travel in the dorsal columns of the spinal cord, and no direct connections exist between CST fibers and the cervical motoneurons. By contrast, in humans and non-human primates, the CST fibers are mainly located in the lateral columns and have developed direct connections with motoneurons . In addiFuture clinical trials for the treatment of SCI should be designed after considering several factors that may influence outcomes. Accumulating more data and comprehensive preclinical testing is essential before initiating clinical trials to minimize the risk of patients experiencing adverse effects or undergoing futile treatment. Moreover, the lack of reproducibility and robustness in preclinical experiments is another major issue contributing to the failure of clinical translation . Thus, iIndividual therapeutic interventions are inadequate to resolve the multifaceted pathological processes that occur after SCI and to promote spinal cord repair. Multi-targeted, combinatorial approaches are expected to maximize therapeutic effect. However, this becomes more complicated because many aspects must be taken into account when different strategies are combined. For instance, the optimal temporal window of treatment and whether the treatments are safe, tolerable, and feasible in combination must be determined to identify the most effective synergistic strategies. To optimize combinatorial strategies, determine analytical frameworks and achieve clinically relevant recovery in patients with SCI, it is therefore essential to enhance collaboration and communication between basic researchers and clinicians.Spinal cord injury interrupts the descending motor pathways and ascending sensory fibers within the spinal cord, leading to multi-system dysfunction and permanent disability. To alleviate the devastating effects of SCI, researchers have developed a variety of novel therapeutic approaches in recent years, some of which have shown promising therapeutic efficacy in preclinical studies and are progressing to clinical trials. This review summarizes the recent progress of preclinical and clinical strategies in SCI treatment and discusses the challenges and prospects for spinal cord repair.Despite encouraging results in preclinical experiments, many interventions have failed to translate to clinical application. This translational failure is partially due to the complex and multifaceted features of SCI pathology. Hence, a better understanding of the pathological processes following SCI and thorough investigation of intrinsic and extrinsic mechanisms controlling axon growth are urgently warranted to develop novel strategies to achieve greater beneficial outcomes. Notably, most individual therapeutic strategies targeting a single pathophysiological mechanism are insufficient to achieve relevant efficacy, resulting in clinical translation failure. Combinatorial strategies that act on multiple pathological processes of SCI have been shown to be more effective than individual treatments alone. Therefore, combinatorial approaches are more promising to wok synergistically to overcome multiple regeneration barriers and foster neural repair in patients with SCI. Furthermore, multidisciplinary collaboration and conversations are essential to ensure the accuracy of therapeutic design and predictive analysis.Neuronal regeneration or the formation of relay neural circuits after SCI is not necessarily accompanied by associated functional improvement. Rehabilitation training could augment the adaptive plasticity of residual pathways and is expected to trigger reorganization and integration of neural circuitry to promote longer-lasting functional readouts. Together with appropriate rehabilitation, combinatorial strategies might further enhance recovery of neurological function in clinical SCI. Furthermore, it is vital to select appropriate animal models for preclinical studies, and potential strategies should be extensively investigated preclinically in diverse SCI animal models to validate their therapeutic effects. Pronounced species divergence exists between primates and rodents or carnivores, and non-human primate models are particularly relevant for designing interventions and validating their therapeutic potential before translated to clinical application. In the future, further investigation is warranted to identify the neural regenerative mechanisms of functional recovery after SCI, especially in non-human primate models, as they are more similar to those in humans. These studies might be crucial to develop novel therapeutic interventions targeting particular neural circuits to improve function restoration."}
{"text": "Lacrimal gland enlargement can be a feature of thyroid eye disease (TED). Unilateral or asymmetric lacrimal gland enlargement is poorly described and may impede diagnosis. We present the histological and clinical findings of four patients with asymmetric lacrimal gland enlargement.A retrospective case note review was performed for patients over two tertiary orbital clinics presenting with an asymmetrical lacrimal gland enlargement with a background of TED that underwent biopsy to exclude alternate diagnoses. Baseline data was collected for each patient and histopathological images and reports were reviewed.All four patients were hyperthyroid at time of lacrimal gland biopsy. Biopsy demonstrated nonspecific, lymphoid aggregates, typically of B cell type, with no diagnostic findings to support lymphocyte clonality or IgG4-related disease. One biopsy specimen demonstrated evidence of some fibrosis.Asymmetrical lacrimal gland enlargement can occur as part of the TED spectrum but may require biopsy to exclude alternate pathology. Histology demonstrates a non-specific lymphocytic infiltrate. Thyroid eye disease (TED) is the commonest cause of orbital inflammation in adults. It can result in expansion and fibrosis of the extraocular muscles and orbital fat . RadioloThe purpose of this study is to report on the histopathological findings of lacrimal gland biopsies in patients with asymmetric lacrimal gland enlargement.A retrospective review of clinical case notes was performed for all patients presenting to two units between the years 2013 to 2020. Inclusion criteria included patients with known thyroid dysfunction, upper eyelid retraction and/or lid lag in keeping with thyroid eye disease, clinical and/or radiological findings of lacrimal gland enlargement, magnetic resonance imaging (MRI) of the orbits and subsequent lacrimal gland biopsy and serological investigations (eg serum immunoglobulin subclasses) to exclude concurrent disease.Baseline data for each patient was collected including age, sex, ocular comorbidity, laterality, ophthalmic findings, and histopathological findings. Clinical Activity Score (CAS) was obtained for the patient\u2019s initial presentation. The CAS evaluates inflammatory signs and symptoms that are often characteristic of active TED.Ethical approval for this study was not required as per the Human Research Authority (HRA) online decision-making tool. Informed consent was provided by each patient for the procedure and use of clinical information.Four patients were identified through case note review Table . The meaThree of the four patients presented with upper lid retraction. All four patients had inactive disease. Other common presentation features included lid lag and proptosis. MRI had been requested as routine baseline imaging of the orbital contents.All patients were biochemically hyperthyroid and demonstrated asymmetrical lacrimal gland enlargement on MRI (Fig.\u00a0Histopathological analysis of lacrimal gland biopsy specimens showed nonspecific chronic inflammation composed largely of B lymphocytes in all four cases Figs.\u00a0,\u00a03,\u00a04. OLacrimal gland enlargement is a common finding in TED and particularly in the active stage of the disease , 6, 7. ARadiological findings may assist the decision-making regarding biopsy of the lacrimal gland. Epithelial neoplasms predominantly involve the orbital lobe whilst inflammatory and lymphoproliferative lesions tend to involve both the orbital and palpebral lobes . LymphopPreviously reported lacrimal gland histopathological findings in TED have also shown nonspecific inflammatory cell infiltration with and without fibrosis , 13, 14.These nonspecific histological changes, to some extent, diagnoses thyroid eye disease by exclusion, given the lack of a specific histopathological marker, although there remains the possibility of other concurrent, non-specific, diseases such as idiopathic dacryoadenitis that tend to present unilaterally.All four patients in the present study were hyperthyroid which contrasts with previous studies which have shown asymmetric TED clinical presentations predominantly in euthyroid or hypothyroid disease states , 18, 19.There are several limitations to this study. Firstly, the retrospective and non-comparative design limit inferences that can be drawn. Secondly, a standard set of immunohistochemical testing was not undertaken due to the retrospective and multi-centre nature of the study. Finally, we have included a small number of patients, although this may reflect the relatively uncommon nature of TED-related, asymmetric lacrimal gland enlargement.This study confirms that those patients with lacrimal gland enlargement presumed secondary to TED typically show nonspecific chronic inflammatory changes on histopathological analysis. Lacrimal gland biopsy is prudent given concurrent malignant or inflammatory disease is possible with asymmetrical enlargement although radiological imaging modalities of the lacrimal gland show promise in diagnosing active TED."}
{"text": "Brain structural and functional alterations have been consistently proposed to be involved in the neurobiological underpinnings of aging and neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease. Given that pathological perturbations of the central nervous system are often intertwined with brain connectivity alteration, it is becoming increasingly accepted that connectome reorganization plays a key role in determining cognitive or motor disability. The advances in connectome-wide association studies (CWAS) have the potential to allow for the identification of novel neural correlates of neurodegeneration at the whole-brain scale, elucidating how brain-network topology can shape neural responses to neurodegenerative damage.This Research Topic aims to encourage the proposal of state-of-the-art methodologies related to CWAS techniques and their applications to neurodegenerative disorders. A total of five studies collected in this topic mainly cover (1) advanced statistical methods to avoid multiple covariates in analyzing brain connectivity; (2) a data-driven CWAS design to clarify and validate brain network findings associated with aging in a large sample of subjects; (3) a virtual analytical approach to describe brain disconnectome reorganization while avoiding the issue of artifacts that are prone to occur in the presence of white matter hyperintensity; (4) advanced dynamic connectivity measurements as novel brain imaging markers to discriminate AD patients at different stages; and (5) the brain structural covariance network analysis and related novel statistical model to unravel pathological progression of AD. In what follows, we summarized the highlights the methodologies and applications in aging and related neurodegeneration of each article.Smith et al. proposed a subject-level regression model to consider multiple covariates, including parcel-wise geographic/homotopic distance and region or network belongings, to move away from reliance on localization assumptions underlying FC comparisons. The key point is to keep each individual's FC in its own geometry, without morphing to a common template. This could be extraordinarily useful when the extent and location of lesions to brain regions varies across subjects. Additionally, the authors demonstrated high repeatability of this model achieved in individual space with test-retest individual scans.Functional connectivity (FC) comparison across individuals can be challenging in CWAS due to complex covariates in inter-subject variations. Du et al. applied a priori-driven independent component analysis, named NeuroMark, on 6,300 healthy adult with an age range of 49\u201373 years from UK Biobank project. They highlighted multiple significant joint between-network FC changes related to aging occurred in default mode and sub-cortical networks. This spatial diversity of brain network reorganization revealed by CWAS may shed new light on mechanism underlying aging-related brain changes.How aging affects functional networks of the brain in both within-network and between-network connectivity is unclear. To comprehensively explore this effect, Li et al. addressed the focal effect when analyzing brain structural network. To avoid potential confounds of white matter hyperintensity (WMH) in CWAS, the authors proposed a virtual lesion approach to estimate brain connectivity changes in aging. Specifically, WMH frequency maps across age ranges were used to generate virtual lesion masks for each decade as regions of avoidance in white matter tractography. They quantitatively described the spatial disconnectome evolving patterns in cortical and subcortical areas, which might underlie cognitive and sensorimotor deficits seen in aging. The advancement of this virtual lesion approach can further help identify brain disconnectome features contributing to dementia risk.Another study conducted by Penalba-S\u00e1nchez et al. compared multiple FC measurements and evaluated their corresponding network segregation and integration in mild cognitive impairment and AD. The authors unexpectedly observed an increase in late stage AD and a slight decrease of FC in early MCI, and explained the potential underlying cognitive mechanism. Understanding the dynamic and non-linear nature of FC might be crucial for unraveling the unclear neuropathological factors affecting behavior symptoms along the trajectory of AD.Emerging evidence has supported that abnormal brain structural or functional connectivity could have been observed 10\u201320 years prior to the onset of clinical symptoms of AD. Aiming to clarify inconsistent brain FC findings in early stage of AD, the study conducted by Xiao et al. applied SCN analysis using T1-weighted MR images from a longitudinal cohort to examine whether and how earlier brain atrophy patterns impact the progressive changes of gray matter atrophy in AD patients over time. After establishing regular structural connectivity by Pearson correlation and causal structural connectivity by Granger causal analysis, they used a new approach named gray matter based spatial statistics to measure the gray matter volume at the core of the cortical plate, aiming to alleviate partial volume effect and inter-subject variability. High discrimination accuracy based on SCN connectivity features suggests that SCN approach may help identify the unique pathological progression of AD and other types of neurodegeneration.Unlike structural connectivity, which is classically represented by the connection strength of white matter tracts on individual level, brain structural covariance network (SCN) analysis highlights synchronized gray matter atrophy undergoing neurological pathological processes across brain regions on population level. In sum, the collective findings represented in these articles reflect the rapidly expanding development of the CWAS field. One could further expect a rising body of brain network analytical tools and statistical models updated in this emerging area, providing new avenues for identification of brain network markers related to aging and neurodegenerative disorders. However, whether and to what degree the brain network construction procedures affects robustness of findings in neurodegeneration is still in dispute. Therefore, before further translating into clinical applications such as individual auxiliary diagnosis and treatment decision-making, we must be cautious whether the reliability and validity performance of these CWAS approaches has been fully reported and validated in large-sample and multi-center brain imaging data.CY: Writing\u2014original draft. TW: Writing\u2014review & editing. AF: Writing\u2014review & editing."}
{"text": "This review article delves into the intricate and evolving relationship between coronary microvascular dysfunction (CMD) and takotsubo cardiomyopathy (TCM), two intriguing cardiovascular conditions increasingly recognised for their potential interplay. We examine their characteristics, shared pathophysiological mechanisms, diagnostic challenges, and management strategies. Emerging evidence suggests a link between microvascular dysfunction and the development of TCM, leading to a deeper exploration of their connection. Accurate diagnosis of both conditions becomes essential, as microvascular dysfunction may modify TCM outcomes. We underscore the significance of understanding this connection for improved patient care, emphasising the need for tailored interventions when CMD and TCM coexist. Collaborative research and heightened clinical awareness are advocated to advance our comprehension of this relationship. Through interdisciplinary efforts, we aim to refine diagnostic precision, develop targeted therapies, and enhance patient outcomes in cardiovascular medicine. Medical interest has surged toward two distinct yet captivating cardiovascular conditions: coronary microvascular dysfunction (CMD) and takotsubo cardiomyopathy (TCM). While initially perceived as separate entities, recent research hints at a potentially intricate link between these conditions. This article delves into this complex interplay between CMD and TCM, probing their shared pathophysiological mechanisms, clinical presentations, diagnostic challenges, and treatment implications -3.Coronary microvascular dysfunction encompasses a spectrum of disorders characterised by anomalies in the microvasculature's structure and function within the coronary circulation. Unlike traditional coronary artery disease, which affects large epicardial vessels, CMD involves dysfunction in the smaller arterioles and capillaries that regulate myocardial blood flow. Despite the absence of significant obstructive coronary artery disease, CMD leads to angina-like symptoms, myocardial ischemia, and abnormal stress test results. The elusive nature of CMD and its limited diagnostic tools pose challenges in diagnosis, rendering understanding its underlying mechanisms and clinical significance increasingly pivotal ,5.In contrast, TCM, or \"broken heart syndrome,\" manifests as transient left ventricular dysfunction mimicking acute myocardial infarction. Chest pain, electrocardiographic changes, and elevated cardiac biomarkers typify this condition. Often arising from emotional or physical stressors, TCM's hallmark is the unique apical ballooning pattern evident in cardiac imaging. While initially viewed as reversible with a favourable prognosis, recent research illuminates potential severe complications and enduring consequences ,7.The realisation of a possible connection between CMD and TCM carries profound ramifications for both clinical practice and research. Evidence suggests that patients with TCM often exhibit microvascular dysfunction, hinting at an underlying link between these conditions. Understanding this association could offer insights into the triggers and pathogenesis of TCM. Furthermore, discerning the relationship between CMD and TCM stands to shape therapeutic strategies and enhance patient outcomes ,9.This review comprehensively explores the evolving relationship between CMD and TCM. We offer a holistic perspective on their shared pathophysiological mechanisms, clinical manifestations, diagnostic hurdles, and therapeutic implications by delving into the crossroads of these two distinct yet potentially intertwined conditions. Through a critical analysis of existing research, clinical observations, and theoretical models, our synthesis aims to provide healthcare professionals, researchers, and clinicians with an exhaustive resource. This resource illuminates conceivable connections between CMD and TCM, emphasising the importance of recognising and addressing this association in clinical practice. Our in-depth examination of CMD and TCM's complexities strives to advance medical understanding, enhance patient care, and formulate precise strategies for managing these captivating cardiovascular conditions.Coronary microvascular dysfunction (CMD)Definition and Pathophysiology of CMDCoronary microvascular dysfunction encompasses a spectrum of disorders characterised by intricate abnormalities within the smaller coronary vessels, including arterioles and capillaries. In contrast to traditional coronary artery disease, which primarily affects the larger epicardial vessels, CMD homes in on the delicate microcirculation. To comprehensively understand CMD's pathophysiology, it's crucial to explore the underlying mechanisms that have been identified. Endothelial dysfunction stands at the forefront of CMD's pathophysiology, playing a pivotal role in impairing the functionality of the microvasculature. This dysfunction is intricately linked to the imbalance of vasoactive factors and nitric oxide availability, ultimately affecting the vascular tone and endothelium-dependent vasodilation . MoreoveClinical Presentation and Diagnostic ChallengesThe clinical presentation of CMD\u00a0closely mirrors that of obstructive coronary artery disease, making it challenging to distinguish between the two based solely on symptoms. Patients with CMD often report chest pain, dyspnea (shortness of breath), and exercise intolerance, commonly associated with traditional coronary artery disease. This similarity in symptoms can lead to confusion in diagnosis, mainly when relying solely on clinical presentation .One of the critical diagnostic challenges in CMD lies in the limitations of conventional diagnostic tests, such as angiography. Unlike obstructive coronary artery disease, CMD does not involve significant narrowing or stenosis of the larger coronary arteries, typically visualised through angiography. This absence of visually apparent coronary stenosis can lead to underdiagnosis or misdiagnosis, as these tests may not capture the microvascular abnormalities characteristic of CMD .Furthermore, the need for well-defined diagnostic criteria and standardised assessments for CMD exacerbates the difficulty in identifying the condition accurately. The absence of universally accepted guidelines to diagnose CMD makes it challenging for healthcare practitioners to consistently recognise and differentiate it from other cardiac conditions. This lack of standardised criteria also hampers research efforts and makes it difficult to compare findings across studies .The confluence of overlapping symptoms, along with the limited sensitivity of existing diagnostic tests, contributes to a significant underrecognition and underdiagnosis of CMD. This diagnostic shortfall is consequential, potentially resulting in treatment delays and impacting patient outcomes. An appreciable aspect to consider is the percentage of undetected cases due to these challenges. Additionally, it is pertinent to discuss the sensitivity and specificity of the employed diagnostic tests and the symptoms associated with CMD. As the landscape of CMD research evolves, the need becomes apparent to establish standardised diagnostic criteria and innovative diagnostic techniques. By addressing this pressing need, the accurate identification and effective management of this intricate condition can be significantly improved .Underlying Causes and Risk FactorsCoronary microvascular dysfunction is a complex condition influenced by various underlying causes and risk factors extending beyond traditional cardiovascular risk factors. While hypertension, diabetes, and dyslipidemia are recognised as conventional contributors to CMD, a growing body of evidence highlights the significance of non-traditional risk factors in its development .Psychosocial stress emerges as a potent contributor to CMD. Chronic stress triggers the release of stress hormones, leading to endothelial dysfunction and impaired vasomotor responses in the coronary microvasculature. This can result in reduced myocardial blood flow regulation and contribute to the manifestation of CMD symptoms .Hormonal imbalances play a role in CMD pathogenesis, particularly in women. Oestrogen, for instance, exerts protective effects on endothelial function, and its decline during menopause might contribute to microvascular dysfunction. Hormonal fluctuations during the menstrual cycle also influence vasomotor responses, potentially impacting coronary microcirculation .Systemic inflammation is increasingly recognised as a critical player in CMD. Chronic inflammation contributes to endothelial dysfunction, oxidative stress, and impaired nitric oxide bioavailability. Inflammatory cytokines can directly affect coronary microvascular function, altering vasodilation responses and contributing to CMD .Endothelial dysfunction, a hallmark feature of CMD, is a common link between these risk factors. It disrupts the delicate balance between vasodilation and vasoconstriction, impairing coronary blood flow regulation. Endothelial dysfunction contributes to the microvascular abnormalities observed in CMD and lays the groundwork for developing ischemic symptoms ,20.Available Diagnostic Techniques for CMDCoronary flow reserve measurements using Doppler ultrasound: Doppler ultrasound measures blood flow velocities within the coronary arteries during rest and stress. The coronary flow reserve is assessed by calculating the ratio of flow velocities before and after vasodilation. Reduced coronary flow reserve indicates microvascular dysfunction and impaired vasodilatory capacity, which can contribute to myocardial ischemia ,22.Positron emission tomography (PET): Positron emission tomography imaging quantitatively assesses myocardial blood flow at rest and during stress, usually induced by pharmacological agents or exercise. The comparison of these flow measurements provides insights into the functionality of the microvasculature. Positron emission tomography can help identify regions of reduced perfusion and abnormalities in microvascular function, contributing to the diagnosis of CMD ,24.Cardiac MRI: Cardiac MRI offers non-invasive visualisation of the myocardium and surrounding structures. Techniques like myocardial perfusion imaging provide information about blood flow distribution, aiding in identifying microvascular dysfunction. Cardiac MRI can help evaluate myocardial oxygen supply-demand balance and detect ischemic regions without obstructive coronary artery disease ,26.Invasive coronary reactivity testing: Invasive procedures involving the administration of vasoactive agents within the coronary arteries allow for direct assessment of microvascular function. Endothelial-dependent and independent vasodilatory responses are measured, providing insights into microvascular dysfunction. However, the invasiveness of this approach limits its routine clinical use ,28.Despite the availability of these diagnostic techniques, challenges persist in interpreting results and establishing definitive diagnostic criteria. The lack of standardised protocols and reference values makes establishing universally accepted thresholds for diagnosing CMD difficult. Variability in patient populations, equipment, and procedural protocols further complicates result interpretation. Overcoming these challenges requires collaborative efforts among researchers and clinicians to establish consensus guidelines and refine the diagnostic approach for CMD, ultimately enhancing its recognition and management .Current Treatment Strategies for CMDLifestyle modifications: Lifestyle interventions stand as the cornerstone of CMD management. Encouraging patients to adopt a heart-healthy lifestyle is paramount. This includes regular physical exercise tailored to individual capabilities, as exercise has been shown to enhance endothelial function and improve microvascular health. Furthermore, weight management plays a pivotal role, as excess body weight can contribute to metabolic disturbances and exacerbate microvascular dysfunction. Smoking cessation is of utmost importance, given that smoking damages endothelial cells and worsens microvascular health. Additionally, addressing psychosocial stressors through stress reduction techniques, mindfulness, and psychological counselling can contribute to overall well-being and potentially mitigate the impact of stress on microvascular function ,31.Pharmacological interventions: Pharmacotherapy for CMD aims to alleviate symptoms, enhance microvascular function, and target underlying risk factors. Endothelial function-enhancing agents, such as angiotensin-converting enzyme (ACE) inhibitors and statins, promise to improve endothelial health and promote vasodilation. Vasodilators, such as calcium channel blockers and nitric oxide donors, can help alleviate microvascular constriction and enhance coronary blood flow. Additionally, anti-inflammatory agents are being explored due to their potential role in reducing vascular inflammation and improving microvascular function ,33.Patient education and psychosocial support: Patient education is integral to holistic CMD management. Empowering patients with knowledge about their condition, its underlying mechanisms, and the significance of lifestyle modifications fosters active participation in their care. Moreover, addressing psychosocial stressors, including anxiety and depression, is essential, as these factors can exacerbate microvascular dysfunction. Psychological support and counselling can help patients cope with CMD\u2019s emotional and psychological impact, promoting a holistic approach to well-being ,35.Takotsubo cardiomyopathy (TCM)Definition and Characteristic Features of TCMTakotsubo cardiomyopathy, often called \"broken heart syndrome,\" is a unique and transient condition characterised by acute left ventricular dysfunction, typically presenting with symptoms resembling acute myocardial infarction. The hallmark feature of TCM is the distinctive ventricular ballooning observed during cardiac imaging, which resembles a Japanese octopus trap known as \"takotsubo.\" Left ventricular dysfunction typically involves the apex but can also affect other heart segments .Proposed Mechanisms for TCM DevelopmentThe precise mechanisms driving the development of TCM\u00a0remain a subject of continuous investigation and exploration. Multiple hypotheses have emerged, each offering insights into the intricate cascade of events that culminate in this unique cardiac phenomenon. These mechanisms include but are not limited to, surge-induced myocardial stunning, microvascular dysfunction, coronary artery vasospasm, and neurogenic influences .Catecholamine surge-induced myocardial stunning: One of the prominent theories centres around the significant role of the autonomic nervous system's response to stress. A sudden and excessive release of stress hormones, particularly catecholamines such as adrenaline, is thought to trigger a surge-induced myocardial stunning. This stunning effect results in transient myocardial dysfunction, marked by impaired contractility and ventricular ballooning .Microvascular dysfunction: Another hypothesis emphasises the role of microvascular dysfunction in TCM development. Under the influence of stress hormones, there is potential for the small coronary vessels, including arterioles and capillaries, to undergo dysregulation. Microvascular dysfunction disrupts normal blood flow regulation, leading to inadequate myocardial oxygen supply. This compromised perfusion contributes to myocardial stunning and the characteristic ventricular ballooning observed in TCM cases .Coronary artery vasospasm: The involvement of coronary artery vasospasm is also proposed as a mechanism for TCM initiation. Stress-induced alterations in vasomotor tone could trigger transient spasms in the coronary arteries, leading to reduced blood flow to the heart muscle. This diminished blood supply can result in myocardial dysfunction, with the apical region particularly susceptible due to its anatomical characteristics .Neurogenic influences: Neurogenic factors, including the brain-heart connection, have gained attention as potential contributors to TCM development. Emotional stressors can stimulate the autonomic nervous system, leading to altered heart rate variability, sympathetic nervous system activation, and hormonal fluctuations. This complex interplay between the brain and the heart might contribute to the intricate pathophysiology of TCM .Clinical Presentation and Diagnostic Criteria for TCMTakotsubo cardiomyopathy is characterised by a distinctive clinical presentation and diagnostic criteria that differentiate it from other cardiovascular conditions. The hallmark symptom is the sudden onset of chest pain, often accompanied by dyspnea, palpitations, and a feeling of impending doom. This presentation can closely mimic acute coronary syndrome, particularly ST-segment elevation myocardial infarction (STEMI), leading to initial diagnostic challenges .Diagnostic criteria for TCM have evolved to aid in accurate differentiation from other cardiac pathologies. Transient left ventricular dysfunction is a central feature of TCM, with echocardiography and cardiac MRI serving as crucial tools for its visualisation. Coronary angiography reveals the absence of significant coronary artery stenosis or plaque rupture, further supporting the diagnosis. This differentiation is paramount, as TCM is managed differently from acute coronary syndromes .Also, diagnostic criteria exclude other conditions that might mimic TCM's presentation. Pheochromocytoma, a rare tumour causing excess catecholamine release, and myocarditis, inflammation of the heart muscle, should be ruled out due to their potential to induce similar stress-related myocardial dysfunction .Cardiac imaging, particularly echocardiography and cardiac MRI is indispensable in confirming the diagnosis. Echocardiography unveils the hallmark feature of TCM, the unique apical ballooning pattern, which distinguishes it from other cardiac pathologies. Cardiac MRI further enhances diagnostic accuracy by providing detailed insights into myocardial tissue characteristics and perfusion patterns, facilitating the differentiation of TCM from other conditions presenting with similar symptoms .Differentiating TCM from Acute Coronary SyndromeDistinguishing TCM\u00a0from acute coronary syndrome (ACS) is paramount due to their shared clinical presentations, which often include chest pain, dyspnea, and electrocardiographic changes. One crucial distinction is the absence of culprit coronary lesions on angiography in TCM cases. Unlike ACS, where obstructive coronary artery disease is typically evident, TCM patients display normal or near-normal coronary arteries. This disparity emphasises the need for comprehensive angiographic evaluation to exclude coronary artery obstruction and confirm the absence of significant stenosis .Furthermore, TCM patients tend to exhibit less pronounced elevations in cardiac biomarkers, such as troponin levels, when compared to the more typical ACS cases. While troponin elevation is a hallmark of myocardial injury, the extent of elevation in TCM is often milder than observed in ACS, further aiding differentiation. However, it is essential to note that a certain degree of troponin elevation can still be present in TCM cases, underscoring the importance of integrating multiple diagnostic criteria .Cardiac imaging is an invaluable tool in the differentiation process, particularly echocardiography and cardiac MRI. The characteristic apical ballooning pattern observed during imaging is a hallmark of TCM. This distinctive morphology, resembling the shape of a Japanese octopus trap (takotsubo), is a strong differentiator from ACS. Imaging findings directly visualise ventricular dysfunction and shape abnormalities, providing critical insights into the diagnosis .Management and Prognosis of TCMTakotsubo cardiomyopathy management encompasses a multi-faceted approach focused on supportive care to stabilise hemodynamics, address complications, and alleviate symptoms. Given the acute nature of TCM, patients often require vigilant monitoring in a specialised cardiac care setting. Stabilising hemodynamics involves carefully managing fluid balance, blood pressure, and heart rate to ensure optimal cardiac function. Efforts to maintain adequate perfusion and oxygenation are crucial, and interventions like supplemental oxygen and intravenous medications might be employed as necessary .Furthermore, addressing potential complications is of paramount importance in the management of TCM. Patients with TCM are at risk of developing heart failure due to transient left ventricular dysfunction. Standard heart failure therapies, including diuretics and beta-blockers, may be considered to manage volume overload and control heart rate. Arrhythmias, such as atrial fibrillation or ventricular tachycardia, might occur in the acute phase and necessitate appropriate treatment to restore a stable cardiac rhythm. Additionally, systemic embolism, particularly involving the left ventricular clot or thrombus formation, is a potential complication that requires attention to prevent embolic events .Most TCM cases exhibit a favourable prognosis with the spontaneous recovery of left ventricular function within weeks to months. Serial cardiac imaging, such as echocardiography or cardiac MRI, is valuable for monitoring the improvement in ventricular function over time. The heart's remarkable ability to heal and return to normal functioning underscores the transient nature of TCM. However, vigilance remains essential, as some cases might experience a protracted recovery period or recurrent episodes .Lifestyle modifications and addressing psychosocial factors play a crucial role in the long-term prognosis of TCM patients. Encouraging patients to adopt heart-healthy habits, including maintaining a balanced diet, engaging in regular physical activity, and avoiding tobacco and excessive alcohol consumption, contributes to overall cardiovascular well-being. Addressing underlying stressors and providing psychological support is equally important, as emotional triggers often precede TCM episodes. Comprehensive care extends beyond the acute phase to mitigate the potential triggers for recurrent episodes and optimise long-term cardiac health .The interplay between CMD and TCMReview of Studies Suggesting a Connection between CMD and TCMRecent years have witnessed a burgeoning body of research that unveils the captivating prospect of a multifaceted interplay between CMD\u00a0and TCM. This intriguing association has emerged through meticulously scrutinising diverse studies, including case reports and retrospective analyses. These inquiries have illuminated instances where TCM manifested in individuals previously displaying indications of underlying microvascular dysfunction. These preliminary observations have ignited curiosity within the medical community, suggesting a compelling nexus between CMD and TCM's pathogenesis .Numerous case reports have documented instances in which individuals diagnosed with CMD, an ailment marked by coronary microvasculature irregularities, subsequently encountered episodes of TCM. These cases potentially offer insights into a shared physiological connection that warrants closer investigation. Likewise, retrospective patient data analyses have unveiled a suggestive pattern that a subset of TCM cases might be heralded by documented or suspected CMD, implying a temporal relationship deserving thorough exploration .While these revelations prompt inquiries into potential mechanisms and implications, they also underline the need to consider additional research methodologies. Could microvascular dysfunction contribute to or even initiate TCM's development? Could CMD influence the trajectory or prognosis of TCM episodes? Rooted in these clinically observed correlations, these queries beckon a deeper understanding of the shared pathophysiological underpinnings that might underscore this intriguing association .The studies discussed undoubtedly build a compelling case for the connection between CMD and TCM. Nevertheless, they simultaneously serve as a launchpad for broader research endeavours. The implications of such an interrelationship could resonate profoundly, impacting diagnostic precision, risk evaluation, and therapeutic strategies. Hence, the clarion call for further investigation into these intricate dynamics transcends academic curiosity. It promises to advance comprehension of these enigmatic cardiovascular conditions and, by extension, elevate patient care in a substantive and impactful manner -57.Shared Pathophysiological MechanismsEndothelial dysfunction: A central component in both CMD and TCM, endothelial dysfunction refers to the impaired function of the endothelium, the inner lining of blood vessels. In CMD, compromised endothelial function reduces vasodilation and impairs blood flow regulation within the coronary microvasculature. Similarly, endothelial dysfunction could hinder normal coronary blood flow responses in TCM, potentially contributing to the transient myocardial dysfunction observed during TCM episodes .Oxidative stress: Elevated oxidative stress, characterised by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defences, is a common denominator in CMD and TCM. In CMD, oxidative stress can lead to endothelial dysfunction and structural alterations in the microvasculature, further impairing blood flow regulation. Takotsubo cardiomyopathy episodes, often triggered by stress, can trigger a surge in oxidative stress, which may contribute to myocardial injury and contractile dysfunction .Neurohormonal pathways: Dysregulation of neurohormonal pathways, particularly the autonomic nervous system's response to stress, plays a pivotal role in both conditions. Excessive release of stress hormones, such as adrenaline, can lead to vasoconstriction, increased heart rate, and myocardial oxygen demand. In individuals with pre-existing CMD, this heightened neurohormonal response could trigger the myocardium towards the transient dysfunction observed in TCM .Abnormal microvascular function and autonomic responses: Aberrant microvascular function, a hallmark of CMD, contributes to impaired myocardial perfusion and ischemia. In the context of TCM, microvascular dysfunction could exacerbate the myocardial stunning observed during TCM episodes. Furthermore, abnormal autonomic nervous system responses, including sympathetic overactivity, could influence both conditions, affecting coronary blood flow and myocardial contractility .Potential Role of Microvascular Dysfunction in Triggering TCMMicrovascular dysfunction is a compelling candidate for triggering TCM\u00a0in specific vulnerable individuals. Coronary microvascular dysfunction, marked by compromised vasodilation and impaired myocardial perfusion in the microcirculation, could set the stage for a cascade of events contributing to the initiation of TCM. The intricate link between these conditions is grounded in the notion that microvascular dysfunction might make the myocardium susceptible to the profound physiological responses of stress-induced catecholamine release .In individuals with CMD, the altered microvascular tone and reduced perfusion capacity might weaken the myocardium's resilience against the surge of stress hormones, particularly adrenaline. Stress-induced catecholamines have been implicated in TCM as potential triggers, initiating a sequence of cardiac events that lead to the distinctive features of this condition. The heightened vulnerability created by microvascular dysfunction could predispose the myocardium to stress-induced myocardial stunning, whereby the heart's contractility becomes impaired and its ability to pump blood effectively diminishes. This state of myocardial dysfunction, combined with the surge of catecholamines, could culminate in the hallmark ventricular ballooning pattern observed in TCM, particularly affecting the apex of the heart .Unravelling the intricate connection between microvascular dysfunction and TCM could provide valuable insights into the complex mechanisms governing the onset of TCM. By understanding how microvascular dysfunction amplifies the effects of stress hormones on the heart, researchers and clinicians can develop a more nuanced understanding of the factors contributing to TCM development. This comprehension, in turn, could inform targeted therapeutic approaches that address microvascular dysfunction and stress hormone responses, potentially mitigating the risk of TCM episodes in susceptible individuals .Impact of CMD on the Prognosis and Outcomes of TCMEmerging evidence underscores the potential significance of CMD\u00a0in shaping the clinical course of TCM. Research suggests that pre-existing CMD in individuals experiencing TCM could influence disease severity and subsequent clinical outcomes. This interaction between CMD and TCM holds implications for risk stratification and the development of tailored management strategies .In the context of TCM episodes, individuals with underlying CMD may exhibit more pronounced left ventricular dysfunction. The compromised microvascular function observed in CMD might render the myocardium vulnerable to the stress-induced catecholamine surge that characterises TCM. Consequently, the acute myocardial stunning and contractile impairment associated with TCM might manifest more severely in those with microvascular dysfunction. This could contribute to a heightened likelihood of complications, including heart failure and arrhythmias, impacting the overall prognosis .Recognising CMD as a potential modifier of TCM outcomes is crucial for risk assessment and management decisions. Risk stratification becomes more nuanced when CMD coexists with TCM, as these individuals might warrant closer monitoring and intensive interventions to mitigate the heightened risk of adverse events. Tailored management strategies could involve a more proactive approach to managing cardiac function, optimising fluid balance, and instituting preventative measures against potential complications. Such individualised management aligns with the complex interplay between CMD and TCM, addressing the unique vulnerabilities presented by their coexistence .Incorporating the potential impact of CMD into the risk assessment and management of TCM provides a broader perspective on the factors influencing disease progression and outcomes. As understanding this interaction evolves, healthcare practitioners can better tailor their approach to patient care, ensuring that individuals with CMD and TCM receive a comprehensive evaluation and strategic interventions that optimise their clinical trajectory .Theoretical Models Explaining the Relationship between CMD and TCMExploring the intricate relationship between CMD and TCM has given rise to several theoretical models to unravel the underlying mechanisms that potentially connect these conditions. These models provide valuable insights into the complex interplay between CMD and TCM, shedding light on possible pathways that link these distinct cardiovascular entities .The \"two-hit hypothesis\": This model postulates that CMD is the first \"hit,\" rendering the myocardium more vulnerable to subsequent stressors, such as catecholamine release triggered by emotional or physical stress. In this scenario, microvascular dysfunction could act as a priming factor, altering myocardial responsiveness and making it more susceptible to the detrimental effects of stress hormones. This susceptibility could lead to myocardial stunning and the unique contractile abnormalities observed in TCM. The \"two-hit hypothesis\" suggests that CMD sets the stage for the development of TCM by modifying the myocardium's response to stressors .The \"common substrate hypothesis\": According to this model, CMD and TCM share underlying mechanisms that make them mutually predisposing conditions. These shared mechanisms could include abnormalities in neurohormonal signalling, endothelial dysfunction, and impaired autonomic regulation. Factors that contribute to CMD, such as chronic stress or metabolic disturbances, could also create an environment conducive to the development of TCM under the right circumstances. The common substrate hypothesis underscores the potential interconnectedness of CMD and TCM, proposing that they arise from an everyday pathophysiological basis . ExploriClinical assessment and diagnostic challengesChallenges in Diagnosing CMD and TCM IndividuallyDiagnosing CMD\u00a0and TCM\u00a0as distinct cardiovascular conditions presents significant diagnostic challenges due to their unique complexities .Coronary microvascular dysfunction's subtle presentation and diagnostic complexity: Coronary microvascular dysfunction's inconspicuous and often asymptomatic nature adds to the difficulty of its identification. Unlike typical angina associated with traditional coronary artery disease, CMD often displays vague symptoms or remains entirely asymptomatic. Recognizing CMD becomes particularly challenging as patients may lack characteristic chest pain, leading to delayed diagnosis or overlooking the condition. Moreover, the absence of well-defined diagnostic criteria for CMD further compounds accurate detection .Diverse diagnostic criteria complicate CMD identification: The absence of universally agreed-upon diagnostic criteria for CMD contributes significantly to the diagnostic predicament. Varied definitions and diagnostic approaches across different medical contexts hinder establishing a consistent identification method. This lack of standardized criteria can lead to underdiagnosis or misclassification, impeding the implementation of appropriate management strategies .Takotsubo cardiomyopathy's resemblance to ACS\u00a0and diagnostic confusion: Takotsubo cardiomyopathy's clinical presentation resembles ACS\u00a0with symptoms like chest pain, electrocardiographic changes similar to\u00a0STEMI, and elevated cardiac biomarkers, which can cause diagnostic confusion. The overlap between TCM and ACS can result in healthcare providers selecting ACS treatment strategies without considering the possibility of TCM. Consequently, TCM patients might receive interventions like invasive coronary procedures or antithrombotic therapy that might not suit their condition .Implications of misdiagnosis: Misdiagnosing CMD and TCM can lead to inappropriate treatment plans and interventions. Mistakenly categorizing CMD patients as having non-cardiac causes for their symptoms could delay proper management, potentially exacerbating underlying microvascular dysfunction. Similarly, misidentifying TCM as ACS might expose patients to unnecessary invasive procedures and therapies, subjecting them to undue risks and potential complications .Overlapping Clinical Features and Diagnostic DilemmasThe convergence of clinical features between CMD and TCM\u00a0challenges their accurate diagnosis. Patients with both CMD and TCM may present with overlapping symptoms, including angina-like chest pain, breathlessness, and abnormal results in stress tests. The shared clinical presentation of these conditions accentuates the complexity of discerning one from the other. The diagnostic dilemma arises because these symptoms are common in various cardiac disorders, making it arduous to attribute them to CMD or TCM solely based on clinical presentation .In times of diagnostic uncertainty, the importance of employing precise diagnostic tools becomes evident. These tools must go beyond identifying symptoms and delve into each condition's underlying mechanisms and structural abnormalities. While symptoms might be the initial presentation, accurate differentiation necessitates comprehensive imaging techniques and functional assessments that illuminate the distinct pathophysiological underpinnings of CMD and TCM. This not only aids in pinpointing the correct diagnosis but also forms the foundation for developing targeted management strategies .Appropriate management hinges on accurate diagnosis, especially given the potential impact of shared symptoms on patient outcomes. The pursuit of enhanced diagnostic precision has driven the exploration of advanced imaging modalities such as cardiac MRI, which can delineate the myocardial microstructure and function, aiding in differentiating CMD from TCM. Moreover, non-invasive functional assessments like coronary flow reserve measurements using Doppler ultrasound offer insights into microvascular function and help discern between these conditions. The development and validation of these diagnostic tools are pivotal in overcoming the challenges posed by overlapping clinical features and ensuring optimal patient care .Novel Imaging and Diagnostic Techniques to Assess CMD and TCMThe continuous evolution of imaging and diagnostic technologies has paved the way for innovative methods of assessing CMD and TCM. These advancements offer promising avenues to enhance our understanding and diagnostic capabilities for these conditions .Cardiac MRI with contrast-enhanced perfusion imaging: Cardiac MRI\u00a0has emerged as a powerful tool for evaluating microvascular dysfunction in CMD. Utilising contrast-enhanced perfusion imaging, cardiac MRI allows for a non-invasive assessment of myocardial blood flow and perfusion patterns. This technique helps identify regions of impaired microvascular function and provides valuable insights into the subtler aspects of CMD. Moreover, cardiac MRI's ability to visualise the unique apical ballooning pattern associated with TCM aids in distinguishing it from other conditions with similar clinical presentations .Invasive techniques for microvascular assessment: Invasive techniques, such as coronary reactivity testing and Doppler ultrasound, are increasingly recognised for their potential in assessing microvascular function. Coronary reactivity testing involves administering pharmacological agents to induce controlled vasodilation and measuring the coronary blood flow response. This approach allows for the direct evaluation of microvascular reactivity and provides valuable information about the functional state of the microvasculature. Similarly, Doppler ultrasound offers insights into blood flow velocities within the microcirculation, aiding in identifying abnormalities in blood flow regulation .These novel techniques promise to improve the accuracy and specificity of diagnosing CMD and TCM. By enabling the direct assessment of microvascular function and subtle myocardial changes, these imaging and diagnostic methods enhance our ability to differentiate between these conditions and guide targeted treatment strategies. As these technologies continue to evolve, they are likely to play an increasingly significant role in the clinical management of CMD and TCM, facilitating earlier diagnosis and more personalised patient care .Importance of Accurate Diagnosis for Appropriate ManagementAccurate diagnosis is a cornerstone for effectively managing CMD\u00a0and TCM. The ramifications of misdiagnosis reverberate across patient outcomes, potentially causing profound harm. A misdiagnosed CMD might lead to inappropriate therapeutic interventions that neglect its unique pathophysiology, thereby failing to mitigate underlying microvascular dysfunction. This mismanagement could perpetuate the progression of microvascular impairment, contributing to a cascade of adverse cardiovascular events. Similarly, inaccurately managed TCM could translate into inadequate care for a condition that requires distinct attention. This misalignment in management could impede the natural recovery process and exacerbate the associated symptoms and complications .A comprehensive diagnostic approach is thus paramount to tailoring treatment strategies precisely to the specific condition at hand. Recognising CMD and TCM individually and understanding their potential coexistence inform appropriate therapeutic decisions. Accurate diagnosis empowers healthcare professionals to provide targeted interventions that address the intricate mechanisms driving each condition. Such precision ensures that interventions are aligned with the underlying pathophysiology, optimising the chances of positive patient outcomes. Through an accurate and holistic diagnostic approach, clinicians can circumvent the pitfalls of misdiagnosis, avoid unnecessary interventions, and significantly enhance patient well-being by offering the most fitting and efficacious treatments .Management strategiesConventional Treatment Approaches for CMDManaging CMD entails a comprehensive and multifaceted strategy that focuses on addressing the underlying risk factors contributing to microvascular dysfunction and improving the health and function of the microvasculature itself. This approach aims to alleviate symptoms, improve myocardial perfusion, and enhance cardiovascular health .Lifestyle modifications: A cornerstone of CMD management is empowering patients to adopt healthy lifestyle practices. Encouraging individuals to embrace a heart-healthy diet is crucial, emphasising the consumption of nutrient-rich foods such as fruits, vegetables, whole grains, lean proteins, and healthy fats while minimising processed foods, sugary drinks, and excessive sodium intake. This dietary approach supports blood pressure control, lipid management, and weight maintenance, ultimately promoting better microvascular health .Regular exercise: Physical activity improves endothelial function, enhances microvascular dilation, and increases cardiac fitness. Tailored exercise programmes that combine aerobic activities, strength training, and flexibility exercises can improve blood flow regulation and oxygen delivery to the myocardium. Regular exercise also positively impacts systemic factors such as blood pressure, lipid levels, and glucose metabolism, which are crucial in mitigating microvascular dysfunction .Stress reduction: Stress reduction techniques are pivotal in CMD management. Chronic stress can contribute to endothelial dysfunction and exacerbate microvascular abnormalities. Incorporating relaxation techniques such as deep breathing, meditation, and yoga can help mitigate the effects of stress on the cardiovascular system. Stress reduction also involves addressing psychosocial factors and adopting strategies to manage daily stressors effectively .Smoking cessation: Smoking significantly contributes to endothelial dysfunction and microvascular damage. Encouraging individuals to quit smoking is paramount to improving microvascular health and reducing the risk of cardiovascular events. Smoking cessation interventions, including counselling and pharmacotherapy, can significantly enhance endothelial function .Pharmacological interventions: Pharmacotherapy often addresses associated risk factors and enhances microvascular function. Angiotensin-converting enzyme (ACE) inhibitors manage hypertension and improve endothelial function by reducing vascular resistance. Statins are beneficial for managing dyslipidemia and mitigating inflammation, which can contribute to microvascular dysfunction. Antiplatelet agents, such as aspirin, may be prescribed to reduce the risk of thrombotic events and improve microvascular flow .Current Management Strategies for TCMMonitoring and assessment: Continuous monitoring of hemodynamics, fluid balance, and cardiac biomarkers is paramount to evaluating the extent of ventricular dysfunction, assessing fluid status, and tracking improvements. Regular blood pressure, heart rate, and oxygen saturation assessments help gauge the patient's cardiovascular stability and guide adjustments in medical management .Fluid management: Optimal fluid management is crucial to maintaining an appropriate balance while preventing fluid overload or depletion. Careful monitoring of urine output and central venous pressure aids in tailoring fluid administration, especially in the acute phase. Diuretics may be used judiciously to manage fluid retention and oedema .Complication prevention: Preventing complications is a cornerstone of TCM management. Standard heart failure therapies, including angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics, might be considered in patients with significant ventricular dysfunction. These medications aim to alleviate symptoms, stabilise hemodynamics, and enhance cardiac function .Spontaneous recovery: One of the remarkable aspects of TCM is its tendency towards spontaneous recovery. Most TCM cases exhibit gradual improvement in left ventricular function over time. This recovery is a testament to the transient nature of the condition, although the timeline varies between individuals. Regular echocardiographic assessments are essential to monitor improvements and guide the adjustment of medical therapy .Long-term follow-up and psychological support: Although TCM cases typically show favourable outcomes, long-term follow-up is recommended to ensure sustained recovery and identify any potential recurrence. Psychological support is an integral component of TCM management, as the emotional stress that triggers TCM can leave a lasting impact on patients. Addressing the psychosocial aspects through counselling and support groups can aid emotional healing .Special Considerations When CMD and TCM CoexistWhen confronted with cases where both CMD\u00a0and TCM\u00a0coexist within an individual, an intricate treatment approach is imperative. The convergence of these conditions necessitates a holistic strategy that navigates the complexities of both CMD and TCM, acknowledging their potential interrelation. Central to this approach is recognising the profound impact that microvascular dysfunction, a hallmark of CMD, can exert on the outcomes of TCM .A critical step in managing such cases is meticulously evaluating individual patient characteristics. This evaluation extends beyond the confines of CMD and TCM, encompassing the patient's broader medical history, comorbidities, and risk factors. These factors play a pivotal role in shaping the optimal treatment path. Comprehensive risk assessment guides the selection of therapies, ensuring that interventions are tailored to address the unique nuances of both conditions while considering potential interactions and complications .The personalised approach in this context acknowledges the intricate interplay between CMD and TCM. Rather than viewing these conditions in isolation, healthcare practitioners should perceive them as interconnected components of the patient's cardiovascular landscape. Tailoring interventions to this interplay enhances patient care, yielding a more effective treatment regimen. This personalised strategy may encompass lifestyle modifications, pharmacological interventions, and psychological support, all seamlessly integrated to address both CMD and TCM harmoniously .By adopting this holistic and personalised treatment paradigm, healthcare professionals optimise patient management in cases where CMD and TCM coexist. This approach reflects a nuanced understanding of their potential relationship, emphasising the need to acknowledge the complex interplay between these conditions for the most effective and comprehensive patient care .Potential Future Therapies Targeting Both CMD and TCMImproving microvascular function: Emerging research suggests that interventions designed to enhance microvascular function could hold significant promise for both CMD and TCM. Therapies focused on endothelial health and vasodilation might alleviate the microvascular dysfunction common to both conditions, potentially preventing the cascade of events that lead to TCM. By improving coronary blood flow regulation, these interventions could mitigate the susceptibility of CMD patients to TCM episodes triggered by stressors .Mitigating the effects of stress hormones: Given the role of stress hormones, particularly adrenaline, in triggering TCM, future therapies could aim to modulate the effects of these hormones on the cardiovascular system. Developing agents that buffer the impact of stress-induced catecholamines might prevent or attenuate the myocardial stunning characteristic of TCM. These interventions could safeguard individuals with CMD, who might be at higher risk of developing TCM due to underlying microvascular dysfunction .Modulating neurohormonal pathways: Neurohormonal imbalances are implicated in both CMD and TCM, suggesting that therapies targeting these pathways could benefit both conditions. Agents that influence autonomic nervous system responses, regulate sympathetic activation, and modulate the release of stress hormones could provide a comprehensive approach to managing the intricate relationship between CMD and TCM. By restoring balance to these pathways, such interventions improve microvascular function and reduce susceptibility to TCM .Collaborative efforts between cardiology subfields: The convergence of CMD and TCM highlights the importance of collaboration among various cardiology subfields. Cardiologists specialising in microvascular disorders and those focused on TCM could work synergistically to develop targeted interventions. A collaborative approach could involve integrating expertise in vascular health, heart failure management, and neurohormonal regulation, resulting in therapies that effectively address the shared pathophysiological mechanisms underlying CMD and TCM .Future directions and research implicationsAreas for Further Research into the CMD-TCM RelationshipThe intricate connection between CMD and TCM\u00a0remains an area for further exploration. Research should delve deeper into understanding the underlying mechanisms that link these conditions, such as the role of shared neurohormonal pathways and their impact on microvascular function. Prospective studies could investigate whether CMD predisposes individuals to TCM and how CMD might modify TCM outcomes. Longitudinal studies assessing the prevalence of TCM in patients with documented CMD could help elucidate the temporal relationship between the two conditions.Novel Treatment Avenues Based on Understanding the LinkThe evolving understanding of the potential interplay between CMD and TCM could lead to novel treatment approaches that simultaneously target both conditions. Strategies focusing on improving microvascular function, addressing endothelial dysfunction, and modulating the impact of stress hormones hold promise in preventing or mitigating TCM episodes in susceptible individuals. Exploring the potential synergies between therapies used for CMD and TCM could yield innovative interventions that improve patient outcomes.Importance of Collaborative Research Between Cardiology DisciplinesGiven the potential overlap between CMD and TCM, collaborative research efforts among various cardiology disciplines are paramount. Cardiologists specialising in microvascular disorders and those focused on TCM should work together to uncover shared mechanisms, define diagnostic criteria, and develop comprehensive management strategies. A multidisciplinary approach integrating expertise from diverse fields, including cardiology, endocrinology, and psychology, can offer a more comprehensive understanding of the complex relationship between these conditions.In conclusion, this comprehensive review has illuminated the intricate relationship between\u00a0CMD\u00a0and\u00a0TCM, shedding light on their potential interconnection. Through thoroughly exploring their distinct characteristics, shared pathophysiological mechanisms, diagnostic challenges, and management strategies, we have unveiled the intriguing possibility that microvascular dysfunction may contribute to the development and outcomes of TCM. This understanding has significant implications for patient care, underscoring the importance of accurate diagnosis and tailored interventions, particularly in cases where CMD and TCM coexist. As we navigate the evolving landscape of cardiovascular medicine, we advocate for ongoing collaborative research efforts and heightened clinical awareness to unravel the complexities of this relationship. By doing so, we strive to enhance diagnostic precision, refine therapeutic approaches, and ultimately improve the well-being and outcomes of individuals affected by these fascinating cardiovascular conditions."}
{"text": "Accurate assessment of gender identity and biological sex in dermatology research is crucial since their conflation or poor demarcation undermines patient respect and study accuracy. Clearer guidance is needed for health care researchers, particularly in light of the notable disparities in skin disease rates, skincare practices, literature representation, and the persistent underrepresentation of transgender and nonbinary patients. Although gender identity is a social determinant of health, its assessment in health care research is inadequate. We highlight the intricacy of gender and biological sex in dermatology research, revealing the need for more robust protocols for their assessment. We begin by evaluating the current protocols used to make such assessments, demonstrating lack of consensus. Next, we evaluate the relationships between biological sex and gender identity and how these impact skin health. We then examine the inadequate representation of gender minorities\u2014including those who identify as transgender or gender nonbinary\u2014in academic literature and how this disparity compromises the applicability of evidence-based medicine to all. Finally, we consider the importance of physician communication about gender identity.The articles analyzed in this study emphasize the importance of transparency when delineating differences between biological sex and gender identity. In addition, researchers should be coached on techniques to extinguish investigators\u2019 biases. The models and tools for discerning gender identity and biological sex are shown in Note that the results obtained from the above methods were analyzed in conjunction with other questionnaires to assess correlations between the factors affecting overall population health ,2,4. GenQuestionnairesStanford Gender-Related Variables for Health Research (GVHR) Bem Sex-Role Inventory (BSRI) ,2BSRI: short form ,2GENESIS-PRAXY (Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond-Premature Acute Coronary Syndrome) Guidelines and recommendationsSex and Gender Equity in Research (SAGER) guidelines Sex-gender variable: methodological recommendations for increasing scientific value of clinical studies Cisgender (gender identity corresponds to sex assigned at birth) males and females exhibit different rates of various skin diseases . IncreasGender-affirming therapies may induce drastic skin changes. Hormone therapies increase the risk of acne vulgaris, androgenetic alopecia, excessive sebum production, melasma, and hirsutism . DermatoResearchers believe numerous factors contribute to skin differences between gender identities . TransmaGender minority populations also face health care barriers from noninclusive treatment eligibility models. For instance, despite the increased prevalence of acne vulgaris in transgender populations, iPledge medication guidelines for isotretinoin use sex assigned at birth and require contraception to remain eligible .Although increasing female participation in clinical trials is widely supported, data on gender minority participation is nonexistent. Additionally, the risks of some conditions fluctuate depending on the stage of gender-affirming therapies. Although existing data sets may not use inclusive models of gender identity assessment, there is value in their implementation given the prospect of large-scale observational studies and meta-analyses in which these variables could be better assessed. As gender minority populations grow, these inclusive models will help physicians support all patients while ensuring that salient trends and health impacts are captured by research analyses.About 28% of transgender individuals delay seeking preventative care because of mistreatment by health care workers; thus, inclusive language is important to build trust in these communities . MedicalMisgendering patients can have profound effects on patients\u2019 health and safety and can damage the patient-provider relationship . As ideaRobust methodologies exist to eliminate subjectivity and maximize data accuracy and utility. Current approaches to distinguishing gender identity and biological sex are inadequate and threaten the applicability of research findings to many patients. Conflating sex and gender neglects the unique dermatologic health impacts of these attributes and contributes to the underrepresentation of gender minority populations in medical literature. While more research is needed to address these issues, communication training for physicians and other health care providers could be improved. The language used must respect patients\u2019 identities while maintaining objectivity in clinical research."}
{"text": "Major educational goals of Infectious Diseases (ID) are to recruit more trainees into ID and promote good antimicrobial decision-making. National survey research revealed that ID curricula that deemphasize memorization are associated with greater odds of trainees entering the field of ID. As ID electives are not required during medical school, preclinical ID courses could represent the last dedicated opportunity for students to gain exposure to the field and acquire key clinical skills for antimicrobial selection. Yet little is known about how students experience preclinical ID courses. We aimed to explore how students experience and engage with these courses to better understand how best to augment their learning and interest in ID.We conducted individual interviews with a purposeful sample of medical students who took the preclinical ID course during three curricular years (2019-2021). Our semi-structured interviews explored students' challenges in learning ID, as well as the motivations, learning principles, and strategies guiding that learning. We generated a codebook through an iterative, inductive process using Dedoose to code interviews and facilitate analysis. We confirmed and refined major themes over 19 interviews.Establishing Relevance, Organized Study, Relating Ideas, Multi-Modal Learning, Socially Constructed Learning, and Active Engagement with Material) that support student learning, deployed through four main strategies .Students face unique challenges learning ID but are motivated to succeed by both intrinsic and extrinsic factors (Table 1). We identified six core learning principles (Our results build on prior research indicating that students learning ID benefit from incorporation of educational principles and strategies that move beyond rote memorization to encourage active engagement and self-reflection. We found that students preference deep, strategic learning methods propelled by intrinsic motivation, despite external pressures. Our findings have implications for optimizing ID education and ultimately increasing interest in the field.All Authors: No reported disclosures"}
{"text": "A perceived increase in weekly quality control (QC) failures prompted the development of an electronic monitoring system for quality assurance of antibiotic susceptibility testing.Antibiotic susceptibility testing (AST) procedures are sensitive to variations in testing conditions. Our diagnostic laboratory is compliant with recommendations set out in Clinical and Laboratory Standards Institute (CLSI) M100 . The trends in cefepime zone sizes against P. aeruginosa ATCC 27853 also prompted an internal review and these improved when antibiotic disk dispensers were consolidated to improve disk utilization .Persistent recurrent borderline results reflected on the monitoring system sparked the implementation of systematic investigations into QC failures; a replacement program for QC strains; and standardization of incubation timings and desiccant usage. Using new American Type Culture Collection (ATCC) reference strains reduced the percentage of QC antibiotic-organism data which failed or were borderline, and led to greater consistency in testing . Visual presentation of QC data triggered greater reflection. For instance, recurrent failures of ertapenem disks against Systemic monitoring of QC trends is low cost and highlights issues which were previously not apparent. Standardization of practices and a systematic troubleshooting process have improved the quality of our disk diffusion susceptibility testing.All Authors: No reported disclosures"}
{"text": "Coronary vasospasm is a known complication after coronary artery bypass grafting surgery but has rarely been described in non-coronary cardiac operations. We report the case of a 51-year-old male with nonischemic cardiomyopathy and paroxysmal atrial fibrillation. He presented with severe mitral and tricuspid regurgitation and was taken for mitral valve replacement, tricuspid valve repair, and Maze procedure. Postoperative emergent coronary angiography demonstrated diffuse coronary vasospasm. Injection of intracoronary nitroglycerin led to clinical and angiographic improvement. This demonstrates the possibility of coronary vasospasm following mitral valve replacement and effective treatment with intracoronary administration of vasodilating agents. Coronary vasospasm is a known and feared complication following coronary artery bypass grafting surgery that has rarely been described in non-coronary cardiac operations . IatrogeWe describe herein the case of a 51-year-old African American male with hypertension, paroxysmal atrial fibrillation, stage III chronic kidney disease, and nonischemic cardiomyopathy presenting with progressive shortness of breath and bilateral lower extremity edema. Echocardiogram demonstrated severe mitral regurgitation with asymmetric systolic restriction (Carpentier Type IIIc) and moderate-to-severe tricuspid regurgitation Figure . Right hCardiopulmonary bypass (CPB) was initiated with Del Nido cardioplegia. The mitral valve was replaced with 33mm St. Jude Biocor Porcine bioprosthetic, tricuspid valve repair was performed with Edwards MC3 30mm annuloplasty ring, LAA was ligated with AtriCure 50mm AtriClip, and Cox-Maze IV was completed with a cryoprobe. The transesophageal echocardiogram showed a well-seated mitral valve prosthesis with a peak gradient of 5 mmHg, a mean gradient of 2 mmHg, and no paravalvular leak Figure . IntraveCoronary vasospasm is a known and feared complication after coronary artery bypass grafting surgery but has rarely been described in non-coronary cardiac operations. Iatrogenic causes of ST-segment changes, hemodynamic instability, or difficulty weaning from CPB must be considered after valvular surgery and anti-arrhythmia procedures. Left circumflex artery injury or occlusion during mitral valve surgery and right coronary artery injuries during tricuspid valve operations are well described ,3. HowevH\u00a0Shafei et al. reportedUnlike most of the cases above, our patient developed ST segment changes while still in the operating room. The decision to pursue coronary angiography rather than reopening and performing a bypass graft is not trivial, but neither is the exercise of attempting a graft to the obtuse marginal branches. We must also consider the potential injury from cryoablation used during the CMP. Direct ablation of the coronary arteries may lead to significant obstruction or total occlusion. There is also a theoretical risk of indirect injury from cryolesions penetrating too deeply or pericoronary edema following the procedure.\u00a0If technical considerations have been ruled out as a source of coronary injury, systemic administration of vasodilators is an appropriate next step. If this fails to address the issue, then in the appropriate patient, transportation to the coronary catheterization laboratory can provide further information via emergent coronary angiography with the potential to deliver intracoronary vasodilators and perform other advanced interventions. This capability does require a close working relationship between the surgical, anesthesia, and interventional teams within the hospital system. The availability of interventional cardiology allowed us to avoid a bypass graft that likely would have failed in the short term and not addressed the underlying pathology.\u00a0Diffuse coronary vasospasm is a rare and potentially devastating complication following noncoronary cardiac surgery that should be considered in the setting of ECG changes and hemodynamic instability. As demonstrated by this case and the others cited, coronary spasms may present intraoperatively, shortly after the patient arrival to the intensive care unit, or in the first days after noncoronary surgery. Consideration of this pathology in the event of new ECG changes and hemodynamic changes will allow for timely diagnosis and treatment."}
{"text": "Neurotrauma and Repair: from Peripheral to Central Nerve Injury\u201d brought together a diverse group of 58 authors, fostering interdisciplinary collaboration and offering new insights into the multifaceted landscape of neurotrauma research.Neurotrauma, encompassing traumatic brain injury (TBI), peripheral nerve injury (PNI), and spinal cord injury (SCI), continues to be a major global public health concern. The complex pathophysiological mechanisms and lifelong neurological deficits associated with neurotrauma emphasize the urgent need for effective clinical interventions. The Research Topic \u201cThis collaborative effort yielded a body of work that has garnered significant attention within the scientific community, underscoring the importance of the research contributions and the demand for advances in neurotrauma understanding and treatment.Effects of a Neurokinin-1 Receptor Antagonist in the Acute Phase after Thoracic Spinal Cord Injury in a Rat Model\u201d delves into the potential therapeutic effects of neurokinin-1 receptor antagonists on neuroinflammation and edema following SCI . While the study suggests limited impact on reducing edema, it demonstrates a notable reduction in T-lymphocyte invasion and apoptotic cell numbers with the treatment. Additionally, it suggests a trend toward reduced fibrinogen leakage, endothelial and microglial activation, chondroitin sulfate glycosaminoglycan deposition, and astrogliosis. Although general locomotion recovery remained modest, CatWalk gait analysis revealed early improvements in several parameters. This research showcases the intricate and multifaceted nature of SCI and the potential of neurokinin-1 receptor antagonists in mitigating some aspects of neurogenic inflammation.\u201cMuscle-Derived Stem Cell Exosomes with Overexpressed miR-214 Promote the Regeneration and Repair of Rat Sciatic Nerve after Crush Injury,\u201d researchers explore the regenerative potential of muscle-derived stem cell exosomes enriched with miR-214 . The study demonstrates the ability of these exosomes to promote the proliferation and migration of Schwann cells, enhance the expression of neurotrophic factors, and facilitate axon extension in dorsal root ganglion neurons. By targeting PTEN and activating the JAK2/STAT3 pathway, these exosomes hold promise for promoting nerve regeneration in the context of sciatic nerve crush injuries. This research not only contributes to our understanding of neural repair mechanisms but also offers a potential avenue for therapeutic intervention.In \u201cPartially Brain Effects of Injection of Human Umbilical Cord Mesenchymal Stem Cells at Injury Sites in a Mouse Model of Thoracic Spinal Cord Contusion\u201d takes an intriguing angle, investigating the consequences of SCI on the brain . This study explores the potential therapeutic mechanisms of human umbilical cord mesenchymal stem cell injection at the injury site. It highlights the intricate interactions between the spinal cord and the brain, underscoring the interconnectedness of neural systems. This research raises important questions about the broader neurological effects of spinal cord injuries and offers insights into potential therapeutic interventions that could extend beyond the immediate injury site.\u201cA Closed-Body Preclinical Model to Investigate Blast-Induced Spinal Cord Injury\u201d introduces an innovative preclinical model for studying blast-induced spinal cord injuries . These injuries are particularly relevant in military contexts, where exposure to blast overpressure can result in significant spinal trauma. This research enhances our understanding of blast dynamics and their effects on the spinal cord, providing valuable insights into the complexities of these injuries. By investigating markers of traumatic axonal injury and neuroinflammation, this study sets the stage for future research into minimally invasive treatment approaches.\u201cHuntingtin-Associated Protein 1 Ameliorates Neurological Function Rehabilitation by Facilitating Neurite Elongation,\u201d researchers explore the role of Huntingtin-associated protein 1 (HAP1) in promoting neurological function recovery . By activating the TrkA-MAPK signaling pathway, HAP1 demonstrates its potential to enhance neurite elongation and improve outcomes in SCI. This study not only advances our understanding of the molecular mechanisms underlying neural repair but also suggests a promising avenue for therapeutic intervention.In \u201cDifferential Effects on TDP-43, Piezo-2, Tight-Junction Proteins in Various Brain Regions Following Repetitive Low-Intensity Blast Overpressure\u201d delves into the often-overlooked issue of mild traumatic brain injuries caused by repetitive low-intensity blast overpressure . This research highlights the varied effects of such exposures on critical proteins in different brain regions, underscoring the structural and anatomical heterogeneity of the brain. The findings emphasize the need for a comprehensive understanding of neurotrauma's diverse impacts, especially in military and combat-related contexts.\u201cA Cutting-Edge Strategy for Spinal Cord Injury Treatment: Resident Cellular Transdifferentiation,\u201d the authors explore a cutting-edge strategy for SCI treatment\u2014resident cellular transdifferentiation . This innovative approach involves reprogramming mature somatic cells into functional neurons, offering new hope for post-traumatic spinal cord repair and functional improvement. While the mechanisms and induced neuronal subtypes are not yet fully understood, this review provides a comprehensive analysis of the current state of research in this exciting field.In the review article \u201cThese contributions collectively advance our understanding of neurotrauma and offer new insights into potential pathways for treatment. While challenges remain, this collaborative effort signifies progress in the field, underscoring our shared commitment to alleviating the burden of neurotrauma for individuals worldwide. As we reflect on these achievements, we acknowledge the road ahead, filled with challenges and opportunities. Neurotrauma research continues to evolve, driven by a global community of researchers dedicated to translating insights into tangible treatments. Together, we embark on a journey that promises to bring healing and recovery to those affected by neurotrauma, one breakthrough at a time.AY: Writing\u2014original draft."}
{"text": "The mesentery is a broad fan-shaped fold of peritoneum that suspends the loops of small intestine from the posterior abdominal wall. Although primary neoplasms arising in the mesentery are rare, the mesentery is a major avenue for the dissemination of tumours, which can spread through hematogenous, lymphatic, direct or peritoneal seeding. Imaging helps in the diagnosis of these tumours and aids in directing appropriate treatment by assessing their size, extent and relationship with adjacent structures. The aim of this article is to describe the spectrum of imaging findings of the various mesenteric lesions using ultrasound and CT.Evaluation of the mesentery is often neglected during routine ultrasound (US) because of inadequate training and unfamiliarity with the common US features encountered with mesenteric disease. CT plays an essential role in the diagnosis of mesenteric disease. Knowledge of imaging characteristics of various mesenteric lesions helps in timely diagnosis and management. The mesentery is a broad, fan-shaped fold of peritoneum that suspends the loops of small intestine from the posterior abdominal wall. Secondary involvement of the mesentery from tumours elsewhere is much more common than primary mesenteric neoplasms such as desmoid tumour, inflammatory myofibroblastic tumour (IMFT), and others. Most patients with mesenteric lesions present with non-specific symptoms of abdominal pain, tenderness, palpable abdominal swelling, abdominal distension and weight loss. These symptoms are shared by pathologies of other abdominal organs and it is therefore very difficult to identify mesenteric lesions clinically.Some mesenteric diseases present with distinctive imaging findings while others have similar findings, thereby complicating their differential diagnosis. Understanding the characteristic radiological patterns on ultrasound (USG) and CT offers valuable insights for differential diagnoses of mesenteric lesions and their treatment.Primary mesenteric solid neoplasms are rare and the majority of them are benign.1 On USG, this tumour appears as a well-defined or ill-defined mass with heterogenous echotexture and internal vascularity. On CT, it appears as a well-defined or ill-defined mass showing heterogenous enhancement usually in the portal venous phase and it may infiltrate the adjacent organs.2 The MRI appearance of desmoid tumours depends on the relative proportion of cellular, myxoid and fibrous components.The most common soft tissue lesion in the mesentery is a desmoid tumour. It usually occurs in patients with familial adenomatous polyposis (FAP) or Gardner syndrome. Trauma or surgery serves as a predisposing factor for the development of desmoid tumours.3 Inflammatory myofibroblastic tumour appears as a hypo or iso-attenuating mass compared with skeletal muscle depending on the amount of myxoid or collagenous stroma, respectively. Dense central calcification may be noticed. They demonstrate various contrast enhancement patterns including early peripheral enhancement because of vascular tissue , associated soft tissue component and thick irregular septations. Liposarcomas are rare malignant tumours of the mesentery. Liposarcomas are divided into five types histopathologically: well-differentiated, myxoid, pleomorphic, round cell and de-differentiated liposarcoma. Well-differentiated liposarcomas have mixed fatty and soft tissue components while de-differentiated liposarcomas have clearly separated soft tissue and fatty components. Myxoid liposarcomas have fluid density on CT with mixed soft tissue and fatty components. Pleomorphic and round cell liposarcomas have soft tissue components only, with no identifiable fatty component on imaging.5Three patterns of mesenteric involvement have been described for Castleman disease, namely a solitary non-invasive mass (most common), a dominant infiltrative mass with associated lymphadenopathy and matted lymphadenopathy without a dominant mass. These tumours show early, homogenous and intense enhancement . Tumours6 is seen as one or more irregular fibrotic soft tissue mesenteric masses10 They show variable attenuation depending on their contents and may insinuate between the mesenteric vessels on USG and as a unilocular or multilocular cyst with enhancement of the wall or septations on contrast enhanced CT. vessels .11These appear as thin-walled anechoic unilocular cysts with posterior acoustic enhancement on USG and unilocular fluid attenuation lesions with no discernible wall on CT.2 They occur because of entrapment of fluid (secreted by the ovaries during ovulation) between peritoneal adhesions.7 They are seen as a fluid attenuation multilocular cystic lesion, multiple unilocular thin-walled cysts or unilocular cystic mass on CT with enhancing but non-calcified septa, which often surround the ovaries. On USG, they appear as unilocular or multilocular cystic lesions, which may be anechoic or may display contents of variable echogenicity and demonstrate homogeneous enhancement following contrast administration . Other findings observed in cases of abdominal tuberculosis include mesenteric nodularity, fat stranding, peritoneal thickening, localised collections, free fluid, clumping of bowel loops, bowel wall thickening and solid organ involvement in the form of hepatomegaly, splenomegaly, liver and splenic granulomas.Tropheryma whipplei. On imaging, small bowel wall thickening associated with enlarged mesenteric lymph nodes demonstrating hypoattenuating centres because of fat deposition can be seen. Diagnosis is made by small intestinal mucosal biopsy.16It is an infectious condition caused by Gram-positive bacterium, Actinomyces israelii is an anaerobic Gram-positive bacterium and is a normal inhabitant of the oral cavity, gastrointestinal tract and female genital tract. It spreads to involve the mesentery when a mucosal breach is present such as inflammation, surgery, trauma or intrauterine contraceptive device (IUCD) use.17 On imaging, an ill-defined heterogeneously enhancing soft tissue mass infiltrating the mesentery and adjacent organs can be seen. Septic embolism leading to hepatic, renal and splenic abscesses can occur.2 Diagnosis is made based on aggressive imaging features and subtle clinical symptoms in predisposed individuals. Biopsy should be performed in indeterminate imaging findings, which reveal sulphur granules representing bacterial colonies.18These usually occur because of intraperitoneal rupture of liver or splenic hydatid cysts . HydatidMesenteric changes in inflammatory bowel disease include mesenteric fibrofatty proliferation, mesenteric lymphadenopathy, fat stranding , abscess19 (Findings in acute mesenteric ischaemia related to superior mesenteric artery (SMA) thrombosis include dilated bowel loops with paper-thin walls, pneumatosis intestinalis, air within mesenteric vessels, mesenteric fat stranding and free fluid on CECT19 .On USG, tangled serpentine vessels can be seen, which show pulsatile waveforms on spectral doppler while on CECT, tangled serpentine vessels can be seen with early opacification of venous channels in the arterial phase. Direct communication between branches of the SMA and superior mesenteric vein (SMV) can be visualised on volume rendering technique (VRT) images.20 Evaluation of lesions is limited on USG because of operator-dependence, obscuration of the mass in the presence of a gaseous abdomen and obese patients, and inadequate visualisation of the extent of large mesenteric lesions. Contrast enhanced CT is the primary workhorse for evaluation of mesenteric lesions. It helps in determining the origin of the lesions, providing thoughtful differential diagnosis of masses, for selecting the site of biopsy, determining the extent of pathology and accessibility for resectability of lesion. CT, however, has several limitations including poor soft tissue contrast resolution, exposure to ionising radiation and contrast reactions. MRI can be used as the next step in characterising mesenteric lesions. It has higher soft tissue contrast resolution and helps in characterising fluid content of cysts as serous, mucinous, chylous or haemorrhagic and the soft tissue component of solid lesions. Fluoro-deoxyglucose (FDG) positron emission tomography (PET) CT is presently used to detect lymph nodes and distant metastases in mesenteric tumours and also for response assessment to chemotherapy.Ultrasound is the primary imaging modality in the evaluation of mesenteric lesions. It helps in characterising mesenteric lesions as solid or cystic. Ultrasound guided percutaneous biopsy offers real time assessment of the needle tract to avoid vascular injury while performing biopsy.21Management of mesenteric lesions depends on symptoms and imaging findings. Mesenteric lesions detected incidentally on imaging need classification as benign or malignant. Definite diagnosis of a few pathologies such as mesenteric panniculitis, lymphoma, desmoid tumour in patients with FAP and benign cystic lesions can be made on imaging. However, lesions with indeterminate imaging findings need to be biopsied to rule out malignancy. Imaging helps in determining the site for percutaneous biopsy in such tumours. Lesions that are inaccessible to percutaneous biopsy or show indeterminate histopathology findings on percutaneous biopsy require surgical biopsy to confirm the diagnosis.Once confirmed by biopsy, management of the mesenteric lesions depends on the histopathology. Lymphomas and desmoid tumours are managed conservatively with chemotherapy and hormonal therapy or imatinib, respectively. Well-circumscribed lesions located in the periphery of the mesentery can be resected completely, without sacrificing significant bowel length or major mesenteric vessels. Infiltrative mesenteric lesions, located in the root of mesentery are usually managed conservatively because of involvement of major vessels and the need for sacrificing a major portion of bowel, which may lead to small bowel syndrome. Well-defined malignant tumours and symptomatic benign tumours are treated surgically. The goal of surgery is R0 resection , while R1 resection followed by adjuvant chemoradiotherapy can also be performed. Well-defined asymptomatic benign lesions can be followed up and resection is performed when they become large or cause symptoms. Symptomatic infiltrative benign or malignant lesions can be managed by debulking surgery to reduce tumour load and prevent complications such as bowel obstruction or mesenteric ischemia.Although histopathology is the gold standard for diagnosis of mesenteric lesions, imaging plays an important role in diagnosis of mesenteric neoplasms, detection of complications and in deciding appropriate treatment options. Ultrasound is inadequate for optimal visualisation of mesenteric neoplasms and in detecting their relation with other structures because of shadowing from bowel gas, calcification or inadequate penetration of sound beams in obese patients. CT is an excellent imaging modality in the characterisation of mesenteric lesions, detecting their extent and relations with surrounding structures, which is useful for surgical planning. However, CT too has several limitations and other imaging modalities such as MRI and FDG-PET can be helpful in further characterisation of mesenteric lesions."}
{"text": "This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old woman had difficulty extending her left-thumb interphalangeal joint several weeks after a palpation-guided local corticosteroid injection. Passive motions remained intact without sensory abnormalities. Ultrasound examination showed hyperechoic tissues at the site of the extensor pollicis longus (EPL) tendon at the wrist level and an atrophic EPL muscle stump at the forearm level. Dynamic imaging demonstrated no motion in the EPL muscle during passive thumb flexion/extension. The diagnosis of complete EPL rupture, possibly due to inadvertent intratendinous corticosteroid injection, was therefore confirmed. This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old female complained of difficulty in extending the left thumb for several months. The medical history comprised radial wrist pain after a contusion injury one year ago, for which corticosteroid injection under palpation guidance had also been performed, with gradual symptom relief. The physical examination revealed loss of the active extension of the left-thumb interphalangeal joint with normal passive motions . Other fThe posterior interosseous nerve (PIN) remained bilaterally intact based on dynamic tracking from the level of the supinator tunnel to the dorsal wrist . Moving Finger drop can ensue due to neurological and orthopedic causes . In caseStatic ultrasound examination can serve as a helpful tool for scrutinizing tendon injury, whereas dynamic imaging can be employed to validate motion problems. The most common sonographic finding of tendon rupture is loss of fiber continuity with the formation of a retracted stump. The absence of normal tendon gliding during passive motion further confirms the diagnosis . In chroOne of the important etiologies of spontaneous EPL tendon rupture is intratendinous corticosteroid injection. Other causes include distal radial fracture, repetitive friction against metal implants, and contusions . Local cNeedless to say, ultrasound is a preferred tool for guiding the needle, in order to avoid unwanted intratendinous corticosteroid injection ,17. Peri"}
{"text": "This case highlights the importance of having constrictive pericarditis (CP) as a differential diagnosis in unexplained sign and symptoms of right-sided heart failure. This case portrays challenges in diagnosing CP caused by certain rheumatologic diseases despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis. Constrictive pericarditis (CP) is a rare condition that often presents with non-specific symptoms and is often misdiagnosed. CP is characterized by a rigid pericardium that restricts the heart, resulting in signs and symptoms of diastolic heart failure. It occurs as a late sequela of pericardial inflammation caused by prior infection or radiation, inflammatory diseases and rarely, connective tissue disorders. We present a case of new-onset right-sided heart failure caused by constrictive pericarditis in a patient with diffuse systemic sclerosis (SSc). This case highlights the importance of having CP in our differential diagnosis in patients with unexplained sign and symptoms of right-sided heart failure and increased systemic venous pressure. This is crucial since CP secondary to SSc is largely curable and failure to diagnosis has devastating consequences. This case portrays the challenges in diagnosing pericardial diseases caused by certain rheumatologic diseases and that despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis.A 27-year-old female with a seven-year history of diffuse systemic scleroderma complicated by recurrent pericarditis and severe Raynaud\u2019s disease resulting in gangrene and amputation of the upper and lower extremity digits presented to the hospital with two weeks of progressive shortness of breath, early satiety, fatigue, abdominal distention, and lower extremity pain and edema. The physical examination was notable for the presence of jugular vein distention with positive hepatojugular reflux, right upper quadrant tenderness, ascites and 3+ lower extremity edema to the thighs. Her heart rate was 108 beats per minute; other vital signs were within normal limits. EKG showed sinus tachycardia with nonspecific ST-T wave changes. Chest x-ray showed a moderate right-sided pleural effusion with right basilar airspace opacity and a cardio mediastinal silhouette. Transthoracic echocardiogram demonstrated a normal left ventricular ejection fraction, mildly reduced right ventricular function, mild pulmonary hypertension with an estimated mean pulmonary artery pressure of 40 mmHg, and no significant valvular abnormalities. Abdominal ultrasound redemonstrated ascites and was also notable for hepatomegaly and a hyperechoic pancreatic mass.Initially the patient\u2019s ascites was attributed to intrinsic hepatic disease and she was started on diuretics. However, her renal function deteriorated, halting diuresis while further diagnostic evaluation was pursued. The patient continued to have abdominal distension and shortness of breath which prompted a cardiovascular evaluation with a right heart catheterization. Mild pulmonary arterial hypertension was noted with elevated mean pulmonary arterial pressure (mPAP) of 28 mmHg. Due to the discrepancy between the mildly elevated cardiac filling pressures and significant anasarca on physical examination, a repeat hemodynamic assessment was pursued. The patient underwent right and left heart catheterization which discovered near equalization of the diastolic filling pressures, raising suspicion for pericardial tamponade constrictive physiology . In addiAs most diagnostic imaging studies were contraindicated due to the patient\u2019s impaired renal function, a cardiac MRI without contrast was obtained to evaluate for possible pericardial disease. Cardiac MRI showed an abnormally thick pericardium (4\u20135 mm) and evidence of significant pericardial adhesion with a small dependent pericardial effusion. The ventricles were cone shaped and a septal bounce was seen during diastole. In addition, free breathing CINE imaging demonstrated ventricular interdependence. These findings were consistent with pericardial constriction.After extensive discussion between cardiology, rheumatology, nephrology and cardiothoracic surgery, the primary team agreed that surgical intervention was the best option to improve this patient\u2019s quality of life and disease prognosis. Subsequently, she underwent successful pericardiectomy with complete resolution of her symptoms. The pathology report revealed extensive dense fibrosis in the pericardium that was likely secondary to patient\u2019s known collagen vascular disease.Cardiac involvement in both limited and diffuse SSc has been recognized over the years as one of the most rare and feared complications due to poor prognosis . CardiacThe noteworthy pathophysiology involved in presentation of this condition is unique in that there is recurrent coronary microvascular ischemia and myocardial inflammation which leads to ischemic necrosis, reperfusion damage, and myocardial fibrosis . This adHowever, constrictive physiology can complicate virtually any condition associated with pericardial effusion . The nonCertain serologic tests for patients with systemic sclerosis can provide useful information about specific organ involvement, including cardiac manifestations. Studies have shown that patients with SSc with myocarditis had cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) and antiproteinase 3 (PR3) antibody positivity . FurtherOverall, due to the high prevalence of cardiac involvement in patients with SSc, it becomes imperative to do a thorough history taking and examination of this population. Prompt recognition and management of constrictive pericarditis can alleviate symptoms such as volume overload, drastically transform these patients\u2019 quality of life, improve prognosis, and decrease mortality.This case portrays the challenges in diagnosing pericardial diseases caused by certain rheumatologic diseases and that despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis.To be able to recognize rare but very specific findings of a constrictive pericarditis physiology.To understand the role of Multidisciplinary approach to benefit the patient\u2019s quality of life.A patient presenting with an odd case of Constrictive Pericarditis due to Systemic Sclerosis."}
{"text": "A hallmark of retroviral replication is stable integration of the viral genome in the host cell DNA. This characteristic makes retroviral-derived vector particles attractive vehicles for gene therapy. However, retroviral integration is not a random process. Lentiviruses preferentially integrate in the body of active transcription units, while gammaretroviruses, including Moloney Murine Leukemia Virus (MLV), favour transcription start sites and CpG islands. In clinical trials using gammaretroviral vectors for gene therapy, leukemogenesis has been associated with integration of vectors near oncogene transcription start sites. We found that the bromodomain and extra-terminal (BET) proteins interact with MLV integrase and direct integration towards transcription start regions. BET proteins specifically bind and co-localize with the gammaretrovirus integrase protein in the nucleus of the cell. The interaction is gammaretroviral-specific and mediated by the integrase C-terminal domain and the BET extraterminal (ET) domain as determined by co-immunoprecipitation assays and in an Alphascreen assay using recombinant proteins. Interfering with chromatin interaction of BET proteins via specific bromodomain inhibitors JQ1 and l-BET decreases MLV virus replication and MLV vector transduction 5-to 10-fold, while HIV vector transduction is not affected. Analysis of viral DNA intermediates by quantitative PCR revealed a block at the integration step. In addition, bromodomain inhibitors do not have an effect on the late steps of viral replication. MLV integration site distribution analysis revealed a strong correlation with the BET protein chromatin binding profile. Finally, expression of an artificial fusion protein that merges the BET integrase binding domain with the chromatin interaction domain of the lentiviral targeting factor LEDGF/p75, retargets MLV integration into the body of actively transcribed genes, paralleling the Human Immunodeficiency Virus (HIV) integration pattern. Our results explain the molecular mechanism behind gammaretroviral integration site targeting and suggest methods for engineering gammaretroviral vectors with a safer integration site profile."}
{"text": "Next-generation DNA sequencing has dramatically affected cancer genomics efforts in several important ways. Although whole genome sequencing remains an analytical challenge, such efforts are yielding data that elucidate the myriad ways in which a genome can be influenced by single point mutations, focused insertions or deletions, and large structural alterations. In addition to cataloguing somatic alterations, various correlation analyses are indicating the genes whose alterations most profoundly determine patient outcomes, patient responses to therapeutics and other important aspects of disease biology. We have recently begun exploring how the digital nature of next-generation sequencing reads allows important information about tumor cell genomic heterogeneity to be inferred, revealing the earliest mutations and how the composition of the tumor cell mass changes over time under the influence of stressors such as chemotherapy."}
{"text": "To study the role of hypotension and associated injuries in increasing the chances of secondary amputation in lower limb with vascular injuries.This study was conducted in the Department of cardiovascular and thoracic surgery( CVTS ), Sher-i- Kashmir Institute of Medical Sciences, ( SKIMS ) Srinagar Kashmir India and comprised all patients sustaining vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height during the last five years. Following admission to our Department, the patients were divided into two groups. The first group with associated injuries was hemodynamically unstable during vascular repair or in post-operative period and the second group had no associated injuries and was hemodynamically stable during vascular repair and in post-operative period.During the past five years, 95 patients were operated for lower limb vascular injury in our department. Of these 25 patients had associated multi-organ injuries and were hemodynamically unstable and needed intensive care monitoring after surgical intervention. Additionally, 10 patients died due to associated multiple organ injuries, 10 needed amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved. Seventy patients who had isolated limb vascular injuries with no associated injuries or hypotension were hemodynamically stable and were kept in low dependency unit after vascular repair. Only Four patients from this group needed amputation for thrombosis of the anastomosis.Patients with shock and related injuries face significant rate of amputation. These patients whether with multi-organ injuries or isolated vascular injuries need judicious treatment for hypovolumic shock during surgical intervention and in post-operative period. Injury to the popliteal vessels has been recognized as one of the most limb-threatening peripheral vascular injuries so far as vascular trauma has been studied. The popliteal artery is a true end artery with a tenuous collateral supply. The popliteal vein provides the bulk of lower limb and foot drainage. This explains why injury to these vessels is so dangerous. Management of these multiply injured patients can be very challenging and restoring perfusion to an ischemic extremity needs to be accomplished within 6\u20138 hours, if limb is to be salvaged. Clean and sharp cut in the artery closed by primary repair behave differently than an arterial repair with RSV(Reverse saphenous vein graft) graft which needs multiple Fogarty catheterization for retrieval of thrombus. Extensive tissue damage increases chances of compartment syndrome (CS). Post\u2013operative infection and CS are most important causes for amputation. Conventionally there are hard and soft signs of vascular injury. Hard signs which warrant immediate intervention include i) external arterial bleeding, ii) rapidly expanding hematoma, iii) palpable thrill, and audible bruit, iv) signs of acute limb ischemia. Soft signs of vascular injury warrant urgent evaluation in the form color Doppler/angiography. The successful management of vascular injury includes two goals: i) treating the life-threatening problems by fluid resuscitation, control of bleeding and ensuring adequate oxygenation; ii) repairing the injured vessel and save the limb. Arterial repairs include: reverse saphenous vein graft, primary repair, PTFE( polytetrafluroethylene) graft, ligation, and vein patch. CS leads to tissue necrosis, permanent functional impairment, or severe renal failure and death. The general consensus is that intra-compartmental pressures (ICPs) greater than 30mm Hg require intervention. During the first and second world wars, important knowledge had been gained both in diagnosis and treatment of vascular injuries, but vascular reconstructive methods were mainly introduced during the Korean and Vietnam wars with tremendous progress , 2.The studied population included patients with sustained vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height and admitted to our center during the past five years. The patients were divided into two groups of hemodynamically unstable and stable patients during vascular rep air or in post-operative period and notes were taken of their other associated injuries. Severity of injury was assessed by MESS (mangled extremity severity score). All hemodynamically unstable patients during and after surgery, had multiple organ injury and needed intensive care monitoring. However, hemodynamically stable patients were managed in a low dependency unit after vascular repair, and had predominantly isolated lower extremity injury or associated minor injuries. All patients operated for lower limb vascular injury were followed for post-operative outcome with respect to patency of the anastomosis and adequate blood flow for viability of the limb. Distal blood flow was assessed by clinical examination followed by Doppler study to confirm doubtful clinical examination. All patients who needed primary or secondary amputation with MESS score equal to or greater than 7 were excluded from the study. The study included only patients with MESS score of <6 and confirmed to have good vascularity on table by clinical as well as by vascular Doppler examination. Hemodynamic parameters and blood gas analysis were checked during and after operation. Post-operative blood gases and electrolytes were determined four hourly in patients who needed intensive care monitoring. Other associated injuries were taken care of by respective departments including general surgery, plastic surgery, neurosurgery and by critical care specialists.0 double arm prolene. As for associated injuries, the patients referred to other specialties. Hemodynamic parameters, blood gas and electrolytes were checked during the operation.After initial resuscitation and assessment, patients with confirmed arterial injury were operated under general anesthesia immediately following basic work-up. Patients with multi-organ injury were directly shifted to the tertiary care hospital from the spot of injury. Forty patients with isolated limb injury were referred after skeletal fixation by an orthopedist. Exposure was made through an incision in the aspect of knee, approximately central to site of injury. After controlling the affected arterial segment, medial proximal and distal embolectomy was performed, and backflow and inflow were assessed. Arterial repair was done either by primary end-to-end anastomosis or by reverse sephanous vein (RSV) graft. RSV was always taken from contralateral large saphenous vein. Suture material used for anastomosis was always 6During five past years, 95 patients, 87 males and 8 females, aged from 18 to 45 years were operated in our department, for lower limb vascular injury. Younger patients sustained vascular injuries mostly due to motorcycle and fire arm accidents, while older patients received vascular injuries either due to blast injury or fall from height. Following surgical intervention, 25 patients with associated multi-organ injuries needed intensive care monitoring. Of these, 10 patients died due to associated multiple organ injuries, and 10 had amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved, but their functional outcome was not as good as those who never had hypotension during surgical intervention or in post-operative period. After vascular repair, 70 patients with isolated limb vascular damage and no associated injuries were kept in low dependency unit. Patients with isolated limb vascular injury and managed in low dependency unit after surgical intervention never had prolonged hypotension, either during vascular repair or in post-operative period and four patients from this group needed amputation for thrombosis of the anastomosis. One of these patients died due to infectious complications followed by DIC even after amputation. In remaining three, one patient had atherosclerosis, one had hypercoagulabe state for protein C deficiency, and the third patient had no apparent sign of thrombosis of anastomosis.Advances in hemorrhage control, wound care, orthopedic and vascular surgery during Iraq and Afghanistan war have allowed greater attention to shift toward limb salvage efforts. They also suggest that hypotension may result in muscle damage at even lower compartment pressures . PatientPatients with vascular and multi organ injuries ,active hemorrhage and shock have a poor prognosis and demand more urgent management than do patients with isolated limb injuries in which perfusion and blood pressure remains optimal. Shock is associated with a significant rate of amputation. These patients, whether with multi-organ or isolated vascular injuries, need judicious treatment for hypovolumic shock during surgical intervention and post-operative period."}
{"text": "The question whether neural activity follows a rate code or a temporal code is still an unsolved issue in neuroscience. Recent theoretical works have suggested that realistic models of spike-timing-dependent-plasticity (STDP) in recurrent networks could resolve this issue because they observed a seemingly unique relation between the neural code and the resulting pattern of synaptic connections . In partWe have disproved both assumptions. In particular, here we show that already simple STDP models can easily grow bidirectional connections for a temporal code based on spike synchronization unless synchronization is extremely precise (see for dispThus, both rate coding and temporal coding based on coarse synaptic synchronization can account for the bidirectional connectivity observed, for example, in visual cortex . However"}
{"text": "Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally on prostate biopsies, transurethral resection specimens, and radical prostatectomy specimens. PSHA has a bizarre histologic appearance and these lesions often raise concern for sarcoma; however, their clinical course is indolent and does not include extraprostatic progression. We discuss a case of PHSA discovered on prostate biopsy performed for an abnormal digital rectal examination and review the literature on this rare pathologic finding. Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally in specimens from transrectal ultrasound (TRUS-) guided needle biopsy of the prostate, transurethral resection of prostate (TURP), radical prostatectomy, and simple prostatectomy . BecauseA 55-year-old man underwent a 10-core TRUS biopsy for a grossly abnormal digital rectal exam. Histologic examination revealed PSHA is characterized by one or more ill-defined, uncircumscribed, and hyperplastic stromal nodules infiltrating around benign acini . ImmunohPSHA does not generally present as a symptomatic lesion in and of itself, though symptomatic cases have been reported . In all This finding has been referred to by a variety of names including: atypical stromal hyperplasia, symplastic leiomyoma, and pseudoneoplastic lesion of the prostate gland. PSHA was previously grouped with low malignant potential findings such as phyllodes tumor and low-grade sarcoma as stromal tumors of unknown malignant potential (STUMP); however, given the univerally benign course of PSHA, this may constitute a misnomer. The current nomenclature emphasizes the expected indolent clinical course with treatment focused on the original disease of interest ."}
{"text": "To understand the impact of integrative medicine (IM) therapies on patients receiving care at BraveNet practice-based research network (PBRN) via longitudinal collection of patient-reported outcomes. Previously, the BraveNet PBRN conducted a cross-sectional study including over 4,000 patients receiving clinical care at the 9 IM clinics, which comprise the Bravewell Clinical Network and BraveNet PBRN. This effort provided important information about patients receiving care at these IM clinics as well as the type of medical condition and IM treatments patients were receiving.The current pilot study extends the prior study by collecting patient-reported outcomes every 6 weeks for 6 months from patients receiving various types of IM services . Patients are asked to complete demographics, substance use, exercise habits, Perceived Stress Scale, Arizona Integrated Health Outcomes, and Patient Related Outcomes Measurement Information System-29 measures. Questions examining the patients\u2019 prior IM history, perceived benefits of IM treatments, and satisfaction with IM clinic are also included. Medical records are reviewed to obtain billing and healthcare utilization information. While electronic questionnaires are completed using the REDCap (Research Electronic Data Capture) system, patients may also complete the questionnaires via paper format.The Penny George Institute for Health and Healing has been successfully piloting this project and 200 participants are enrolled to date. Additional BraveNet PBRN sites are joining the pilot study and expanded results of the entire pilot study will be presented.Practice-based research and patient-reported outcome measures will be key factors in demonstrating the effectiveness of IM interventions in the treatment of many clinical conditions. Multicenter participation provides increased enrollment and allows for generalizability of results from which future randomized controlled trials may be developed."}
{"text": "Gene expression profiling has been widely used to study molecular signatures of many diseases and to develop molecular diagnostics for disease prediction. Gene selection, as an important step for improved diagnostics, screens tens of thousands of genes and identifies a small subset that discriminates between disease types. A two-step gene selection method is proposed to identify informative gene subsets for accurate classification of multiclass phenotypes. In the first step, individually discriminatory genes (IDGs) are identified by using one-dimensional weighted Fisher criterion (wFC). In the second step, jointly discriminatory genes (JDGs) are selected by sequential search methods, based on their joint class separability measured by multidimensional weighted Fisher criterion (wFC). The performance of the selected gene subsets for multiclass prediction is evaluated by artificial neural networks (ANNs) and/or support vector machines (SVMs). By applying the proposed IDG/JDG approach to two microarray studies, that is, small round blue cell tumors (SRBCTs) and muscular dystrophies (MDs), we successfully identified a much smaller yet efficient set of JDGs for diagnosing SRBCTs and MDs with high prediction accuracies . These experimental results demonstrated that the two-step gene selection method is able to identify a subset of highly discriminative genes for improved multiclass prediction."}
{"text": "Pain responses can be suppressed by heterotopic continuous noxious conditioning, e.g. continuous noxious cold stimulation.These diffuse noxious inhibitory controls (DNIC) may be abnormal in migraine . DNIC eWe examined in healthy volunteers blood oxygenation level dependent (BOLD) responses in prefrontal cortex to repeated continuous noxious cold stimulation. The relationships between those responses and degree of inhibition of laser-induced pain during heterotopic cold stimulation were analyzed.Our results show that cold-induced BOLD response in anterior cingulate, orbitofrontal and lateral prefrontal cortices predict cold-induced heterotopic analgesia and attenuation of cerebral BOLD responses to laser stimulation. Prefrontal responses to the onset of cold stimulation were strongly related to the subsequent DNIC effect.We conclude that early responses to noxious conditioning are important for prediction of the analgesic DNIC effect. We hypothesize that this predictive effect of frontal cortices may be abnormal in chronic migraine."}
{"text": "Rapid and efficient selection of emotionally salient or goal-relevant environmental stimuli is crucial for flexible and adaptive behaviors. Emotional events rapidly and automatically capture attention by activating subcortical neural structures Ohman, . BehavioWith regard to the interaction of emotion and attention, there are unsolved and controversial issues. For example, to what extent does emotional stimulus processing depend on attentional resource availability? Previous studies have shown conflicting results, probably due to several factors, including attentional load allocated to competing tasks. Some studies have demonstrated that emotional faces evoke amygdalar responses even when attention is diverted to other stimuli, suggesting that some types of emotional perception occur outside of top-down directed attention and two ignore-faces conditions (easy and difficult digit/letter-matching tasks). The behavioral data suggested that the experimental design successfully controlled the attentional load and perceptual properties of emotional stimuli presented foveally or peripherally in the visual field. Their study resulted in two main findings. First, amygdalar activity was strongly suppressed during high attentional loads, which suggests that emotional information processing might be suspended when attention-demanding cognitive tasks are performed simultaneously. Although this finding is not new (Pessoa, Morawetz et al. directly Pessoa, , this waIn summary, Morawetz et al. provided"}
{"text": "Examining process rates alone may obscure the microbial physiological mechanisms that underlie climate-induced changes in soil C cycling, leading to contradictory patterns among different studies. For instance, in a large-scale survey of soil protease activities from climate manipulations, drier and warmer conditions resulted in lower extracellular enzyme activities (EEA) compared to ambient conditions (Brzostek et al., In this issue, Steinweg et al. examine These findings challenge our existing knowledge about the mechanisms driving EEA in soils. In the laboratory, EEA increases linearly with temperature over the narrow temperature range observed here (German et al., The work of Steinweg and colleagues is an example of how shifts in gross process rates emerge from multiple interacting microbial mechanisms. However, these physiological feedbacks are often not incorporated into biogeochemical models. For instance, despite ample evidence that soil microbes shift allocation to enzyme production depending upon resource availability, EEA is often modeled simply as a function of the microbial biomass pool size. This approach may be valid in some ecosystems under steady state conditions or during the growing season (Kivlin and Treseder, Shifts in intracellular C allocation may also affect element cycling at the ecosystem scale if the stoichiometric requirements of the microbial biomass are altered. Steinweg and colleagues found that enzyme ratios varied with season, indicating higher microbial C vs. N demand in the winter. They suggest that changes in enzyme stoichiometry may reflect increased microbial maintenance cost during freeze-thaw cycles, which impose a high C cost on the microbial biomass. Shifts in biomass C:N have also been observed in response to altered substrate stoichiometry (Fanin et al., Based on the findings of Steinweg et al. many of While Steinweg et al. focus onMultiple processes will have large consequences for soil C storage in future climates, including climate controls on enzyme production and turnover, and tradeoffs in microbial allocation to growth, respiration, and resource acquisition. Yet, because all of these processes interact, the effects of climate change on soil C pools and fluxes can be extremely variable. As Steinweg and colleagues demonstrate, measuring mass-specific microbial responses is the first step toward improving our understanding of microbial physiological responses to altered climate regimes. However, studies that simultaneously examine the links among these mechanisms will be necessary to predict when tradeoffs in microbial C allocation occur and their long-term effects on soil C storage. By viewing ecosystem responses to temperature and precipitation through the lens of microbial physiology, we may arrive at a more mechanistic understanding of soil feedbacks on climate change."}
{"text": "Globally, forests store ~45% of carbon sequestered terrestrially, contribute more to the terrestrial sink per area than any other land cover type, and assimilate an important portion of anthropogenic emissions Bonan, . ForestsThe justification for physiological research on drought-induced tree mortality is often stated as a need to improve the predictive capability of vegetation models through incorporation of mortality mechanisms must be simulated across the Earth. Dynamic global vegetation models (DGVMs) coupled with general circulation models are a common tool for simulating vegetation response to climate change , derived from tree-ring records and predictable from regional climate, is highly correlated with forest mortality in the southwest USA improved experimentation to distinguish physiological causes from symptoms, (2) continued model development based on existing knowledge and emerging discovery, (3) improved model validation against both experimental results and regional-scale mortality observations, and (4) high-resolution measurement of forest composition at large scales. While ecologists studying tree mortality have favored investigating physiological mechanism, measuring species composition and mortality at high resolution across regions is crucial for providing baseline observations to constrain model predictions. Without improved input on current forest conditions, even accurate models of forest mortality cannot generate useful predictions of change."}
{"text": "Age-related macular degeneration (AMD) is the most common cause of legal blindness among the elderly in developed countries. The prevalence of advanced forms of AMD is increasing; it is expected to rise by 50% by the year 2020 in the United States. Early identification of AMD susceptibility and implementation of preventive measures are important management strategies. Antibodies against vascular endothelial growth factor (VEGF) have become the treatment of choice in patients with choroidal neovascularization (CNV); however, substantial improvement of vision occurs only in approximately one-third of patients. Early diagnosis and treatment of CNV may increase the success rate of treatment.Standard diagnostic modalities including fundus angiography and optical coherence tomography can detect CNV in clinical stages when vision is affected. In a novel approach, Takeda and coworkers evaluated the role of an eosinophil/mast cell chemokine receptor, CCR3, in CNV. They studied CCR3 expression among patients with AMD and previously untreated surgically excised CNV membranes, donor eyes of age-matched non-AMD controls, atrophic AMD, uveal melanoma, and surgically excised epiretinal membranes. Additionally, in vivo CCR3 bioimaging was performed in transgenic mice with spontaneous CNV using intravenous quantum-dot labeled CCR3 antibody fragments followed by fundus fluorescent imaging which demonstrated hyperfluorescent signals in regions of the fundus that were silent on standard fluorescein angiography. These hyperfluorescent dots were subsequently confirmed to be CNVs using histologic examination. The investigators showed that CCR3 was specifically expressed in the endothelial cells of all human CNV membranes but not in other conditions. Interestingly, they found that CCR3 neutralization was superior to VEGF blockade in suppressing laser-induced CNV in mice. Considering emerging safety concerns about continual blockade of VEGF, which is constitutively expressed in the normal adult human retina and needed for retinal health, a treatment strategy based on more specific targeting of CNV would be desirable.These findings suggest that CCR3 targeting may be a viable strategy for early detection and treatment of CNV, and might be superior to the current standard of care. CCR3 bioimaging would probably be most useful in eyes at high risk for CNV such as multiple large drusen or sound fellow eyes of patients with clinically evident CNV; it can also serve as a useful tool for differentiating lesions mimicking CNV."}
{"text": "Background. Aberrant right hepatic duct (ARHD) draining intocystic duct (CD) is relatively rare but clinically importantbecause of its susceptibility to injuries during cholecystectomy. These injuries are often-times missed or diagnosed late and as aresult can develop serious complications. Methods. Fourconsecutive patients diagnosed with ARHD draining into CD wereidentified for inclusion. Results. The mean age of patients was42.5 years. The diagnosis in one of the patient was incidentalduring a routine endoscopic retrograde cholangiopancreatography(ERCP). Other three patients were diagnosed post-cholecystectomy-one presented with suspected intra-operative biliary injury, onewith persistent bile leak and another with recurrent cholangitis. Inadequate filling of the segment of liver on ERCP with dilationof intrahepatic ducts in the corresponding segment on imaging waspresent in two patients with complete obstruction of ARHD whichwas managed surgically. In another patient, the partiallyobstructed ARHD was managed by endoscopic therapy. Conclusion. ARHD draining into the CD can have varied clinical manifestations. In appropriate clinical settings, it should be suspected inpatients with persistence of bile leak early aftercholecystectomy, segmental dilation of intrahepatic-bile ducts onimaging and paucity of intrahepatic filling in a segment of liveron ERCP. Bile duct injury is an uncommon complication following cholecystectomy. With the increasing use of laparoscopic cholecystectomy (LC), there has been an associated increase in the incidence of bile duct injuries . Early s Therefore, the knowledge of various biliary anomalies and their early identification may further assist in decreasing the rate of biliary tract injuries. Here we present a case-series on various presentations and management of a rare anomaly of biliary tree.A 55-year-old woman presented 3 days postcholecystectomy (LC) with upper abdominal pain. HIDA scan revealed a bile leak. ERCP with minimal contrast injection revealed a leak from cystic stump; therefore a 10 F biliary stent was placed. Six weeks later a repeat ERCP revealed no leak from the cystic duct stump. However, large branch of the right intrahepatic duct was filled through the cystic duct stump . MinimalA 38-year-old Caucasian woman was referred to our hospital for recurrent episodes of gram-negative bacteremia. On presentation she was asymptomatic. Her past surgical history was significant for complicated cholecystectomy requiring conversion from laparoscopic to open technique six years earlier when she was 28 weeks pregnant. The surgical report described normal common and cystic ducts and described bile staining within the hilum where a drain was placed. After a few days drainage stopped and drain was removed. She was found to have minimally abnormal LFT's during a routine blood workup, a year after the surgery. Ultrasound at that time demonstrated dilated biliary tree in a segment of the right lobe of the liver and an ERCP revealed a questionable cystic dilation of distal common bile duct (CBD), for which sphincterotomy was performed. She had recurrent episodes of fever in the subsequent years and blood cultures persistently grew Klebsiella species. Computerized tomography (CT) scan and MRCPA 27-year-old healthy young woman with history of generalized fatigue presented for further evaluation of abnormal liver biochemistries. Her alkaline phosphatase levels had nearly increased 3 times the upper limits of normal. The most recent LFT revealed elevation of aspartate aminotransferases (AST) (104\u2009U/L) and alanine aminotransferases (ALT) (234\u2009U/L), which were reported as normal two years ago. An abdominal ultrasound showed no focal lesions. MRCP was performed which did not reveal any abnormal findings. Clinical examination was normal. In view of strong clinical suspicion of sclerosing cholangitis, ERCP was performed which revealed diffuse multifocal strictures with beading of intrahepatic ducts bilaterally, suspicious for primary sclerosing cholangitis. An aberrant branch of right hepatic duct draining into CBD with cystic duct originating from the aberrant branch was noted on ERCP .A 50-year-old woman presented with symptomatic cholelithiasis. Elective LC was attempted at an outside facility. Intraoperative cholangiogram (IOC) was interpreted as-right intrahepatic ducts filling without opacification of mid-CBD and CHD. Surgery was aborted in view of suspicion of bile duct injury. Two JP (Jackson-Pratt) drains were placed and she was referred to our center. ERCP performed at our center revealed cystic duct remnant leak and staples were noted close to CBD. There was inadequate filling of intrahepatic ducts in a segment of right hepatic lobe . SphinctAberrant right hepatic duct (ARHD) is branch providing biliary drainage to variable portion of right hepatic lobe and drains directly into the extrahepatic biliary tree. ARHD is a common bile tract anomaly with the incidence of 4.6%\u20138.4% and it frequently drains into common hepatic duct, CBD or even left hepatic duct . HoweverIOC during LC has been utilized to identify anatomic variants of biliary tract, even though it's routine use is debatable . While sPersistent bile leak may be an initial presentation of injury to the ARHD during cholecystectomy . These pLess frequently, patients with ARHD injury can present in the postoperative period weeks to months later, with cholestatic pattern of abnormality on LFT's, if the aberrant duct is blocked. In addition, these patients can also present with episodes of cholangitis in the obstructed segment of biliary tree as was the case with our second case. A high index of suspicion is required to look for these complications. Segmental dilation of intrahepatic ducts may be revealed on a CT-scan. These patients will require cholangiography (PTC or ERCP) to define the anatomy of biliary tree. Scantiness of intrahepatic filling on ERCP with dilation of intrahepatic branches in the same sector on radiologic imaging should be a useful clue to the diagnosis of obstruction of aberrant branch of bile duct. PTC can be performed when intrahepatic ducts are dilated; sometimes both the procedures may be required to obtain the diagnosis as was tUsually, the initial management of patients presenting with a bile leak after LC is decompression of biliary tree by placing a stent with or without sphincterotomy or placement of naso-biliary drain or percutaneous drain . If an aThe diagnosis of aberrant right hepatic duct draining into cystic duct can be incidental during ERCP or MRCP if performed before surgery, as in our third patient. In these situations, the knowledge of aberrant anatomy of biliary track would be important for a surgeon to avoid any inadvertent complications if they undergo cholecystectomy or any other biliary surgery. In addition, the safe approach to avoid injury to aberrant bile-ducts during cholecystectomy is adhering to the gallbladder itself, identifying the triangle of Calot and using the \u201ccritical view of safety (CVS)\u201d, as described by Strasberg, before dividing the cystic structures. CVS involves 3 steps: (i) clearing triangle of Callot of fat and fibrous tissue, (ii) separation of lowest part of GB from liver bed, (iii) only 2 structures (cystic artery and cystic duct) should be seen entering GB . In summary, we present a varied clinical presentation and management of a relatively rare but clinically significant anatomic variation of bile duct anatomy. Aberrant bile-duct injury is often missed as subtle signs of injury remain unrecognized both by surgeons as well as by gastroenterologists. Aberrant bile duct injury after cholecystectomy should be strongly suspected in following situations: (i) paucity of intrahepatic filling in a segment of liver on ERCP; (ii) abnormal LFTs with segmental dilation of intrahepatic-bile ducts on abdominal CT-scan or ultrasound."}
{"text": "They provide a broad overview of the important advances that such mechanistic studies in Drosophila have made to our understanding of the age-related decline in muscle mass and strength, immune response, stress resistance, sexual behavior, and cognitive function. Walton and Pizzitelli (Caenorhabditis elegans. The authors dissect molecular and cellular mechanisms through which the spatiotemporal dynamics of unsaturated fatty acids regulates longevity by modulating the Nuclear Hormone Receptor signaling and maintaining the integrity of various organellar membranes. They also explore the mechanistic links between hydrolysis of neutral lipids and several longevity-defining processes, discuss how lipid-derived signaling molecules impact signaling networks central to longevity assurance, and outline the essential roles of mitochondrial membrane lipids in longevity regulation via multiple cellular pathways. Postnikoff and Harkness (Aging of multicellular and unicellular eukaryotic organisms is a highly complex biological phenomenon that affects a plethora of processes within cells. This wide array of longevity-defining cellular processes\u2014which are governed by an evolutionarily conserved signaling network\u2014includes oxidative metabolism and protein synthesis in mitochondria, lipid, and carbohydrate metabolism, NADzzitelli demonstrzzitelli explore zzitelli provide Harkness offer usHarkness outline Harkness provide Harkness summarizHarkness provide"}
{"text": "Luminescent colloidal quantum dots (QDs) possess numerous advantages as fluorophores in biological applications. However, a principal challenge is how to retain the desirable optical properties of quantum dots in aqueous media while maintaining biocompatibility. Because QD photophysical properties are directly related to surface states, it is critical to control the surface chemistry that renders QDs biocompatible while maintaining electronic passivation. For more than a decade, investigators have used diverse strategies for altering the QD surface. This review summarizes the most successful approaches for preparing biocompatible QDs using various chemical ligands. These applications require an appropriate fluorescent probe having specific chemical and optical properties. Organic and genetically-encoded fluorophores generally have narrow absorption, broad emission, and are vulnerable to continuous irradiation by the excitation source which limits their usefulness in some applications such as multiplexed measurements, long-term imaging, and single molecule imaging, among others ..83].4.2.n-alcanoic acids (PE-PEG) was the attached to SiO2-OTMS-coated QDs through hydrophobic interactions [2 and PE-PEG showed similar brightness over pH 1\u201314. They also evaluated the cellular toxicity of these nanoparticles with and without embedded QDs and found that the toxicity is purely due to the exposure of bare nanoparticles, indicating QDs were adequately protected within the silica spheres with no appreciable leaching of heavy metals [Gao\u2019s group found thractions . As Figuy metals .5.To enable the use of QDs in a wider range of biological applications, all of the preceding methods require a route for attaching biomolecules stably onto the QD surface. A suitable ligand candidate should allow attachment of a diversity of biomolecules including nucleic acids, proteins , polysaccharides, and peptides. Biomolecules are commonly conjugated to the QD surface through the following approaches : (1) cov6.in vivo diagnostics and treatments.Biocompatible QDs are typically generated through either an organic synthetic route requiring subsequent ligand exchange or encapsulation, or a more direct aqueous synthetic route where the nanocrystals are inherently water-soluble. There are nearly countless variations of these methods reported in the literature where each protocol carries its own inherent advantages and disadvantages and must be considered in light of the eventual application. A ligand exchange procedure that uses small charged molecules can maintain minimal hydrodynamic diameters, but they are usually more susceptible to aggregation in biological buffers or solutions of high ionic strength. These compact capping ligands often fail to maintain suitably high luminescence without additional processing. Methods that improve the density of ligands on the QD surface while ensuring a strong binding interaction appear to have the most promise. Polymer and silica coatings are better able to isolate QDs from solution which results in improved colloidal stability, limited non-specific binding, and high QY. However, these characteristics are often achieved at the expense of compact size which can impede cellular mobility and limi"}
{"text": "In trial design, decisions are made about which intervention components/processes to standardise and which remain flexible to maximise utility and/or effectiveness. The intervention-context-system fit for complex interventions impacts on trial recruitment, delivery and outcomes. Survey vignettes and discrete choice experiments are quantitative researcher led approaches which focus on a few measurable attributes. Our aim was to explore the utility of qualitative vignettes as a methodological tool allowing service users/providers to contribute to intervention design.A case series of four acceptability and feasibility studies with service users and providers. Data were collected at different pre-trial stages: i) vignettes of studies in a systematic review of incentives for breastfeeding and smoking cessation in pregnancy, subsequently modified following emergent qualitative analysis; ii) emergent vignettes in the last of up to 8 serial qualitative interviews investigating infant feeding behaviour, following a systematic review showing poor generalizability of effective interventions in the UK context; iii) intervention vignettes of an effective intervention (groups for weight management) to refine the design for a new population (women treated for breast cancer) and iv) emergent intervention vignettes explored at a second interview with obese older adults.Illustrations of how qualitative vignettes can complement quantitative design tools will be presented.Carefully constructed qualitative vignettes combining known effective and emergent promising intervention aspects can optimise trial design. When talking service users and providers through a potential intervention, different perspectives emerge compared with responses to closed or more abstract questions."}
{"text": "Eating disorders (ED) are chronic, deadly illnesses and especially for adults with anorexia nervosa, existing treatments have limited proven efficacy. Growing knowledge about the neural underpinnings to ED provides an avenue for more targeted, brain directed interventions. Brain stimulation techniques, such as Transcranial Magnetic Stimulation (TMS), transcranial Direct Current Stimulation (tDCS), Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation (DBS) have the ability to directly alter neural activity within the brain. Such methods are being used extensively within both research and clinical settings to treat movement disorders such as Parkinson's and a range of psychiatric illnesses including depression. Findings within such disorders, relevant animal models and more recent research within ED populations have led to a strong rationale for the use of brain stimulation in ED. This paper systematically reviews this literature, identifying deficits in the current knowledge in an attempt to help guide future research and clinical practice within the imminent field of brain directed interventions for ED.Understanding and Treating Eating Pathology stream of the 2013 ANZAED Conference.This abstract was presented in the"}
{"text": "Biomedical imaging is a rapidly growing field to provide a state-of-the-art tool for preclinical biomedical research and clinical applications, in view of its ability to noninvasively reveal subtle structural variations of biological tissues and visualize in vivo physiological and pathological processes at the cellular and molecular levels. Mathematical methods are involved with imaging theories, models, and reconstruction algorithms in biomedical imaging. X-ray computed tomography (CT) was a successful application of mathematical method in medical imaging. The CT mathematical model can be reduced to a Radon transform. The inverse transform of Radon transform is invented by Radon in 1917. Magnetic resonance imaging (MRI) is a versatile medical imaging modality. MRI can provide more diagnostic information than any of the existing imaging techniques. It does not involve the use of ionizing radiation, hence free from associated harmful effects. Inverse Fast Fourier Transform (IFFT) is a standard method of image reconstruction in MRI from uniformly sampled K-space data. From nonuniform K-space data, iterative algorithms can improve image quality of image reconstruction for MRI. In the optical molecular imaging, the radiative transport equation (RTE) is the fundamental equation to describe photon propagation in biological tissues. The forward solution predicts photon propagation in the optical molecular imaging. The inverse solution can reconstruct molecular probe distribution in a small animal for providing unique insights into disease pathogenesis, drug development, and responses of therapy. The solutions for RTE usually involve analytical methods, Monte Carlo (MC) method, diffusion approximation (DA) method, simplified spherical harmonics method, and some numerical methods.In this special issue, each paper was reviewed by at least two reviewers and revised according to review comments. This special issue covered most of common biomedical imaging models and various image processing methods, such as registration, segmentation, and so forth, were involved. For Positron Emission Tomography (PET) imaging model, two attenuation correction methods based on X-rays CT (CTAC method) and segmentation of emission images (SE-AC method) were simulated with Monte Carlo method and compared. For synchrotron Micro-CT imaging model, a semiautomatic segmentation algorithm for extracting the complete structure of acini has been proposed. For ultrasound imaging model, a common carotid artery segmentation scheme based on active shape model can get better result and promote the translation of carotid 3D US to clinical care for the monitoring of the atherosclerotic disease progression and regression. For MRI model, a mesh-deformation constraints based image registration algorithm was carefully investigated. Also the development of image segmentation for intracranial aneurysms and rotation covariant image processing method for biomedical applications are summarized. Furthermore, in order to accelerate the parallel imaging, a sparse constrained reconstruction approach with variable splitting methods was proposed and verified: total variation (TV)-minimization interior tomography algorithm, dynamic and robust blind watermarking scheme to resist against common distortions, modified global and modified linear contrast stretching techniques for identification of various stages and species of malaria, a 3D surface-based deformable model as guidance for nonrigid 3D medical image registration and fusion, mathematical or computational modeling for oncogene inactivation, a group factor analysis model for neuroimaging applications by assigning separate factor patterns to control and patient groups yielding more reasonable factor scores and patterns, different MISO Volterra methods to model simulated ultrasound contrast agents signals, an automated process that determines whether an aortic object in a slice is a candidate for aortic dissection or PAU based on contrast enhanced CT data, image-based computational techniques to quantify the severity and directionality of individual scratches and scrapes, combination of genetic algorithm and closed loop to obtain optimal ternary command which maximized the contrast to tissue ratio, and magnetoacoustic tomography with magnetic induction (MAT-MI) for generating electrical conductivity images of biological tissues with high spatial resolution. An acceleration strategy for fluorescence molecular tomography (FMT) with early photons is proposed using graphics processing units (GPUs). The fluorescence molecular tomography (FMT) with early photons can efficiently improve the spatial resolution and fidelity of the reconstructed results. An efficient compressed sensing-based algorithm is proposed for CT image reconstruction from few-view data to suppress the streak artifact. The compressed sensing (CS) algorithm shows the potential to accurately recover images from highly undersampled data. The discriminant analysis techniques are discussed using MRI to identify the correlative pattern of brain changes for differentiating parkinsonian syndromes. A hybrid multiscale and multilevel image fusion algorithm for green fluorescent protein (GFP) image and phase contrast image of Arabidopsis cell is proposed. This algorithm uses different fusion strategies for different detailed subbands, which include neighborhood consistency measurement (NCM) that can adaptively find balance between color background and gray structure. A detrended fluctuation analysis (DFA) method is applied to image analysis to investigate the characteristic of different type of simulated and lymphoma image. A method is presented to estimate the tilt and decentration of intraocular lens (IOL) more accurately. The Bayesian hierarchical model for the analysis of categorical longitudinal data is investigated from sedation measurement for MRI and CT. In vivo MRI of local drug delivery is discussed to visualize and quantify the time resolved distribution of MRI contrast agents.These papers represent an insightful observation into the state of the art, as well as future topics in this biomedical imaging field. We hope that this special issue would attract a wide attention of the peers.Wenxiang CongKumar DurairajPeng Feng"}
{"text": "Although the advent of MRI impacted significantly our presurgical investigation, ictal semiology with interictal and ictal EEG has clearly retained its roles in localizing epileptogenesis. MRI-identified lesions considered epileptogenic on semiological and electroencephalographic grounds have increased the likelihood of resective surgery effectiveness whereas a nonlesional MRI would diminish this probability. Ictal propagation and the interplay between its source and destination have emerged as a significant component of seizure evaluation over the past 30 years. Epilepsy and Functional Anatomy of the Human Brain [Ictal semiology and EEG dominated our localization of intractable epileptogenesis prior to the introduction of MRI. Dr. John Girvin and I each attempted to outdo the other in obtaining patient and observer descriptions of the patients' seizures, guided by the most comprehensive observations and perceptions documented by Wilder Penfield and Herbert Jasper in an Brain . SeizureIn addition to Penfield's identification for a semiological pattern as representing temporal lobe epilepsy and subsequent description of mesial temporal ictal semiology , subsequThe works of International League against Epilepsy Commissions on Epileptic Seizure Classification and Terminology have, in sequential fashion, clarified our clinical analyses. The 1981 ILAE Commission classified partial seizures into simple partial (consciousness preserved) and complex partial (consciousness impaired). This division has encountered clinical and heuristic limitations as it depends upon evaluating an entity\u2014consciousness\u2014that can neither be defined nor assessed. Gloor discusseCombined with ictal semiology, ictal and interictal EEG were the principal tools before the mid-1980s to localize epileptogenesis in virtually all patients whose intractable focal epilepsies required resective surgery for alleviation. Focal temporal interictal spikes, if predominant over one temporal lobe, lateralised temporal lobe seizure origin in over 90% of patients [For many years, nasopharyngeal or sphenoidal EEG leads supplemented the Ten Twenty EEG electrode system to better record anterior-mesial temporal EEG activity, especially spikes. As illustrated by F. A. Gibbs and E. L. Gibbs , the antOur group at Western/University Hospital was the first to formally study and describe the morphology of scalp-recorded focal seizures-temporal and extratemporal . Recognisubdural electrodes. Inserted as imbedded in silicon strips through burr holes to avoid a craniotomy during the patient's evaluation, these electrodes record directly from the cortical surface. Moreover, they may extend to mesial and inferior cortical surfaces, areas remote from scalp electrodes. For patients with temporal lobe epilepsy, SDE provides more precise and sensitive ictal and interictal recording from the mesial temporal regions. In 1979, Dr. John Girvin and Mr. Dan Jones, EEG technologist, designed Commercially manufactured subdural electrodes were not available in the early 1980s, resulting in some other epilepsy centres purchasing our in-house-manufactured electrodes. Design and manufacture of SDE at UH without any complication continued by Dan Jones and Frank Bihari for over 20 years. Figures However, in 2004 London Health Sciences Centre chose to make use of commercially produced electrodes, though at a significantly greater cost. Our centre was the first to routinely employ subdural electrodes (SDE), and they continue today as a major part of evaluation of about 50% of our patients ultimately operated upon. We studied 27 consecutive patients whose temporal lobe epilepsy clinically implicated both temporal lobes from ictal semiology, scalp EEG, and imaging features. We found that the side of SDE-recorded seizures correlated with that containing most scalp spikes and most scalp-recorded seizures in most but not all patients, confirming the value of both EEG and SDE .Although unable to detect small cortical epileptogenic lesions, plain skull X-rays had disclosed several cranial and intracranial abnormalities of lateralising value. Cranial erosion on skull roentgenography could have resulted from a previous wide fracture or from a subdural or subarachnoid cyst; one or more asymmetrical cranial features may have indicated cerebral hemiatrophy, compatible with accompanying epileptogenesis; intracerebral calcification may have represented tumours or congenital lesions. Pneumoencephalography disclosed displaced or deformed ventricles from tumours, abscesses, hematoma, and other lesions. Cerebral arteriography helped localize expanding lesions but proved less helpful in the study of atrophic lesions . A major advance in evaluating patients for temporal lobe surgery was the advent of MRI. Imaging afforded by MRI discloses focal structural abnormalities underlying intractable epilepsy that may remain undetected by earlier neuroimaging methods . SubsequThree common epileptogenic lesions are particularly well displayed by MRI: mesial temporal sclerosis, cortical dysplasia (CD), and benign tumours such as dysembryoplastic neuroepithelial tumours (DNETs) and gangliogliomas (GGL). Rhythmic epileptiform discharges (REDs) may characterize the scalp EEGs of those with focal CD ; abundanThe presence or absence of mesial temporal sclerosis (MTS) became far better displayed by MRI than any previous imaging modality. This greatly facilitated, with EEG, an assessment as to whether one or both temporal lobes are epileptogenic. In the latter instance, assessment of their relative epileptogenicities may influence a surgical decision. In some patients, MRI and EEG (via REDs) have demonstrated both MTS and CD with comparable epileptogenicity in each, termed \u201cdual pathology\u201d , 19. OriThe appearance of dual pathology in some patients augmented our awareness of seizure propagation and its influence on semiology. Thus, ictal symptoms and signs may signify the site of seizure spread rather than origin. Both normal cerebral connectivity and neuronal pathways developed in the process of epileptogenesis likely participate in seizure spread. For example, occipital seizures may propagate to the mesial temporal region via the \u201cventral stream,\u201d a multisynaptic pathway that terminates primarily in the amygdala but also in the parahippocampal area . Munari personal communication). However, often a full temporal lobectomy has been performed . Surgical approach and technique have not measurably changed over the years.Three approaches to the mesial temporal region have been described: sylvian fissure, middle temporal gyrus, and inferior temporal pole . Our surThat a substantial left temporal lobectomy will significantly impair verbal memory has become increasingly realized over the past decades creating a distinction between left and right temporal epilepsy in terms of surgical candidature , 25. Con"}
{"text": "This study is the first to use quantitative perfusion CMR to evaluate regional differences in myocardial blood flow (MBF) in patients with left bundle branch block (LBBB).LBBB is often associated with underlying CAD but its presence can limit the diagnostic accuracy of non-invasive imaging tests. In particular, there is a high incidence of false-positive results with exercise SPECT due to apparent septal perfusion defects. The use of vasodilator stress has reduced but not eliminated this problem. Several hypotheses have been postulated to explain the cause of such perfusion defects, and these include early activation of the septum, leading to shortened diastole and reduced blood flow; partial volume effects caused by impaired septal thickening; and increased septal intra-myocardial pressure during diastole, resulting in reduced flow reserve. A number of small studies using PET or early quantitative SPECT techniques have evaluated regional differences in MBF in patients with LBBB, but the results have been conflicting and have shown either no regional differences or a relative but not absolute reduction in septal perfusion. This study re-evaluates the unresolved question of septal perfusion in LBBB using quantitative perfusion CMR.9 patients with LBBB and no significant CAD underwent adenosine stress/rest perfusion CMR at 1.5T and X-ray coronary angiography. Absence of CAD was defined as luminal stenosis <40% on quantitative coronary angiography in all major vessels. Mid-ventricular perfusion data were segmented into 3 regions for each patient: septal, adjacent (anterior-inferior) and lateral. MBF and myocardial perfusion reserve (MPR) were then determined for the septal and lateral regions by Fermi function deconvolution.Resting MBF was similar in both septal and lateral regions in all patients ."}
{"text": "Coincident expression of otherwise unrelated inborn errors of metabolism may occur as a result of large deletions of multiple gene, referred to as the contiguous gene deletion syndrome. We describe two male infants who presented with failure to thrive and raised urinary glycerol levels, leading diagnosis of glycerol kinase deficiency, congenital adrenal hypoplasia and myopathy.These clinical diagnoses, suggest Xp21 contiguous gene deletion syndrome.The two male infants currently 48 months and 3 months old, presented with failure to thrive at 10 months and 1 month of age respectively. On evaluation for metabolic causes of poor weight gain, urine organic acids showed high levels of glycerol. Further results revealed pseudo-hypertriglyceridemia which raised the suspicion of glycerol kinase deficiency. Both infants were persistently hyponatremic and hyperkalemic, and the synacthen test showed a suboptimal cortisol peaks. Plasma renin was high with low aldosterone indicating mineralocorticoid defiency.The older male infant who presented at 10 months of age also had significant developmental delay with muscular weakness and markedly raised creatinine kinase.He was confirmed to have Duchene Muscular Dystrophy.Both the infants were started on steroid and salt replacement and monogen feeds containing medium chain triglycerides. Their weight improved with normalization of sodium & potassium levels. The above spectrum of clinical & biochemical features is consistent with a diagnosis of Xp21 contiguous gene deletion syndrome. Although rare, raised urinary glycerol and serum triglycerides leads to suspicion and allows early recognition of this condition, where prompt treatment can prevent life-threatening adrenal crises."}
{"text": "Dilated cardiomyopathy (DCM) occurring due to an unknown etiology or genetic predisposition is termed as idiopathic dilated cardiomyopathy (iDCM), although iDCM may also result from viral exposure. However, the incidence of myocardial inflammation and its relation to left ventricular (LV) function in iDCM remains unknown.Cardiovascular magnetic resonance (CMR) imaging allows for the visualization of myocardial inflammation using early Gadolinium enhancement (EGE). We applied EGE imaging in the setting of clinically suspected iDCM to determine both the incidence and relation of myocardial inflammation to LV function.26 patients were referred to us for the assessment of iDCM following a clinical suspicion of iDCM, based upon the following criteria: ejection fraction below 45%; invasive exclusion of significant coronary artery disease using a cutoff of 50% stenosis; stable clinical course for at least 3-months prior to the CMR study; exclusion of myocarditis within the past 12 months; as well as exclusion of comorbidities which may otherwise account for patient presentation including valvular heart disease.Standard CMR imaging procedures for the assessment of LV function and EGE were utilized. EGE images were acquired before and early after (over 4 minutes) Gd-DTPA 0.1ml/kgBW contrast injection using T1-weighted images.LV function was assessed by manually tracing endo- and epicardial contours. Myocardial signal intensity was normalized to skeletal muscle, generating a ratio that had to be greater than or equal to 4 to be considered positive for EGE.Eighteen patients (69%) presented with EGE and a significantly increased EGE ratio . The ratio of EGE correlated with LVEDVI and LVESVI , LVSVI , and LVEF . Patients with elevated EGE had significantly dilated left ventricles and globally reduced ventricular function: LVEDVI and LVESVI were increased, while LVSVI and LVEF were reduced (Figure Using CMR-based EGE as a surrogate marker of myocardial inflammation, we provide first evidence for a high incidence of inflammation in patients with clinically suspected iDCM. The extent of myocardial enhancement was directly related to reduced ventricular function. CMR-based assessment of myocardial inflammation may be utilized as a biomarker for patient prognosis and guide medical therapy to target those patients in whom there is active myocardial inflammation."}
{"text": "This case report illustrates two unusual cases of parapharyngeal schwannomas mimicking carotid body tumors in terms of characteristic vascular displacement. Carotid body tumors classically cause splaying of internal and external carotid arteries demonstrating the Lyre sign on imaging. Also interestingly, both of these cases were seen in younger ages and include cervical sympathetic chain schwannoma and vagal schwannoma. However, these schwannomas revealed hypovascularity on imaging studies allowing differentiation from hypervascular carotid body tumors. Preoperative distinction between carotid body tumors and schwannomas is very important. Carotid body tumors, cervical sympathetic chain schwannomas, and vagal schwannomas have common location in neck that is the retrostyloid compartment of parapharyngeal space \u20133. AmongAn 18-year-old female was referred to the otolaryngology department with a swelling on the left side of the neck since 4 months. On examination, nonpulsatile mass near angle of the left mandible was seen. Cranial nerve examination was normal. Doppler ultrasonography revealed hypoechoic mass in the left carotid space showing mild peripheral vascularity . ComputeA 17-year-old female came with history of painless swelling on the left side of the neck and change in voice since 2 months. On examination, there was nontender swelling noted posterior to the angle of the left mandible. USG neck revealed hypoechoic mass on the left parapharyngeal space showing mild vascularity on the Doppler study . On CT sVagal schwannomas, carotid body tumours and cervical sympathetic chain schwannomas are the most common tumours of the retrostyloid parapharyngeal space , 2. CaroSchwannomas or neurilemomas, are derived from schwann cells. They are common in middle age with female preponderance \u20133. In thPreoperative diagnosis is very important in these retrostyloid parapharyngeal masses as management of carotid body tumors varies from surgery to radiation to observation, while complete surgical excision is the therapy of choice in vagal and cervical sympathetic schwannomas . Also, rBoth of the described tumors displayed splaying of external and internal carotid arteries on CT contrast study, MRI, and DSA which was also confirmed at surgery. However both of these tumors demonstrated mild vascularity on the Doppler USG, CT, and DSA.Although characteristic vascular displacement, that is, splaying of carotid bifurcation helps to distinguish carotid body tumor from other retrostyloid parapharyngeal masses, similar vascular displacement can be seen in vagal and cervical sympathetic chain schwannomas. So, this imaging pitfall should be taken into account while considering differential diagnosis of retrostyloid parapharyngeal tumors.Both of these tumors showed hypovascularity, hence favor schwannomas rather than carotid body tumors. Internal vascularity and enhancement characteristics of the tumor should be given more importance while differentiating schwannomas from carotid body tumors. Hence enhancement pattern is the imaging pearl in differentiating carotid body tumors from schwannomas."}
{"text": "Drug addiction is a serious public health problem that consists of a compulsive drive to take drugs despite repeated severe adverse consequences . FactorsThe accumulated evidence supports the view that a large number of substance users suffer from significant neuropsychological impairments . NeuroimBefore elaborating the idea of drug-induced cognitive changes in patients addicted to illicit drugs, it is important to briefly discuss the influence of potential premorbid deficits on the cognitive performance of some drugs abusers . For exaThe prefrontal cortex (PFC) and the striatum participate in integrated functions that are modulated by glutamate and dopaPathological changes in the orbitofrontal cortex (OFC) might also be involved in the manifestation of addiction-related behaviors because it is relevant to outcomes related to primary reinforcers . OFC neuImpaired self-control plays a fundamental role in drug-taking behaviors in addictive states . ImpulsiThe available evidence does support the thesis that impulsivity is a vulnerability marker for substance abuse , 12. SevInterestingly, abnormalities have been identified in frontal networks that subsume poor self-regulation and impulse control in cocaine dependency. Specifically, cocaine users were reported to show stronger connectivity within the perigenual anterior cingulate cortex (ACC) social processing/\u201cmentalizing\u201d network . This stAttention represents a number of intimate mechanisms that facilitate the filtering, selection, and processing of information . In subsPoor cognitive performance in areas of risk-taking and decision making may influence the degree to which illicit drug users engage in risky behaviors with consequent negative health consequences. Deficits in tests of decision making have been found in patients who suffer from marijuana , 50, cocIn summary, drug addiction is marked by mild, yet pervasive, cognitive disruptions that may cause the negative progression of the clinical course, threaten sustained abstinence , or incr"}
{"text": "The letter by Mullier8C intervals,The inhibition of pre-hepatic/hepatic CYP3A4 metabolism of amiodarone alters both plasma and cardiac substrate:metabolite ratios. It therefore reduces alterations of PR and QTC by inhibiting the rapid component of delayed rectifier K+ current (Ikr), leading to significant QT prolongation in healthy subjects and in patients with dilated or hypertensive cardiomyopathy,The interaction of grapefruit juice with amiodarone is more complicated than previously thought. Naringenin, the naringin (the predominant flavonoid in grapefruit juice) aglycone, has recently been reported to prolong QTEven though cases of QT prolongation and torsades de pointes with amiodarone are rare, a case has been reported of a female patient who presented with marked QT prolongation associated with ventricular arrhythmias including torsades de pointes, requiring electrical cardioversion after amiodarone administration, after she had been drinking large quantities of among others grapefruit juice."}
{"text": "Chronic heart failure (CHF) is the leading cause of hospitalization and death in industrialized countries. CHF is frequently associated with humoral and metabolic disturbances, including reduced bioavailability of the important signalling molecule nitric oxide (NO), which has vasodilating properties. Several studies reported high plasma levels of asymmetrical NG, NG-dimethyl-L-arginine (ADMA), an endogenous inhibitor of NO production, in CHF, contributing to endothelial dysfunction. The Dynamic Vessel Analyzer (DVA) enables dynamic analyses of retinal vessels. NO is a mediator of retinal vasodilator response to flicker light. Reduced response of retinal arterioles to flicker light may be an attractive technique to non-invasively assess endothelial dysfunction. The aim of the study was to test the hypothesis that retinal vessel response to flicker light is reduced in patients with CHF and correlates inversely with serum ADMA levels.16 patients with non-ischemic cardiomyopathy and 22 healthy volunteers were included. Retinal arteriolar flicker response as percent change from baseline and serum ADMA level were measured.Retinal arteriolar flicker response was significantly reduced in CHF patients compared to the healthy control group . ADMA levels tended to be higher in CHF patients . Noteworthy, we observed a highly significant inverse correlation between retinal arteriolar flicker response and ADMA levels .Our findings suggest that analysis of retinal vessels could be an attractive non-invasive method to quantify endothelial dysfunction in CHF."}
{"text": "Candida is the most common human fungal pathogen and the cause of invasive candidiasis, the fourth leading cause of nosocomial bloodstream infection in the United States with an estimated annual cost of \u223cUS$2 billion and mortality that exceeds 40% despite administration of antifungal therapy in modern intensive care unit facilities Candida yeast cells intravenously and mimics skin-derived bloodstream human candidiasis, has been successfully employed to study fungal and host factors that regulate susceptibility to the infection Candida expresses a variety of virulence factors that contribute to its pathogenesis and could be exploited for development of vaccines and targeted therapeutic strategies. Firstly, Candida albicans filaments' virulence factors, including secreted aspartyl proteases and phospholipases, are thought to be important for Candida invasion in infected organs and, probably, for mediating fungus-induced tissue immunopathology Candida is able to efficiently adhere to and invade epithelial and endothelial cells via induced endocytosis and active penetration; both adhesion and invasion facilitate Candida dissemination Candida to form biofilms on implanted medical devices such as central venous catheters, which are a frequent portal of entry for invasive infection in humans Candida factors that promote its adhesion and invasion, the agglutinin-like sequence (Als) family has attracted significant attention; Als3 in particular, a C. albicans\u2013specific virulence factor, was recently shown to mediate brain-specific Candida endothelial invasion and tissue penetration vps51\u0394/\u0394 C. albicans mutant was shown to be responsible for its increased ability to invade brain endothelial cells in vitro and traffic to the brain in vivo via binding to the gp96 heat shock protein, which is expressed specifically on brain endothelium Candida tissue burden C. albicans virulence factor is its ability to transition between unicellular yeast cells and filamentous growth during infection; in fact, it is the interchange between these morphotypes that is critical for pathogenesis, as strains locked either in the yeast or the filamentous forms have attenuated virulence in vivo albicans Candida species such as Candida glabrata, which is an important cause of invasive candidiasis in humans even though it does not form hyphae. Strikingly, the ability of C. albicans to form filaments in vivo is tissue-specific Candida growth in mice such as the liver and spleen prevent Candida filamentation, whereas hyphal formation is abundant in the kidney, the target organ of murine disseminated candidiasis, where Candida proliferation is inexorable Candida filamentation could lead to the discovery of novel therapeutic interventions.Moreover, a fundamental Candida immune response is fungal recognition by the innate immune system. Over the past decade there has been an explosion in our understanding of how soluble and membrane-bound pattern recognition receptors (PRRs) recognize various pathogen-associated molecular patterns (PAMPs) of Candida yeast and filamentous forms in modulating downstream anti-Candida immune responses. In addition, more studies are needed to understand how Candida influences its recognition in vivo by employing immune evasion strategies; for example, \u03b2-glucan exposure on the Candida surface occurs in infected mouse tissues only late after infection The challenge for future research will be to define how Candida experimental strains impedes on drawing definite conclusions about the in vivo role of certain PRRs, as apparently discrepant results have been reported for some TLRs and CLRs with different fungal strains Candida strains in mammals could potentially be ameliorated by employing non-vertebrate and/or mini-vertebrate model hosts that have evolutionarily conserved innate immune pathways , and could allow for facile and inexpensive high-throughput screening of greater numbers of Candida strains C. albicans is the most common agent of human invasive candidiasis, research performed until now has predominantly focused on the recognition of this species, and much less is known about the interaction of other Candida species with the immune system. It is expected that research aiming to gain more insight on the recognition of emerging non-albicans Candida species will represent an important area of research in the coming years.In addition, the notable diversity in PAMP structure among various Candida killing Candida ingestion is followed by assembly of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex at the phagosomal membrane and oxidative burst, which leads to generation of candidacidal reactive oxygen species and K+-influx\u2013induced activation of neutrophil candidacidal granular proteases Candida yeast-to-hyphae conversion, a process dependent on the oxidative burst Candida yeasts and hyphae and appear important for anti-Candida host defense in vivo Neutrophils are indispensable for host defense against invasive candidiasis, and neutropenia is a well-recognized risk factor for development of and adverse outcome after infection in humans Nonetheless, neutrophils have differential effects in invasive candidiasis in vivo depending on the phase of the infection in mice. Specifically, early neutrophil presence after infection is protective, whereas neutrophil presence late after infection is pathogenic Candida phagocytosis and secretion of a variety of pro-inflammatory cytokines and chemokines that orchestrate the antifungal innate immune response Candida compared to neutrophils; the lack of macrophage myeloperoxidase and extracellular trap formation may, at least in part, account for this deficit Candida effects in mice; yet, the importance of Candida-induced nitric oxide formation in human phagocytes is unclear Candida infection. In addition, future studies should aim to shed light on the relative role of recruited versus resident monocytes/macrophages in host defense against invasive candidiasis.Besides neutrophils, monocytes/macrophages are key phagocytic cells for protection against invasive candidiasis, as their depletion in mice leads to increased mortality Candida challenge, monocytes were recently shown to also confer protection following systemic Candida re-infection via functional reprogramming that involves the dectin-1/Raf-1 non-canonical signaling pathway and results in enhanced cytokine production Intriguingly, besides the protective role of monocytes/macrophages in host defense against primary Candida yeast and hyphal forms and respond differentially to the Candida morphotypes by priming the production of distinct cytokines + dendritic cells were recently shown to activate invariant natural killer T cells to mediate innate immune responses against fungi (including Candida) via dectin-1- and MyD88-dependent mechanisms without apparent requirement for fungal lipid antigen presentation Candida effects after systemic infection Candida-specific CD4+ T cells after systemic infection of mice vaccinated with the Als-derived peptide pALS Candida immunity could lead to the design of effective vaccination and immunomodulatory strategies against invasive and mucosal candidiasis in patients.The role of other hematopoietic cells in host defense against invasive candidiasis merits further investigation. For example, dendritic cells are able to phagocytize Candida killing capacity of human myeloperoxidase-deficient phagocytes, invasive candidiasis occurs in patients with myeloperoxidase deficiency, the most common inherited phagocytic disorder In agreement with the requirement of innate immunity for effective host defense in the mouse model of invasive candidiasis, certain innate immune factors have been associated with protection against the infection in humans Candida immunity in humans \u2212/\u2212Card9 and \u2212/\u2212dectin-1 mice are both susceptible to invasive candidiasis Click here for additional data file."}
{"text": "Unfortunately, at present, degenerative retinal diseases such as retinitis pigmentosa remains untreatable. Patients with these conditions suffer progressive visual decline resulting from continuing loss of photoreceptor cells and outer nuclear layers. However, stem cell therapy is a promising approach to restore visual function in eyes with degenerative retinal diseases such as retinitis pigmentosa. Animal studies have established that pluripotent stem cells when placed in the mouse retinitis pigmentosa models have the potential not only to survive, but also to differentiate, organize into and function as photoreceptor cells. Furthermore, there is early evidence that these transplanted cells provide improved visual function. These groundbreaking studies provide proof of concept that stem cell therapy is a viable method of visual rehabilitation among eyes with retinitis pigmentosa. Further studies are required to optimize these techniques in human application. This review focuses on stem cell therapy as a new approach for vision restitution in retinitis pigmentosa. At present, degenerative retinal diseases such as retinitis pigmentosa (RP) and dry type age related macular degeneration (AMD) remain untreatable. Patients with these conditions suffer progressive visual decline resulting from continuing loss of photoreceptor cells and outer nuclear layers. Both disorders are characterized by the progressive dysfunction and death of the light sensing photoreceptors of the retina and other supportive cells. Because of the limited regenerative capacity of the mammalian retina, retinal progenitor cell are being developed to serve as \u201cspare parts\u201d for lost photoreceptor cells. Advances in molecular biology have identified innovative approaches that, for the first time, provide hope for permanent visual rehabilitation. Stem cell therapy can potentially replace lost photoreceptor and retinal pigment epithelial cell and subsequently restore visual function in eyes with degenerative retinal disorders .A potential target disease for stem cell therapy is retinitis pigmentosa (RP). RP is the most commonly inheritable eye disease that causes progressive loss of photoreceptor cells resulting in gradual visual decline. While the onset of RP may occur during infancy, the first symptoms are usually observed in early adulthood, beginning with nyctalopia or night blindness followed by loss of peripheral vision and eventually, as the central photoreceptors in the macula are damaged, loss of fine central vision. Morphologically, these retinas are characterized by centripetal proliferation of bone spicule-like pigmentation, attenuation of retinal blood vessels and optic nerve pallor . At leasTransplantation of progenitor stem cells that can be stimulated to become replacement photoreceptors and supportive outer retina cells can theoretically lead to treatments that restore visual function . RecentlTwo types of stem cells may be utilized to produce retinal progenitor cells. Firstly, Embryonic stem (ESC) and secondly, induced pluripotent stem (IPS) cells. Both types of cells are pluripotent and capable of becoming any cell type. ESC\u2019s are derived from embryos while IPS cells are obtained from a variety of adult tissues such as skin, bone marrow, teeth. IPS cells, if successfully implanted and optimized, can potentially provide an unlimited supply of stem cells for transplantation. Cell replacement is one approach for restoration of vision in RP. Because visual loss usually occurs when the outer retinal photoreceptor layer is lost, therapeutic timing should be at this stage of disease. Singh and colleagues have demonstrated using a murine model of severe human retinitis pigmentosa, that at a stage when no host rod cells are remaining, transplanted rod precursors can reestablish an anatomically distinct and appropriately polarized outer nuclear layer. In their study, restoration of a trilaminar retinal organization was restored to RD1 hosts with only two retinal layers before treatment. The introduced rod precursors continued to develop in the host niche to become mature rods complete with light-sensitive outer segments and connections to host neurons downstream. Visual function was also restored. These findings indicated that stem cell therapy may reinstate a light-sensitive cell layer de novo and restore structurally damaged visual circuits. In this model, total photoreceptor layer reconstruction is one approach to further develop cell-based strategies for retinal repair .ESC\u2019s have been shown to generate functional photoreceptor cells restoring light response of photoreceptor-deficient mice, but there is concern over the risk for tumor formation using ESC. Li and colleagues successfully cultured Nestin(+)Sox2(+)Pax6(+) multipotent retinal stem cells (RSCs) from the adult mouse retina. These ESC\u2019s are capable of producing functional photoreceptor cells that restore light response of photoreceptor-deficient RD1 mutant mice. After several cycles of expansion using growth factors, cultured RSCs still maintained proliferation and differentiation potential .Under optimized differentiation conditions, ESC\u2019s can differentiate into all the major retinal cell types found in the adult retina such as photoreceptor cells under optimized differentiation conditions. Following transplantation into the subretinal space of slowly degenerating RD7 mutant eyes, RSC-derived photoreceptor cells were shown to integrate into the retina, and develop into cells morphologically resembling endogenous photoreceptors and forming synapses with resident retinal neurons. When transplanted into eyes of photoreceptor-deficient RD1 mutant mice, an RP model, RSC-derived photoreceptors can partially restore light response, indicating functionality. In animal studies, no evidence for tumor development was found . Along similar lines, autologous IPS cells are being developed for stem cell transplantation. This lack of immunogenicity confers an important advantage. Because IPS cells are autologous or derived from the same organism, they do not incite immunological reaction nor require use of immunosuppressive medication . Li and colleagues recently transplanted human IPS cell-derived retinal pigment epithelium (RPE) cells into the subretinal spaces of mouse models with the Rpe65rd12 /Rpe65rd12 form of RP. A healthy adult provided skin fibroblasts cultured with lentivirus-delivered genes encoding transcription factors OCT4, SOX2, KLF4, and MYC. Antibody staining of markers and a teratoma assay demonstrated pluripotency of the hiPS cells. Culturing in differentiation medium guided their fate to RPE. By 12 weeks, from 30% to 50% of the surfaces of 12-well dishes were coated with RPE with characteristic hexagonal shapes, perinuclear melanin granules, and microvilli [The target mice had albinism, which provided a white contrast against which the transplanted pigmented cells would be visible. The mice also had severe combined immune deficiency to prevent graft-vs-host disease. An injection of 1000 hiPS-derived RPE cells was administered into the subretinal space in the right eyes of 34 mice at two days following birth. The mice were sacrificed at six months, shortly before they would have died from severe combined immune deficiency .Successful development into RPE cells was indicated by: 1) microscopic confirmation of pigmented hiPS-derived RPE admixed into the native, albino RPE; 2) quantitative polymerase chain reaction detection of markers of human fetal RPE and IPS-derived RPE; 3) positive staining for rhodopsin indicating that the hiPS-derived RPE cells phagocytosed photoreceptors. Furthermore, in some mice, electroretinogram (ERG) response to measure neuronal function, demonstrated a small but significant improvement of mean \u03b2-wave peak difference between treated and control eyes of 13.7 \u03bcV P = 0.0246). Furthermore, no tumor growth was observed [. FurtherThe use of retinal progenitor sheet transplantation is another promising approach. Seller and Aramant demonstrated that when freshly dissected sheets of fetal-derived retinal progenitor cells are mixed with RPE and transplanted subretinally, improvements of visual acuity are observed among animals and humans. Visual improvement in this model is attributed to restoration of synaptic connections between transplant and host when transplant processes proliferate into the inner plexiform layer of the host retina and presumably form synapses. One drawback of widespread use of this method is limited supply of fetal donor tissue .Future areas for stem cell development include methods for optimizing stem cell production and delivery. The use of specific extracellular matrix can stimulate the development of human pluripotent stem cells into transient organized neuroepithelum with rapid differentiation into retinal progenitor cells . Garit-HPreviously, RP was considered a devastating and untreatable condition. These pioneering animal studies provide hopeful evidence for the hypothesis that stem cell therapy is a viable means for visual rehabilitation of RP patients. What is now known is that stem cell therapy can potentially replace degenerate photoreceptors and outer retinal cells. When placed in the appropriate tissue niche, these stem cells not only survive but differentiate into critical retinal cells, develop a retina-like organizational structure and exhibit functional characteristics of full-fledged photoreceptors and outer retinal cells. Further studies are needed to optimize techniques and validate these findings before proceeding to human trials. Conflicts of Interest: None declared."}
{"text": "Bone plays metabolic roles through osteocalcin(OC) when it is released into the systemic circulation in uncarboxylated form. Identified novel metabolic roles of OC include increasing insulin secretion and sensitivity, energy expenditure, reduction of fat mass and mitochondrial proliferation and functional enhancement. The onset of puberty can be influenced metabolic factors. This study was aimed to determine serum OC levels in girls with central precocious puberty(CPP) and to investigate the effects of OC on the onset of puberty.Serum OC levels of girls CPP (n=30) and their age-matched controls (n=30) were measured. GnRH stimulation test was performed in CPP group. Bone age was determined in all subjects.Serum OC levels were significantly higher in CPP group compared with control group . Serum OC levels were correlated with peak LH levels during GnRH stimulation test , bone age and bone age advance , but not related to age, height, weight and BMI.Serum OC seems to be associated with the onset of puberty leaving casual relations unresolved."}
{"text": "To report a case of central serous chorioretinopathy after solar eclipse viewing.A middle-age man developed a sudden-onset unilateral scotoma after viewing a partial solar eclipse in Hong Kong. Fundus examination, fluorescein angiography, and optical coherence tomography showed features compatible with central serous chorioretinopathy. The patient was managed conservatively and reevaluated periodically. Serial optical coherence tomographic evaluations demonstrated an initial increase in the amount of subretinal fluid which spontaneously resolved 10 weeks after the onset of symptoms.This case demonstrates the possibility of development of central serous chorioretinopathy following solar eclipse viewing. Retinopathy following viewing of a solar eclipse without the use of safe eyewear has been well-documented in the literature. The usual lesion consists of mild foveal changes due to photochemical damage to the retina. Patients usually present with reduced visual acuity and a central scotoma. Classical findings on fundus examination include a yellow-white spot in the fovea surrounded by granular changes in the retinal pigment epithelium (RPE). Fundus fluorescein angiography (FA) may reveal a small central foveal window defect. Optical coherence tomography (OCT) may also demonstrate hypo- or hyperreflective lesions in the outer retina and RPE.4Central serous chorioretinopathy (CSCR) is an entity characterized by neurosensory retinal detachment with or without RPE detachment. Previous studies have reported the association of CSCR with various risk factors such as psychological stress, type A personality, pregnancy, untreated hypertension, use of corticosteroids, and psychopharmacologic medications.7Herein, we describe a rare case of CSCR after viewing a solar eclipse. To our knowledge, the association between CSCR and solar eclipse viewing has not been reported in the literature.A 44-year-old Caucasian man with good past health and unremarkable ophthalmic history presented with an acute-onset relative scotoma in his left eye after viewing a partial solar eclipse in Hong Kong on July 22, 2009.The patient was reassessed six weeks later and he still complained of a persistent central scotoma. Nonetheless, visual acuity remained stable. Fundus examination of the left eye showed an increase in subretinal fluid. OCT demonstrated an increase in the serous neurosensory retinal detachment . Ten weeTo the best of our knowledge, this is the first report describing acute CSCR after direct solar eclipse gazing. Unprotected sun-gazing, particularly during an episode of solar eclipse, is a well-known cause of solar retinopathy.Clinical features of CSCR include accumulation of subretinal fluid, neurosensory retinal and RPE detachment, and leakage with angiographic evidence of RPE hyperpermeability.The exact pathogenetic mechanism of CSCR in our case remains unclear. We hypothesize that intense sunlight was preferentially absorbed by melanosomes in the RPE, causing localized RPE damage and thus resulting in CSCR."}
{"text": "In addition, no change in intracerebral incubation period was observed following active rumen digestion of unbound hamster HY TME prions and HY TME prions bound to a silty clay loam soil. These results demonstrate that both unbound and soil-bound prions readily survive rumen digestion without a reduction in infectivity, further supporting the potential for soil-mediated transmission of chronic wasting disease (CWD) and scrapie in the environment.Before prion uptake and infection can occur in the lower gastrointestinal system, ingested prions are subjected to anaerobic digestion in the rumen of cervids and bovids. The susceptibility of soil-bound prions to rumen digestion has not been evaluated previously. In this study, prions from infectious brain homogenates as well as prions bound to a range of soils and soil minerals were subjected to in vitro rumen digestion, and changes in PrP levels were measured via western blot. Binding to clay appeared to protect noninfectious hamster PrP Sc, a misfolded isoform of a normal cellular prion protein (PrPc) found in all susceptible species Sc exhibits resistance to proteolysis and inactivation, increased hydrophobicity, and a propensity for aggregation Sc can seed conversion of PrPc to PrPSc (\u2018replicate\u2019) and thereby initiate prion propagation and, presumably, disease infection Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases that afflict ruminants, including cattle , sheep and goats (scrapie), and deer, elk, and moose (chronic wasting disease or CWD), as well as humans (Creutzfeld-Jakob disease or CJD) Natural transmission of CWD and scrapie occurs primarily or exclusively through ingestion or inhalation of prion-contaminated material shed from infected hosts or present in mortalities Sc survives the digestive processes in the rumen and lower gastrointestinal system. Results from previous in vitro studies of PrPSc fate in rumen digestion have been varied. Scherbel and colleagues observed a near-complete loss of 263 K hamster PrPSc, as detected by western blot, following rumen digestion Sc in scrapie-infected sheep brain homogenates following exposure to rumen and other alimentary fluids Sc was detected post-digestion when precipitation and proteinase-K digestion were used prior to western blotting. An additional limited study found no evidence of scrapie PrPSc digestion in rumen fluids Sc.Prions are orally infectious Sc (both CWD-elk and hamster) has been shown previously Ingestion of prion-contaminated soil has been implicated as a likely mechanism of natural CWD and scrapie transmission Sc levels were measured by western blotting. Intracerebral hamster bioassay was also employed to measure changes in infectious titer. The results demonstrate the strong resistance of both unbound and soil-bound prions to rumen digestion, which further supports the efficacy of soil-bound prion ingestion as a natural route of disease transmission in ruminants.Adsorption of prions to soil may alter prion resistance to host degradation, thus potentially altering their oral infectivity and transmissibility. The objective of this research was to evaluate and compare the ability of rumen digestion to degrade unbound prions as well as prions bound to a range of soils and soil minerals. In vitro anaerobic digestion assays seeded by bovine rumen fluid were conducted, and the resultant PrPAll procedures involved in animal bioassay were approved by the Creighton University Institutional Animal Care and Use Committee and complied with the Guide for the Care and Use of Laboratory Animals. Collection procedures for rumen fluid from cannulated dairy cows was approved by the University of Nebraska-Lincoln Institutional Animal Care and Use Committee.++ or Mg++ using strain-dedicated Tenbroeck tissue grinders .Prion-infected brain tissue was collected without prior buffer profusion from golden Syrian hamsters infected with the hyper (HY) strain of transmissible mink encephalopathy (TME) as previously described Sc/PrPc and uninfected PrPc from brain homogenates were sorbed to a range of soils as described previously 2, Sigma Aldrich, St. Louis, MO) were used and have been described previously HY TME PrP2, 10% H2, and 5% CO2. Rumen fluid was diluted 1\u223610 or 1\u22365 in McDougall's buffer with soluble carbohydrates . There was no difference in immunoblot results between 1\u223610 and 1\u22365 rumen\u2236buffer dilutions (data not shown).Standard in vitro rumen digestion assay methods were followed Resazurin dye was used as an indicator of redox state and does not affect in vitro digestion Sc in digested and undigested samples was accomplished using SDS-PAGE/Western blotting as described previously without modification Detection of PrPIntracerebral inoculations of male golden Syrian hamsters were conducted as described previously Two-tailed student's T-tests assuming unequal variances were performed using Microsoft Excel to determine statistical significance as noted. P values less than 0.05 were considered statistically significant.An in vitro digestion assay was employed to simulate rumen digestion of prion-contaminated material. Standard methods, including standard rumen fluid sampling procedures and substrate and buffer compositions, were used Sc from brain homogenate was not significantly reduced in actively digested samples compared to inactive and buffer controls .Unbound HY TME PrPSc following in vitro rumen digestion, but somewhat inconsistent with Scherbel et al. Sc degradation during active digestion in the absence of detergents. Methodological differences such as rumen fluid seed or western blotting techniques may be responsible for the observed differences. For instance, we collected rumen fluid from a live, cannulated dairy cow while Scherbel et al. collected fluid from a slaughtered beef bull.These results are consistent with the result of Nicholson and colleagues Sc was sorbed to a range of soils and soil minerals and exposed to in vitro rumen digestion. Consistent with the unbound results, HY PrPSc bound to silty clay loam (SCL) soil was not reduced following active rumen digestion (Sc bound to SCL soil demonstrated similar resistance to digestion (data not shown). Increased detection of PrPSc bound to bentonite clay (2) and not a direct effect on PrPSc.To determine the effect of soil on the susceptibility of prions to rumen digestion, PrPabnormal , the lowSc was not detected on sand samples actively digested .HY TME bound to sandy loam (SL) soil and sand was susceptible to rumen digestion , and PrPdigested , lane 4.c from uninfected hamster brain homogenate (data not shown). Since there is a well-established relationship between HY TME infectious titer and incubation period Sc levels before and after digestion in unbound and SCL soil-bound PrPSc (Hamsters were inoculated with unbound and SCL-bound HY TME prions subjected to either active or inactive (pre-autoclaved) in vitro rumen digestion. The incubation periods of hamsters inoculated with inactive or active samples were equal . The incnd PrPSc .Sc replication efficiency Also consistent with previous results, the mean incubation time of SCL soil-bound HY TME was significantly longer (13 d) than unbound HY TME [27]. ThSc resistance to in vitro rumen digestion Sc abundance To initiate infection via absorption across the lower gastrointestinal epithelium, orally ingested prions must survive passage through the rumen bundance , and conbundance . MoreoveSc resistance to digestion with respect to soil type, where, in contrast to the other soils and minerals, PrPSc levels bound to sand and sandy loam soil were reduced following digestion (2 is not significantly different than unbound prions (data not shown). Based on the established relationship between PMCA replication efficiency and infectious titer We did observe variance in PrPigestion . VariancA number of factors must be considered in extending the present results. First, the results were obtained using in vitro digestion, which is a simulation of in vivo processes with limitations Sc, it may alter PrPSc uptake efficiency, which would not be detected by immunoblot or intracerebral bioassay. Thus, study of soil-bound prions in, for example, the gut-loop system employed by Dagleish and Jeffery Finally, unbound and soil-bound prions surviving rumen passage will be exposed to stomach and intestinal digestion before uptake. These two processes are less complex than rumen digestion, and previous results indicate unbound prions are resistant to both Figure S1Sc without proteinase-K treatment.Rumen digestion of unbound HYTME PrP(DOCX)Click here for additional data file.Table S1PrP Adsorption to Soil and Soil Minerals.(DOCX)Click here for additional data file."}
{"text": "Escherichia coli sepsis in baboons strongly induces procoagulant responses and affects the integrity of the lung. These effects are diminished by the treatment with compstatin, a C3 convertase complement inhibitor [Pulmonary fibrosis is a major and common medical condition, characterized by progressive scaring and decline in lung function. Persistent inflammation and acute lung injury in response to sepsis are potential triggers of the fibrotic response. Recently, we have reported that nhibitor .E. coli sepsis triggered metabolic and signaling pathways related to lung remodeling and fibrosis, and whether complement inhibition could attenuate these pathways.Here we used the baboon model described in conjuE. coli challenge. Immunochemical and biochemical analysis reveals enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Compstatin treatment decreases sepsis-induced expression of extracellular matrix genes, including eight collagen genes. Sirius Red and immunofluorescence staining for procollagens 1 and 3 confirms the collagen deposition in the lung. Ingenuity\u00ae pathway analysis of transcriptomics data shows that compstatin treatment reduces sepsis-induced expression of genes involved in fibroblast transformation and connective tissue production, cell chemotaxis, migration and proliferation (see Table Microarray gene expression analysis shows that sepsis augments several fibrotic gene clusters in the lung as early as 24 hours post Our data demonstrate that bacterial sepsis initiates pulmonary collagen deposition, and complement inhibition effectively attenuates the fibrotic response. This suggests that complement inhibitors could be used for prevention of sepsis-induced pulmonary fibrosis."}
{"text": "Endogenous retroviruses (ERVs) have much lower mutation rates than exogenous retroviruses (XRVs), therefore they are an important tool in analysing the long-term evolutionary history of retroviruses. Their transmission patterns also act as useful markers when studying host phylogenetics.[Oryctolagus cuniculus) [Lepus europeaus) [Microcebus murinus) [Cheirogaelus medius) [gamma- and beta- retroviruses, which are present in many vertebrate species The aim of this project is to look for and characterise further examples of primate ERVs and therefore gain insight into the evolutionary history of retroviruses and their primate hosts. This will involve data mining of primate genomes for previously unknown ERVs as well as PCR based screening of genera for which genome sequences are not available. Preliminary work suggests that prosimian primate genomes contain previously unclassified endogenous lentiviruses, so PCR-based screening will be used with DNA samples from lemurs, bushbabies and lorises to sequence and characterise these viruses.Recently, the first examples of endogenous lentivirus were characterised. The earliest was rabbit endogenous lentivirus type K in the European rabbit pol), group-specific antigen (gag) and envelope (env) genes of representative XRVs from all known retroviral genera were used to identify regions of the host genome which are highly similar to retroviral genes. We have validated this method by successfully searching the human genome for known ERV insertions. Regions of interest are then extracted and analysed in detail.The bioinformatics analysis component of this project used Exonerate to perfopol gene on sampM. murinus genome sequence identified 3542 ERV-like regions. This included 256 regions of less than 10,000 base pairs which incorporated gag, pol and env-like sequences in the correct orientation. The subset of pol genes which were within these 256 proviruses appear to be closely related to known gamma- and beta-retroviruses from other species.Bioinformatics analysis of the low-coverage Varecia variegata, Eulemur rufus and Mirza coquereli; the loris Perodictus potto and the bushbaby Galago moholi, although these insertions are yet to be further characterised.Preliminary laboratory work has shown previously uncharacterised lentiviral insertions in several species of lemur - murinus genome. Preliminary laboratory results suggest that there are undescribed endogenous lentiviruses in further prosimian primate species. Methodology has been established which can be used to screen further species for proviral insertions and to explore these in detail.Multiple potential ERV sequences have been found in the M."}
{"text": "Entropy is an elusive and somehow non-intuitive concept. Nevertheless, entropy governs spontaneous thermodynamic processes as important contribution to Gibbs Free Energy. Information theory defines Shannon entropy as a measure for uncertainty. In the context of protein binding the inherent link between flexibility, thus conformational entropy, and substrate specificity is discussed. Substrate promiscuity of proteases is quantified as cleavage entropy correlating local binding site flexibility directly with substrate readout. Caspases are examined as example protease family, where active site dynamics play a major role in mediating substrate specificity. Direct comparison of entropy in substrate data allows highlighting previously unexpected similarities in substrate recognition in proteases. Promiscuous binding to several protease targets demonstrates the emerging importance of quantitative studies on binding specificity. Shannon entropy applied to probability densities is used to rationalize ordering or disordering by binding processes. We have developed a data-driven method to reconstruct probability densities from discrete sampling by computer simulations. Application to solvent degrees of freedom leads to excellent correlation with experimental data."}
{"text": "Bisphenol A (BPA) is a chemical widely used to make polycarbonate plastics and epoxy resins lining food and beverage containers. A number of in vitro and in vivo studies have demonstrated that BPA has an estrogenic effect by binding to the nuclear estrogen receptor, and early BPA exposure could in induce early puberty. However, effects of human exposure to BPA on pubertal onset and the association of gonadotropin levels have not been fully evaluated. We aimed to study whether serum bisphenol A levels are associated with central precocious puberty (CPP) in Korean children.A total of 103 girls were enrolled. Pubertal staging, anthropometry, bone maturation were assessed. Gonadotropin releasing hormone-stimulation test were conducted to determine the basal and peak levels of luteinizing hormone (LH). Serum bisphenol A levels were analysed by gas chromatography/mass spectrometry method. Geometric mean serum BPA levels were higher in CPP girls than in controls . In partial correlation analysis controlling for age and body mass index, serum BPA level showed significant positive correlation with bone age , fat mass , waist circumference , basal LH levels , and peak LH levels . Bone age, height, basal/peak LH levels and prevalence of CPP increased significantly with increasing tertile of serum BPA. Increased risk of CPP [Odds ratio] was observed across increasing serum BPA tertile after adjusting for age and BMI.Serum BPA level was higher in CPP girls compared with controls, and higher serum BPA level was associated with increased risk of CPP. Prospective studies are needed to determine potential causal links between BPA exposure and CPP."}
{"text": "We present a case of myocardial infarction in a 19 year old female with cystic fibrosis who had a heart and lung transplant performed at the age of four years old. She presented atypically with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. A coronary angiogram showed proximal stenosis of the left anterior descending artery and right coronary artery. She was treated with percutaneous coronary intervention, involving drug eluting stents to the left anterior descending artery (LAD) and the right coronary artery (RCA). In this study we discuss the pathophysiology, investigations and treatment of cardiac transplant vasculopathy. Although complete reversal of LAD and RCA stenosis was achieved, routine follow-up with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events. Heart and lung transplantation in children with cystic fibrosis (CF) and end-stage lung disease are now rarely performed, with bilateral sequential lung transplantation (BSLT) being the preferred procedure . AlthougA 19 year old female with CF who had a heart and lung transplantation in 1997 presented to the Emergency Department (ED) with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. This was associated with intermittent paraesthesia, pallor and coldness in her left hand. The chest pain was worse on deep inspiration but was not positional or exacerbated by movement. Over the previous four weeks she had been having a productive cough with a reduced exercise tolerance but no chest pain.9/L), creatinine (138 \u03bcmol/L) and urea (12.8 \u03bcmol/L).On examination there was no swelling, pallor or erythema of her left arm/hand and no chest wall tenderness. She was well perfused with a regular pulse and a stable blood pressure. No murmur or added heart sound was present and vesicular breath sounds were heard on auscultation. A chest radiograph showed no acute changes and an initial electrocardiogram (ECG) taken in the ED showed a sinus tachycardia with no ST or T wave changes. Initial blood tests were normal apart from an elevated white cell count was 10,801. A computed tomography pulmonary angiogram (CTPA) the following day showed no pulmonary embolus (PE) and no vascular abnormalities. A coronary multi-slice computed tomography (MSCT) was not performed as it is not used as an investigation of acute MI in inpatients at St James\u2019s University Hospital.Later that day the patient was reviewed by a cardiology registrar who performed a bedside echocardiogram. This demonstrated moderate left ventricular impairment due to extensive apical akinesis and anterior/antero-septal hypokinesis with an ejection fraction of 42%. No valvular dysfunction was identified. That evening the patient received percutaneous coronary intervention (PCI) which illustrated a 95% proximal stenosis of the left anterior descending artery (LAD), normal left circumflex artery (LCx) and 80-95% proximal stenosis of the right coronary artery (RCA) Figure\u00a0. Drug elCardiac transplant vasculopathy (CTV) is a rapidly progressive form of atherosclerosis involving thickening of the intima, leading to stenosis of coronary artery grafts and subsequent myocardial ischaemia . It is gThe development of CTV is thought to be due to a combination of an immune-mediated process and non-immunologic risk factors resulting in endothelial injury and subsequent fibroelastic proliferation of the intima . Risk faThe diagnosis of CTV is particularly challenging as it rarely presents with typical angina, despite 10-30% of patients with heart transplants having partial reinnervation . HoweverIn many transplant centres, patients with heart transplants receive annual coronary angiography. However, due to the diffuse nature of CTV, angiography may underestimate the severity of disease or miss it completely . The patThe gold standard investigation of CTV is intravascular ultrasound (IVUS) which has the ability to assess the amount of intimal thickness and identify vessel wall morphology . A studyA number of non-invasive radiological modalities (e.g. dobutamine stress echocardiography (DSE), myocardial perfusion imaging (MPI) and multislice computed tomography (CT) coronary angiography) have also been utilized to assist in the diagnosis of CTV, with variable degrees of sensitivity and specificity . A pilotThe most effective treatment of CTV is prevention and modification of risk factors using antihypertensive agents , statins (e.g. pravastatin) and strict diabetic control. Coronary artery bypass grafting is rarely an option in CTV due to the diffuse nature of the disease process and the limited availability of donor hearts makes re-transplantation unlikely. In patients with heart transplants presenting with chest pain or features of congestive heart failure, if the ECG or echocardiogram show ischaemic changes or wall motion abnormalities, acute coronary syndrome should be suspected and patients should be treated accordingly with antiplatelet agents and PCI .A systematic review of six small, retrospective, nonrandomised studies comparing the use of bare-metal stents (BMS) with drug-eluting stents (DES) in the treatment of CTV (328 lesions treated with BMS and 287 lesions treated with DES) showed that DES were associated with a lower restenosis rate at 6\u201312 months, but in only half of the six studies were the differences statistically significant . There wA recent retrospective nonrandomised study involving 34 patients receiving a total of 46 stents (27 DES vs 19 BMS) is the first to suggest a clinical benefit with DES compared to BMS in the treatment of CTV . RandomiMaintenance immunosuppression following heart transplantation usually consists of a triple therapy of corticosteroids , a calcineurin inhibitor (CNI) (cyclosporine or tacrolimus) and an antiproliferative agent . AzathioTacrolimus and cyclosporine have failed to demonstrate prevention of CTV after heart transplantation and there appears to be little difference between these CNIs in terms of long-term development of CTV . HoweverIn terms of CTV prevention, the optimum maintenance immunosupression regime is unclear and a long-term randomised trial is required to determine this. The maintenance immunosupression regime following heart and lung transplantation for the patient in this case consisted of tacrolimus and prednisolone without the use of an antiproliferative agent. There was no change in the maintenance immunosupression regime post MI.MI must be considered in young patients with CF and a heart and lung transplant with atypical chest pain. Although complete reversal of LAD and RCA stenosis was achieved in this case with the use of PCI and DES, routine follow-up with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events.Written informed consent was obtained from the patient for publication of this case report and any accompanying images.BMS: Bare-metal stents; BSLT: Bilateral sequential lung transplantation; CF: Cystic fibrosis; CFRD: Cystic fibrosis related diabetes; CMV: Cytomegalovirus; CNI: Calcineurin inhibitor; CTV: Cardiac transplant vasculopathy; DES: Drug eluting stents; DSE: Dobutamine stress echocardiography; ECG: Electrocardiogram; ED: Emergency Department; CTPA: Computed tomography pulmonary angiogram; IVUS: Intravascular ultrasound; LAD: Left anterior descending artery; LCx: Left circumflex artery; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PE: Pulmonary embolus; RCA: Right coronary artery; MPI: Myocardial perfusion imaging; CT: Computed tomography.The authors declare that they have no competing interests.JE and DP were both involved in the management of the case. JE wrote the case report with assistance from DP. Both authors read and approved the final manuscript."}
{"text": "The patient with a history of bone pain and muscle weakness, was thought to have oncogenic osteomalacia as a result of biochemical investigations and directed to Nuclear Medicine Department for a whole-body bone scintigraphy and 111In-octreotide scintigraphy. There was no focal pathologic tracer uptake, but generalized marked increase in skeletal uptake on bone scintigraphy. Octreotide scintigraphy showed accumulation of octreotide in the region of the left lobe of the thyroid gland in the neck. Thereafter, parathyroid scintigraphy was performed with technetium-99m labeled metroxy-isobutyl-isonitryl (99mTc-MIB) and MIBI scan demonstrated radiotracer uptake at the same location with octreotide scintigraphy. The patient underwent left inferior parathyroidectomy and histopathology confirmed a parathyroid adenoma. Somatostatin receptor positive parathyroid adenoma may show octreotide uptake. Octreotide scintigraphy may be promising and indicate a possibility of using somatostatin analogues for the medical treatment of somatostatin receptor positiveConflict of interest:None declared. HowevA 48-year-old woman was presented to our department with history of bone pain, muscle weakness. Biochemical investigations showed hypophosphatemia ; increased alkaline phosphatase ; normocalcaemia supporting hypocalcaemic onkogenic osteomalacia.Whole body bone scintigraphy was performed after intravenous administration of 20 mCi (740 MBq) of methyleno-diphosphonate labeled with technetium-99m (Tc- 99m MDP). Bone scan showed metabolic bone disorder featured by the following characteristics: Prominent tracer uptake in the calvarium, mandible, spine, rib, and bilateral femora; intense uptake at the costochondral junctures and faint kidney visualization . BesidesParathyroid adenoma is part of a spectrum of parathyroid proliferative disorder that includes parathyroid hyperplasia, parathyroid adenoma and parathyroid carcinoma . Eighty Patients with primary hyperparathyroidism may present clinical evidence of elevated serum calcium levels which include non-specific symptoms such as fatigue, pain and weakness as well as polydipsia, polyuria, and nephrolithiasis . SonograSome studies also have suggested a role for somatostatin analogues in the medical treatment of hyperparathyroidism ,12,13. FIn conclusion, when a focal uptake was observed in the region of the thyroid gland on octreotide scintigraphy, the presence of parathyroid adenoma should also be considered. Parathyroid tumors expressing somatostatin receptors may show octreotide uptake and octreotide scan may be promising and indicate a possibility of using somatostatin analogues for medical treatment of somatostatin receptor positive parathyroid tumors in some situations which surgery is not possible and parathyroid tumor recurrence."}
{"text": "Dear Editor,Atrial fibrillation (AF) is one of the most frequent complications after cardiac surgery. It occurs in approximately 20% to 35% of patients after coronary artery bypass graft (CABG) surgery and in more than 50% of patients after valve surgery . AF afteAlthough many of potential risk factors for development of post-operative AF have previously been demonstrated in cardiac surgery patients ; the resRegarding the relatively high prevalence of opium abuse among patients undergoing cardiac surgery and considering its potential role in prediction of AF after cardiac surgery, anesthesiologists and cardiac surgeons should provide better preventive measures when planning surgery in opium addict patients. Since most of the studies performed in this field were retrospective, with inherent limitations, future prospective studies are needed to confirm this association."}
{"text": "In the traditional view on brain activity dynamics, the cognitive flow of information wanders through multiple stable states driven by task-dependent inputs -3. This It has been recently proposed that such transient states are basically shaped by anatomical connectivity and transitions between them occur even in the absence of external stimuli : Noise eA different metaphor of transient brain dynamics was proposed by Rabinovich and colleagues . In suchIn this work we develop an empirical criterion to discern whether observable neural ensemble activity can be originated by non-autonomous yet deterministic dynamical systems or rather by stochastic fluctuations between temporally attracting states. Towards this goal, we used in vivo multiple single-unit recording in rodent frontal cortex during a decision making task. Effective dynamics of neural activity is first empirically reconstructed in nonlinear state spaces . Then, tUnderlying dynamics of recorded ensemble activity is probably driven by a slowly drifting, non-autonomous dynamical system containing low-order nonlinear interactions."}
{"text": "Colorectal cancers are the third most common type of cancers globally, affecting both sexes . As of nNine normal and 25 tumoral colon tissue sections (3mm diameter x 10 \u00b5m thick) embedded in the form of paraffinized tissue microarray, stabilized in an agarose matrix were analyzed directly by IR imaging. To avoid chemical deparaffinization, a modified Extended Multiplicative Signal Correction (EMSC) method[EMSC permitted mathematical correction of the spectral interferences originating from paraffin and agarose. K-means classification allowed to identify and to distinguish important histological features of the colonic tissues such as crypts, lamina propria, tumor, etc. When compared to HPS stained images, after whole slide image analyzed with crop and score Calopix module from TRIBVN or through pathologist control, color-coded spectral images not only reveal features representative of the biochemical make up of the tissues, but also highlight additional features like intra-tumoral heterogeneity and tumor-associated stroma, which are difficult to discern by conventional histopathology. The LDA prediction model was promising since an average sensitivity of 91 % was achieved in the identification and prediction of tumoral tissues.IR imaging allowed differentiating and detecting normal and tumoral colon tissue features based on their intrinsic biochemical information. This chemical-free approach on paraffinized tissue biopsies combined with multivariate statistical image analysis opens a new avenue for numerical spectral histopathology and appears as a promising tool for colon cancer diagnosis. Further work to improve the model and to predict tumors in blind samples is ongoing."}
{"text": "The regulation of gene expression plays a pivotal role in complex phenotypes, and epigenetic mechanisms such as DNA methylation are essential to this process. The availability of next-generation sequencing technologies allows us to study epigenetic variation at an unprecedented level of resolution. Even so, our understanding of the underlying sources of epigenetic variability remains limited. Twin studies have played an essential role in estimating phenotypic heritability, and these now offer an opportunity to study epigenetic variation as a dynamic quantitative trait. High monozygotic twin discordance rates for common diseases suggest that unexplained environmental or epigenetic factors could be involved. Recent genome-wide epigenetic studies in disease-discordant monozygotic twins emphasize the power of this design to successfully identify epigenetic changes associated with complex traits. We describe how large-scale epigenetic studies of twins can improve our understanding of how genetic, environmental and stochastic factors impact upon epigenetics, and how such studies can provide a comprehensive understanding of how epigenetic variation affects complex traits. The term epigenetics was originally introduced to describe how interactions between genetics and environment can give rise to phenotypes during development de novo methylation and the maintenance of methylation patterns during replication Epigenetic mechanisms are present in many taxa, but DNA methylation has been most extensively studied in mammals where it appears to be restricted to the cytosine base, and especially in the context of CpG dinucleotides. CpG dinucleotides are cytosine\u2013phosphate\u2013guanine sequences that typically cluster in genomic regions referred to as CpG islands (CGI), which are often located in gene promoters and exhibit low levels of DNA methylation. However, DNA methylation in mammals can also occur outside the CpG context, and this has been reported for example in embryonic stem cells H19 locus control imprinting and gene expression at the maternally imprinted and transcriptionally-silenced insulin-like growth factor II (IGF2) locus and at the paternally imprinted and silenced H19 region de novo DNA methylation has also been suggested twins are traditionally regarded as genetically identical, therefore any phenotypic differences within MZ twin pairs are classically attributed to environmental factors. However, epigenetic variants can also associate with phenotypic differences, and the identification and interpretation of such associations is currently an important area of research. Epigenetic studies of disease-discordant MZ twins, who are completely matched for genetics, age, sex, cohort effects, maternal influences and common environment, and are closely matched for other environmental factors, should be considerably more powerful in detecting disease-related epigenetic differences than epigenetic studies of unrelated disease cases and controls with different life-histories. In the following sections we consider the value of twin studies in epigenetics and discuss recent findings highlighting the possibility that epigenetic variation can be transmitted through generations and impact upon common diseases.Heritability is the proportion of the phenotypic variance in the population that is attributed to genetic variation. Heritability estimates are traditionally obtained by comparing the extent of similarity between relatives in classical twin studies, twin-adoption studies, sib/half-sib studies, and transgenerational family studies. Each has weaknesses, but for most traits twin studies are generally regarded as the most reliable because they are unbiased by age effects and offer the ability to separate common environment from genetic effects post hoc in twins who differed most in lifestyle. However, the study was cross-sectional instead of longitudinal, potentially obscuring comparison of individual variability; furthermore, comparing epigenetic patterns in fast-growing children and adults might not be generalizable to the aging process. To this end, a recent longitudinal study of twin epigenetic heritability assayed DNA methylation patterns in the promoters of three genes in 46 MZ and 45 DZ twin pairs sampled at 5 and 10 years of age Several studies have examined DNA methylation patterns in twins. Early work focused on X-chromosome inactivation patterns in females \u2013 where one X chromosome is inactivated at random and the silent state of the inactive X-chromosome is maintained by DNA methylation IGF2) gene and the paternally imprinted H19 region, estimating high epigenetic heritability in those regions using multiple tissues from 182 newborn MZ and DZ twins Substantive evidence for epigenetic heritability has been obtained from further studies of age-matched twins using larger samples Overall, these findings confirm that DNA methylation is a heritable trait on a genome-wide basis, but also highlight the importance of taking age into account when studying epigenetic processes. Furthermore, the results are consistent with recent population-based findings of quantitative trait loci (QTL) for DNA methylation DNA methylation patterns can be affected by genetic variation, environmental changes, heritable and non-heritable changes in other epigenetic processes , and stochastic changes over time. All these factors can contribute to DNA methylation heritability estimates, which are therefore time-, tissue-, locus- and population-specific. There are three further important aspects of epigenetic heritability. First, does twin epigenetic heritability reflect stability in methylation transmission during mitosis and meiosis? Second, does epigenetic variation contribute to phenotype heritability? Finally, how do epigenetic heritability findings relate to time-dependent methylation changes?In mammals, maintenance DNA methyltransferases and histone methyltransferases ensure propagation of epigenetic marks through mitotic cell divisions with high fidelity in two discordant or concordant pairs of schizophrenic twins; this study found greater methylation differences between discordant MZ twins than in unrelated cases Recently, several epigenetic studies of MZ discordant twins have examined differences in DNA methylation profiles, aiming to identify differentially methylated regions (DMRs) in human disease The power of discordant MZ twin studies to detect DMRs will depend on a number of factors, including the effect size of the epigenetic change on the phenotype, the similarity of methylation profiles between MZ twins, sample size, and the sensitivity and coverage of the methylation assay. An estimate of the power of the discordant MZ twin design for a specific microarray methylation assay There are several aspects of epigenetic studies where twins present novel opportunities to understand the biology and the mechanisms underlying complex traits. We suggest a few examples.http://www.muther.ac.uk/), which aims to assay gene expression variation in multiple tissues in twins and to identify regulatory genetic variants, can be linked with epigenetic data to explore the tissue specificity and functional consequences of epigenetic variation in twins. This project is being extended to RNA sequencing (via the EUroBATS project), and this will also allow differential allelic expression to be explored. Allele-specific expression (ASE) patterns are relatively common and are under strict genetic control Twin resources such as the MuTHER (multiple tissue human expression resource) project affect epigenetics. ARTs include IVF and related technologies http://www.twinsuk.ac.uk/) aims to discover methylated genes responsible for discordance of ten common traits and diseases. The study is using MeDIP-seq on blood samples to assay epigenomic differences in 5000 adult UK twins aged 16\u201385, discordant and concordant for a wide variety of diseases and environments. Next-generation sequencing, although currently at significant cost, has the potential to prove powerful in detecting disease-related methylation differences at a high level of resolution in a sample of this size. Another ongoing large-scale prospective study consists of a cohort of Australian newborn twins http://www.euengage.org/), where MeCAP-seq is being performed by sample pooling across multiple traits in discordant twins.A recent large-scale study (EpiTwin \u2013 Two further areas that can benefit from the epigenetic differences observed in MZ twins are forensic science and medical transplantation. Although twins are no more likely to be criminals than the general population, one in 250 people are MZ twins and legal cases involving MZ twins are high-profile. For example, the genetic identity of MZ twins can allow twins to provide each other with alibis in criminal cases. Differences in epigenetic profiles between MZ twins, if consistently replicated, could in future lead to closing this loophole. In transplantation there are reports of occasional graft failures in identical twins. Studying subtle differences in twin epigenetic profiles could improve transplantation outcomes, where small epigenetic changes of immune-related genes in the host or in transplanted organs could affect transplant success The study of epigenetic profiles in twins offers an excellent opportunity to understand the causes and consequences of epigenetic variation. Twin epigenetic heritability estimates tell us about the genetic control of DNA methylation variability and the stability of methylation patterns during cell division. The contribution of epigenetic variants to complex phenotypes can be assessed using disease-discordant MZ twins who are otherwise matched for genetics, age, sex, cohort effects, maternal effects and a common environment. These twin designs are considerably more powerful discovery tools than studies on singletons. In the near future, large-scale epigenetic studies in twins across different ages, tissues, and diseases will improve our understanding of the etiology and mechanisms of a wide range of common complex traits and diseases."}
{"text": "Vaccination strategies capable of eliciting neutralizing antibody responses to HIV remain elusive despite extensive efforts. Alternative antibody functions offer opportunities for protection without necessarily achieving broad neutralization breadth. Viral immune exclusion through aggregation has been proposed as an alternative protection pathway, but mechanisms for studying this phenomenon at the scale necessary for clinical trials have not been explored.Concentrated fluorescent virions of two colors, suspended in hydroxyethylcellulose (HEC) gel, which has been formulated to simulate the diffusion characteristics of cervical mucus, are imaged over time. Mean squared displacement and incidence of colocalized viral particles are determined. The addition of monoclonal antibodies of various specificities and isotypes affects these parameters is explored. Immunoglobulin isolated from HIV-1 positive individuals was examined as well. Correlative scanning electron micrographs of the same preparations were performed to confirm the nature of suspected aggregates.Multimeric antibodies, rather than monomeric isoforms, selectively hinder the diffusion characteristics of colocalized virions, more so than non-aggregated virions. The incidence of colocalized virions is also increased in a concentration dependent manner. Excessive antibody or virus concentration is seen to obviate aggregate formation. These results are seen in both monoclonal antibody experiments alongside polyclonal patient IgA isolated from breast milk and IgM from serum.Virus aggregation has been demonstrated as a feasible effector function of HIV-1 specific antibody preparations. This assay platform is amenable to adaptation for medium to high throughput sample screening and low sample size. Monoclonal antibodies as well as patient samples are able to induce similar behaviors. Measurement of viral aggregation as a corollary of vaccine efficacy is deserving of further exploration in a clinical setting."}
{"text": "The resulting adducts were fully characterized by spectroscopic and analytical methods; they constitute interesting substrates for further organic transformations.The chemical behaviour of various alkyl-substituted, acyclic conjugated bisallenes in reactions involving polar intermediates and/or transition states has been investigated on a broad scale for the first time. The reactions studied include lithiation, reaction of the thus formed organolithium salts with various electrophiles , oxidation to cyclopentenones and epoxides, hydrohalogenation , halogenation (Br"}
{"text": "X-linked hypohidrotic ectodermal dyplasia (XLHED) is the most common form of ectodermal dysplasia. It often presents with ocular symptoms, already in early childhood. Multiple ophthalmological tests are available, but in early childhood only tests of lower invasiveness can be applied. We have evaluated tear film tests and ocular surface staining as screening methods in pediatric patients with signs of ectodermal dysplasia. These tests may also be used in adults with confirmed XLHED to determine the severity of ocular surface disease.Twelve children and 14 adults with XLHED were subjected to a panel of tests including the ocular surface disease index (OSDI), non-invasive measurement of tear film break-up time (NIBUT), osmolarity, Schirmer test, lissamine green staining, fluorescein staining, meibography and infrared thermography. Sensitivity and specificity were determined for single tests and selected test combinations. For adults with XLHED, OSDI, NIBUT and osmolarity were the best single routine tests . Their combination increased the sensitivity to 92.8%. Meibography yielded optimal results (100% sensitivity and specificity). Infrared thermography revealed a typical pattern for XLHED. In children with XLHED, NIBUT or OSDI were the most convincing single tests , combination of which increased the sensitivity to 100%. More invasive tests such as meibography and infrared thermography led to good results if they were tolerated.Tear film tests can help to establish an early diagnosis in individuals with suspected XLHED, even before genetic test results are available. Meibomian gland disorder and resulting hyperevaporative dry eye are typical features of XLHED. Once the diagnosis is made, tear film tests are an important instrument to establish an effective therapy of dry eye disease."}
{"text": "Spinal cord injury (SCI) causes chronic peripheral sensitization of nociceptors and persistent generation of spontaneous action potentials (SA) in peripheral branches and the somata of hyperexcitable nociceptors within dorsal root ganglia (DRG). Here it is proposed that SCI triggers in numerous nociceptors a persistent hyperfunctional state that originally evolved as an adaptive response to compensate for loss of sensory terminals after severe but survivable peripheral injury. In this hypothesis, nociceptor somata monitor the status of their own receptive field and the rest of the body by integrating signals received by their peripheral and central branches and the soma itself. A nociceptor switches into a potentially permanent hyperfunctional state when central neural, glial, and inflammatory signal combinations are detected that indicate extensive peripheral injury. Similar signal combinations are produced by SCI and disseminated widely to uninjured as well as injured nociceptors. This paper focuses on the uninjured nociceptors that are altered by SCI. Enhanced activity generated in below-level nociceptors promotes below-level central sensitization, somatic and autonomic hyperreflexia, and visceral dysfunction. If sufficient ascending fibers survive, enhanced activity in below-level nociceptors contributes to below-level pain. Nociceptor activity generated above the injury level contributes to at- and above-level sensitization and pain (evoked and spontaneous). Thus, SCI triggers a potent nociceptor state that may have been adaptive (from an evolutionary perspective) after severe peripheral injury but is maladaptive after SCI. Evidence that hyperfunctional nociceptors make large contributions to behavioral hypersensitivity after SCI suggests that nociceptor-specific ion channels required for nociceptor SA and hypersensitivity offer promising targets for treating chronic pain and hyperreflexia after SCI. My focus is on the many uninjured nociceptors that are chronically altered by SCI and positioned to help drive below-level and at-level pain.Neuropathic pain in general and spinal cord injury (SCI) pain in particular are usually viewed as maladaptive consequences of neural injury , sprout new branches within the dorsal horn after SCI, which potentially could lead to more extensive nociceptive input to dorsal horn neurons 3 days to 8 months after SCI compared to what has been reported (0\u201320%) for dissociated small DRG neurons sampled from rats with peripheral neuropathy under these quite different conditions can be triggered in nociceptors by a combination of events after SCI that mimic patterns of signals used by nociceptors to recognize particularly severe e Figure . I then Long-lasting changes in intrinsic functional properties of primary sensory neurons are likely to depend upon changes in gene expression in these neurons to the nociceptor's own branches. This includes immediate injury discharge and both positive injury signals , and negative injury signals transported from damaged axons to the nucleus , which are unlikely to have axons projecting close enough to the lesion to experience axotomy or other forms of direct damage are conveyed directly to cells within the DRG after peripheral injury/inflammation and after SCI Figure . Periphe2) that avoids apparent tissue inflammation produce behavioral hypersensitivity for at least 1 month afterwards, which is accompanied by Nav1.8 upregulation and is dependent upon Nav1.8 expression, suggesting a key role for intrinsically altered nociceptors continuing release of extrinsic signals, such as inflammatory mediators, that continuously refresh the hyperfunctional state, (2) positive feedback loops between nociceptor activity and inflammatory and retrograde synaptic effects, and (3) switching of the nociceptor into a potentially permanent intrinsic hyperfunctional state that remains after the extrinsic induction signals fade (\u201cnociceptor memory\u201d). First, widespread inflammation may persist chronically after SCI . Somata of nociceptors identified thus far in vertebrates, molluscs, and annelids are often located centrally, distant from their peripheral receptive fields, which ensures that these cells can survive sublethal injury that destroys their peripheral branches. In the mollusc, Why haven't chronic, somally expressed HSA states in nociceptors been reported previously in mammalian models of long-lasting pain? Few chronic studies have tested somal excitability in nociceptors, or recorded under conditions where nociceptor SA generated in the DRG could be distinguished from SA generated peripherally. Moreover, most studies of dissociated nociceptors have examined ionic currents under voltage clamp, without testing for somal hyperexcitability or SA. In addition, common models of long-lasting pain, including models based on cutaneous injection of inflammogens, surgical incision models (which produce relatively little inflammation or nerve damage), and various nerve injury models may not mimic adequately severe peripheral injuries that involve extensive amounts of tissue destruction combined with prolonged inflammation\u2014i.e., the traumatic conditions most likely to result in chronic pain in humans. Thus, while standard pain models produce many sensitizing effects on nociceptors and other hyperfunctional alterations in nociceptors contribute significantly to human at- and below level pain, as well as to hyperreflexia and visceral problems after SCI, pharmacological agents that selectively target nociceptor hyperexcitability should be clinically useful. A number of genes important for excitability are preferentially expressed in nociceptors, raising the possibility that blocking their function could ameliorate some of the suffering caused by SCI while producing minimal side effects. Indeed, preliminary results show that SA in dissociated nociceptors depends upon nociceptor-specific Nav1.8 channels, and indicate that knocking down the expression of these channels can attenuate behavioral hypersensitivity after SCI (Yang et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Daphnia magna) \u2013 bacterium (Pasteuria ramosa) system typifies such specificity and high virulence. We studied the North American host Daphnia dentifera and its natural parasite Pasteuria ramosa, and also found strong genetic specificity for infection success and high virulence. These results suggest that Pasteuria could promote Red Queen dynamics with D. dentifera populations as well. However, the Red Queen might be undermined in this system by selection from a more common yeast parasite (Metschnikowia bicuspidata). Resistance to the yeast did not correlate with resistance to Pasteuria among host genotypes, suggesting that selection by Metschnikowia should proceed relatively independently of selection by Pasteuria.The Red Queen hypothesis can explain the maintenance of host and parasite diversity. However, the Red Queen requires genetic specificity for infection risk and strongly virulent effects of infection on host fitness. A European crustacean ( R0 when all else is equal, Genetic specificity between hosts and their parasites shapes the ecology and evolution of infectious disease Daphnia magna and its sterilizing bacterial parasite Pasteuria ramosa exemplify genetic specificity Pasteuria \u2013 the physical attachment of spores to the host oesophageal wall Pasteuria inflicts high virulence on infected hosts through sterilization Pasteuria epidemics can become large D. magna-Pasteuria system The European freshwater crustacean Pasteuria could maintain genetic diversity in other susceptible host species. Therefore, Pasteuria could act as a general catalyst of Red Queen-driven coevolution in freshwater systems. To test this possibility, we looked for genetic specificity for infection with Pasteuria in a natural North American host, Daphnia dentifera, using an established experimental design Pasteuria castrates its European D. magna hosts: Pasteuria's specificity and virulence effects are general, the European Daphnia \u2013 Pasteuria story may apply more broadly.These results suggest that D. dentifera populations, epidemics of the yeast Metschnikowia bicuspidata are usually larger and more frequent than Pasteuria epidemics Metschnikowia does not, however, exhibit genetic specificity with D. dentiferaPasteuria may not necessarily resist Metschnikowia. Such parasite-specific resistance and five Pasteuria isolates all originated from Midland Lake, Greene County, Indiana, USA. The five Pasteuria isolates were taken from five different infected hosts in 2010 and were propagated by feeding homogenized, infected hosts to a single host genotype (H119). These isolates likely consist of a mix of Pasteuria clones and represent ecologically relevant sub-populations of Pasteuria . We used only this lab-based culture because Metschnikowia isolated from different lakes and in different years show no genetic variation in infectivity or virulence on D. dentiferaD. dentifera (which is not a protected or endangered species), but permission was obtained for access to lakes.The experiments used host and parasite cultures and previously established laboratory protocols. The six clonal genotypes of Pasteuria isolates, one Metschnikowia isolate, and a sham-exposure control), replicated 15 times, for a total of 630 experimental units. Four of the Pasteuria replicates were lost due to accidental death after treatment exposure. Maternal lines consisted of individual Daphnia kept under favourable conditions (20\u00b0C and 16\u22368 hour light/dark) in 40 mL of medium . Experimental animals consisted of second clutch offspring of third-generation maternal lines and were also kept in 40 mL of medium and fed ample food. In the parasite exposure treatments, each neonate (<24 hour old) received a high dose of spores produced by gently crushing and diluting infected hosts. These doses aimed to yield similar infection levels among parasite species (based on pilot data). Sham controls received 100 \u03bcL of a Daphnia solution (50 uninfected hosts ground in 10 ml nanopure water). Replicates were fed lower food during exposure to increase spore uptake by hosts 6Ankistrodesmus algal cells) again. Hosts were checked daily for reproduction and mortality for 25 days. Medium was refreshed every 2\u20133 days.The experimental design involved a factorial manipulation of these hosts and parasites. We crossed the six host genotypes with seven parasite treatments (five http://www.r-project.org). We analysed infection risk by testing the fixed effects of host genotype and parasite species using data from only parasite-exposed hosts (not sham-exposed hosts). We tested for genetic specificity of Pasteuria infection using the fixed effects of host genotype and parasite isolate. Both Generalized Linear Models (GLM) were estimated with a binomial error distribution, and significance of each treatment was evaluated with deviance tests . However, in previous Daphnia-parasite studies, genotype is fitted as a fixed effect, a random effect or both (e.g. Metschnikowia and Pasteuria (averaged over the five isolates) for each host genotype using a Spearman rank correlation.All analyses were performed using the statistical package R . Fecundity was analysed by testing the fixed effects of infection status (infected or not), host genotype, and parasite species. Both host survival and r were analysed by testing the fixed effects of host infection status (infected or not) and parasite species. All of these tests used data from parasite-exposed hosts only; for r, the means of data from each infection category and parasite species for each host genotype were used.We examined the fitness consequences of infection by the two parasites using three metrics: production of host offspring (fecundity), host survival, and the instantaneous rate of host population growth, Metschnikowia's capacity to disrupt Red Queen dynamics between D. dentifera and Pasteuria should be reduced if the host pays an activation cost of resistance to Metschnikowia We looked for evidence of an activation cost of resistance to Metschnikowia by comparing host fecundity, survival, and r in controls (sham-exposures) with hosts that were exposed to parasites but did not suffer infection .Fecundity across treatments was examined using a GLM fit with a quasipoisson error distribution (used due to over-dispersion of the fecundity data), and survival analyses used Cox's proportional hazards. Measures of Pasteuria) and between parasite species. Infection risk from Pasteuria depended on the specific combination of host and parasite genotypes . As expected based on prior studies, host genotype strongly influenced infection risk from Metschnikowia . There was, however, no correlation between a genotype's risk of infection by Metschnikowia and its overall risk of infection by Pasteuria depended on both infection status and parasite species: infection with either parasite reduced r, but Pasteuria infections reduced r more than Metschnikowia infections. Thus, Pasteuria was more virulent . Thus, there was no evidence for a fitness cost of mobilising resistance mechanisms against Metschnikowia to a lesser extent than Pasteuria should reduce host population densities, even during small epidemics Due to differences in specificity and virulence, these two parasites may exert different ecological impacts on host populations. Theory suggests that specificity can reduce invasion success of parasites; i.e., they will have a lower reproductive ratio Pasteuria and Metschnikowia could either amplify or dampen Red Queen oscillations. A negative correlation would indicate antagonistic pleiotropy, where resistance to Pasteuria would come at a cost to resistance to MetschnikowiaMetschnikowia and Pasteuria suggests evolution of D. dentifera in response to the two parasites should proceed relatively independently. Thus, we do not expect Metschnikowia epidemics to amplify or dampen Red Queen dynamics between D. dentifera and Pasteuria.Correlations between host resistance to Pasteuria could promote genetic diversity in multiple host species through host-parasite coevolution. Pasteuria exhibits strong genetic specificity and high virulence with its North American host, D. dentifera, just as it does with its European host, D. magna. Can Pasteuria then promote host diversity in North American lakes? We cannot yet fully answer that question with these or other data, but the D. dentifera-Pasteuria system in isolation certainly contains several of the essential ingredients of the Red Queen. Still, it seems likely that the larger epidemics of the more common Metschnikowia yeast may mean that parasite-mediated selection in D. dentifera is driven primarily by Metschnikowia, making Red Queen dynamics relatively rare. This possibility further highlights the need to consider other co-occurring parasites when exploring host-parasite coevolution.In conclusion,"}
{"text": "Cardiogenic shock is very uncommon in healthy people. The differential diagnosis for patients with acute heart failure in previously healthy hearts includes acute myocardial infarction and myocarditis. However, many drugs can also depress myocardial function. Propofol and fentanyl are frequently used during different medical procedures. The cardiovascular depressive effect of both drugs has been well established, but the development of cardiogenic shock is very rare when these agents are used.After a minor surgical intervention, a 32-year-old Caucasian woman with no significant medical history went into sudden hemodynamic deterioration due to acute heart failure. An urgent echocardiogram showed severe biventricular dysfunction and an estimated left ventricular ejection fraction of 20%. Extracorporeal life support and mechanical ventilation were required. Five days later her ventricular function had fully recovered, which allowed the progressive withdrawal of medical treatment. Prior to her hospital discharge, cardiac MRI showed neither edema nor pathological deposits on the delayed contrast enhancement sequences. At her six-month follow-up examination, the patient was asymptomatic and did not require treatment.Although there are many causes of cardiogenic shock, the presence of abrupt hemodynamic deterioration and the absence of a clear cause could be related to the use of propofol and fentanyl. Cardiogenic shock is the most serious form of presentation of heart failure (HF). The anticipation of hemodynamic deterioration and multiple organ failure in these patients is very important in terms of survival. The outcome for patients with refractory acute cardiogenic shock remains disproportionately poor. Technological advances in recent years have enabled the development of new treatments, such as extracorporeal life support (ELS). ELS is a variation of cardiopulmonary bypass which could improve the outcomes of patients in cardiogenic shock . AlthougWe report the case of a 32-year-old Caucasian woman who experienced sudden, severe hemodynamic deterioration after undergoing a minor surgical procedure. Her medical history was unremarkable except for a vaginal delivery two years before. She underwent surgery to remove a Bartholin cyst, and no infection in the gland was found. The operation was performed while the patient was under sedation and being given an analgesic. Spontaneous breathing was maintained by infusing a propofol bolus 1 mg/kg) and fentanyl 100 \u03bcg intravenously. During surgery, the patient remained hemodynamically stable. She has nausea and vomiting in the early post-operative period, which were treated with intravenous ondansetron 4 mg). A few minutes later the patient went into sudden hemodynamic deterioration, with sinus tachycardia (113 regular beats/minute) and hypotension (50/30 mmHg). Pulse oximetry showed that her oxygen saturation level had decreased to 80% despite oxygen supplementation through a face mask (fraction of inspired oxygen 40%). In this clinical situation, we treated her with intravenous dopamine and dobutamine, as well as with mechanical ventilation because of global respiratory failure . The electrocardiogram showed sinus tachycardia. Signs of HF were found on her chest X-ray, and urgent transthoracic echocardiography (TTE) revealed severe biventricular dysfunction with global hypokinesia and a LVEF estimated to be 35%. Coronary angiography showed no coronary lesions, and an intra-aortic balloon pump was inserted for counterpulsation. Repeat TTE revealed a LVEF of 20% with a dilated left ventricle showing severe left ventricular dysfunction during the acute phase.Click here for fileShort-axis view showing severe left ventricular dysfunction. Transthoracic echocardiography showing severe left ventricular dysfunction during the acute phase.Click here for fileApical four-chamber view after total recovery of left ventricular function. Transthoracic echocardiography showing total recovery of left ventricular function before discharge.Click here for fileShort-axis view after total recovery of left ventricular function. Transthoracic echocardiography showing total recovery of left ventricular function before discharge.Click here for file"}
{"text": "Cellular and molecular regulation of the immune system is exquisitely controlled in the brain and is disrupted in neoplasia. Despite accumulation of immune cells in the tumor microenvironment, glioblastoma (GBM) growth persists while the mechanisms suppressing immune function remain largely unknown. Myeloid derived suppressor cells (MDSCs) are a heterogeneous class of immune cells responsible for immunomodulation through the suppression of cytotoxic T-cells. These populations are elevated in the peripheral blood of GBM patients, but their roles within the GBM microenvironment are uncharacterized. Through immunofluorescence analysis, we identified MDSCs within human GBM specimens, suggesting an immunosuppressive phenotype marked by arginase 1 (Arg1) staining. We have also observed co-localization between MDSCs and GBM cancer stem cells (CSCs) in both human tissues and mouse xenografts, leading to the hypothesis that CSCs recruit MDSCs to the tumor microenvironment, promote their survival, and that MDSCs are responsible for the immune-evasive properties of CSCs Fig. . Intracr"}
{"text": "Hypertrophic cardiomyopathy (HCM) is most common in patients under 40 years and is associated with early sudden death, but HCM is increasingly recognized in elderly patients. We sought to characterize and identify features unique to elderly HCM patients when compared with youthful patients using CMR.Cine CMR and late gadolinium enhancement (LGE) imaging were performed in 902 HCM patients, including 202 young , and 143 elderly patients .Elderly HCM patients had a lower proportion of males . They had significantly lower left ventricular (LV) mass and lower maximal LV wall thickness . The most common maximal thickness segment in the elderly patients was in the basal anterior septum . Elderly patients were also more likely to have the thickest segment located within the septum . Elderly patients were far less likely to have massive hypertrophy .Elderly HCM patients had a smaller LV cavity size, with lower LV end-diastolic volume and smaller LV end-diastolic dimension . The elderly patients had similar LV ejection fraction (LVEF) and similar rates of depressed (<60%) LVEF .The prevalence of LGE (a marker of fibrosis) was similar in both groups . When present, both LGE mass and percentage of LV with LGE were similar.Substantial amounts of late gadolinium enhancement are compatible with normal longevity in many patients with hypertrophic cardiomyopathy. Presence of LGE may thus have different prognostic significance across the vast spectrum of HCM. This has potential implications for using LGE as a risk stratification tool for sudden death in HCM.Nil."}
{"text": "Successful scientific investigations at CAM institutions are often hampered by limited research infrastructure. Enhancing the clinical trial capabilities of our chiropractic research center was one goal of 2 NIH/NCCAM developmental center grants.Web applications were enhanced and customized based on individual project needs and trial team requests. Templates were built to support quick development and standard functionality of project web applications. We also developed standardized processes to effectively provide project-specific participant management, data collection, staff training, and quality control.Web applications included: the Centralized Participant Database System and Project/Users Permissions System to securely capture participant contact information and control personnel access to web modules; a real-time participant tracking report to monitor recruitment and participant flow; a role-specific Reminder System to track outstanding activities requiring personnel follow-up; and double key-entry verification on web data used for an adaptive treatment allocation algorithm. Templates of these tools can be incorporated into any new trial\u2019s web application. Study protocol templates facilitate timely, accurate translation of research proposals into detailed protocols for IRB applications, DSMC review and training. A revised training plan included role-specific training logs for tracking training objective completion and a thorough certification process for key protocols to ensure accurate and consistent performance. Quality control templates support the informed consent process and fidelity of trial interventions and outcomes assessment. We implemented these enhanced resources in 5 clinical trials. To date, our team has completed 3378 phone screens, conducted 1439 first and 473 second in-person screening visits, enrolled 394 participants, and followed 315 through trial end. The study protocol templates have been used in two additional clinical trials currently undergoing IRB review.We expanded our capacity to support multiple, diverse trials with complex methodologies. This is a successful example of a CAM institution successfully leveraging research grant funding to enhance research infrastructure."}
{"text": "Synapses in neuron networks filter incoming spikes with a wide variety of time constants, affecting the stability of various collective dynamics , the selHere, we addressed this issue working out a unified framework in which from small to large synaptic time scales the same approximated theoretical description holds for the firing rate dynamics of spiking neuron networks. Starting from single-neuron stochastic dynamics, we derived a set of ordinary differential equations for the population emission rate relying on the spectral expansion of the associated Fokker-Planck equation, eventually extending to the colored noise case a previous derivation obtained under white noise hypothesis . The resMoreover, such perturbative approach allowed to avoid the analytical difficulties of dealing with multi-dimensional Fokker-Planck equations with discontinuous boundary conditions. A simplification which helped in highlighting as main result that networks of neurons with non-instantaneous synapses can, under fairly broad assumptions, be described by equivalent networks with suitable distributions of transmission delays. A formal analogy valid from simple VIF models to more realistic point-like simplifications like LIF or EIF neurons."}
{"text": "Late gadolinium enhancement (LGE) is excellent for identifying focal lesions in the myocardium , but diffuse homogeneous abnormalities are not readily detectable. Quantitative measurement of the myocardial extracellular volume (ECV) fraction using MRI has recently been validated histologically, and implemented for parametric imaging in patients. We hypothesized that quantification of ECV using ECV imaging could detect focal lesions detected by LGE, and diffuse homogenous disturbances in the myocardial extracellular volume fraction which are not detectable by LGE. The objective of the study was to examine the diagnostic utility of ECV MRI for detecting myocardial tissue abnormalities compared to LGE.Consecutive patients referred for clinical cardiac MRI evaluation of known or suspected heart disease were prospectively enrolled . MRI was undertaken at 1.5T using a Modified Look-Locker Inversion recovery (MOLLI) sequence before and 15 minutes after an intravenous bolus of a gadolinium-based extracellular contrast agent . Maps of the extracellular volume fraction (ECV images) were generated using MOLLI-derived T1-mapping before and after contrast, calibrated to hematocrit from a venous blood sample. Motion correction and co-registration was performed offline using an automated dedicated algorithm. ECV images were interpreted quantitatively and the results were compared to clinical assessment of LGE images. Increased myocardial ECV was determined by quantitative comparison to established normal values where the 95% confidence limits are 20-32%.Out of 32 patients, 10 had focal lesions . All lesions identified by increased ECV were also identified by blinded clinical read of LGE images (100% agreement). Among patients with normal LGE findings (n=22), two patients (9%) had diffusely increased myocardial ECV . The figure shows examples of LGE and ECV images in a normal finding, a focal lesion and a case with diffusely increased ECV.Our initial findings suggest that ECV and LGE imaging have excellent diagnostic agreement for identifying focal myocardial findings such as those seen in myocardial infarction and non-ischemic heart disease. The ability of ECV imaging to quantify and detect diffuse abnormalities in myocardial ECV increased the number of diagnostic findings compared to LGE in 9% of cases with otherwise normal LGE. Further studies in larger populations are warranted to explore the diagnostic and prognostic benefits of ECV imaging in assessment of diffuse pathologies of the myocardial extracellular space.The study has been funded in part by a grant (PI: Dr. Ugander) from the Swedish Society for Medical Research."}
{"text": "Central statistical monitoring (CSM) can identify trial misconduct, and help to prioritise on-site visits and additional training. Key risk indicators (KRIs) focus CSM on variables most likely to affect study reliability or patient safety. We developed the use of robust minimum covariance determinant (MCD) distances to detect outlying centres in the context of KRI analyses.Initially, a summary statistic (e.g. mean) describing the KRI is calculated for each centre and robust MCD-based distances are calculated by the FAST-MCD algorithm . For each KRI, robust estimates of the multivariate location Robust MCD distances offer a flexible approach for analysing both univariate and multivariate KRIs and can be implemented in standard statistical software."}
{"text": "Major trauma is the leading causing of death in young adults across the globe. Themortality from traumatic cardiac arrest remains high but survival with good neurologicaloutcome from cardiopulmonary arrest following major trauma has now been reported. Rapid,effective intervention is required to address potential reversible causes of traumaticcardiac arrest if the victim is to survive. There is no standard treatment algorithm fortraumatic cardiac arrest. We present a simple algorithm to manage the major traumapatient in actual or near cardiac arrest.We reviewed current pre-hospital clinical practice and the published literature on majortrauma management. An algorithm was developed and used regularly by London\u2019s AirAmbulance pre-hospital physician/paramedic trauma team.The algorithm addresses the need treat potential reversible causes of traumatic cardiacarrest. This includes immediate resuscitative thoracotomy in cases of penetrating chestor abdominal trauma resulting in cardiac arrest, airway management, optimisingoxygenation, reversal of hypovolaemia using intravenous/intraosseous fluid replacementand chest decompression to exclude tension pneumothorax.A standard approach to traumatic cardiac arrest is feasible. Use of a treatmentalgorithm can rapidly, simultaneously address reversible causes of traumatic cardiacarrest and has the potential to save lives."}
{"text": "MDLcompress. We apply this tool to explore the relationship between miRNAs, single nucleotide polymorphisms (SNPs), and breast cancer. Our new algorithm outperforms other grammar-based coding methods, such as DNA Sequitur, while retaining a two-part code that highlights biologically significant phrases. The deep recursion of MDLcompress, together with its explicit two-part coding, enables it to identify biologically meaningful sequence without needlessly restrictive priors. The ability to quantify cost in bits for phrases in the MDL model allows prediction of regions where SNPs may have the most impact on biological activity. MDLcompress improves on our previous algorithm in execution time through an innovative data structure, and in specificity of motif detection (compression) through improved heuristics. An MDLcompress analysis of 144 over expressed genes from the breast cancer cell line BT474 has identified novel motifs, including potential microRNA (miRNA) binding sites that are candidates for experimental validation.We describe initial results of miRNA sequence analysis with the optimal symbol compression ratio (OSCR) algorithm and recast this grammar inference algorithm as an improved minimum description length (MDL) learning tool:"}
{"text": "Optical coherence tomography (OCT) has enhanced our understanding of changes in different ocular layers when axial myopia progresses and the globe is stretched. These findings consist of dehiscence of retinal layers known as retinoschisis, paravascular inner retinal cleavage, cysts and lamellar holes, peripapillary intrachoroidal cavitation, tractional internal limiting membrane detachment, macular holes (lamellar and full thickness), posterior retinal detachment, and choroidal neovascular membranes. In this review, recent observations regarding retinal changes in highly myopic eyes explored by OCT are described to highlight structural findings that cannot be diagnosed by simple ophthalmoscopy. Pathologic or high myopia is defined as a refractive error of \u22126.00 diopters (D) or greater and an axial length exceeding 26 mm.2Optical coherence tomography (OCT) has recently made it possible to explore changes in ocular layers as axial myopia progresses and the globe is stretched. These findings consist of dehiscence of retinal layers known as retinoschisis, paravascular inner retinal cysts and lamellar holes, peripapillary intrachoroidal cavitation , tractional internal limiting membrane detachment, macular holes (lamellar and full thickness), posterior retinal detachment and choroidal neovascular membranes.In this review, we describe retinal changes in highly myopic eyes according to findings observed by OCT.The early stages of myopic retinal changes can easily be underestimated by biomicroscopy, angiography or ultrasonography, and therefore remain undiagnosed. Recently, OCT with its fine cross-sectional imagery of retinal structures has greatly facilitated the evaluation of posterior vitreoretinal anatomy in eyes with high myopia. It can also reveal otherwise undetectable retinal changes in asymptomatic patients. The OCT ophthalmoscope produces longitudinal retinal B-scans and coronal C-scans.B-scan produces cross-sectional images of retinal morphology which bears strong resemblance to histology. OCT C-scans are represented as 2-dimensional transverse slices at any given depth through the retina, thereby enabling visualization of the lateral extent of different structures. OCT C-scans are associated pixel-to-pixel points with simultaneously confocal images used to identify the exact position of lesions on the posterior pole. With en face OCT, localization and relation of retinal lesions can be precisely defined, especially in myopic eyes. En face OCT provides accurate imaging of retinal abnormalities in high myopia and allows width measurement and point-to-point localization of changes.Myopic posterior staphyloma, with its outward globe bulge, results in a deep concave B-scan OCT and distorted retinal structures. Because of the smaller base curvature of the horizontal section and larger base curvature of vertical section, macular structures can be defined more easily by vertical sections . Remarkably, the incidence of internal limiting membrane (ILM) detachment and macular retinoschisis was significantly higher in eyes with paravascular lamellar holes than those with other paravascular abnormalities. Paravascular lamellar holes were associated with ILM detachment in 44% and with macular retinoschisis in 20% of eyes. More than 80% of eyes with macular retinoschisis had paravascular lamellar holes.Tractional ILM detachment was reported in 2.4%\u20136% of highly myopic persons.In a study by Bando et alThe prevalence of myopic foveoschisis (MFS) ranges from 9% to 34% in highly myopic eyes with posterior staphylomas.23MFS tends to occur in eyes with severe myopic retinopathy.25Half of patients with MFS have been reported to develop retinal detachment or macular holes within two or more years of follow-up.26Choroidal neovascular membrane (CNV) is considered to be the most important sight-threatening complication of high myopia. Myopic CNV has been classified into active, scar and atrophic stages.In the scar stage, only the surface of the neovascular tuft shows high reflectivity and the tissue underneath is markedly attenuated. Overlying retinal layers are not disarranged or disorganized, cystic changes are also absent.In the atrophic stage, the CNV becomes flat and chorioretinal atrophy around the regressed CNV is highly reflective.29Macular holes always exist at the edge of a pigmented lesion suggestive of an old CNV. Therefore periodic OCT examinations for evaluation of macular holes or macular retinoschisis, even in patients in atrophic stages, are recommended. The retina in the area of chorioretinal atrophy around the CNV is very thin regardless of coexisting macular retinoschisis, but the retina at the edge of CNV in myopic eyes with large chorioretinal atrophy (larger than 1 disc diameter) has been reported to be significantly thinner in eyes with chorioretinal atrophy smaller than 1 disc diameter around the CNV.28Posterior retinal detachment is another consequence of ocular expansion and posterior staphyloma in high myopic eyes. Full thickness macular hole and tractional maculopathy may accompany this finding and may be its contributor .Macular hole formation in myopic eyes has multiple etiologies. Expansion of the globe, tractional components and growth of neovascular membranes through clefts in the posterior pole may create partial thickness and/ or full-thickness macular holes. In asymptomatic myopic persons, macular holes were detected in 6.26% of cases.Pathologic myopia is accompanied by thinning and stretching of the globe. With increasing age and myopia, these changes further progress.Individuals with high myopia are subject to various retinal pathologies including posterior pole and peripapillary lesions. Because of extreme retinal thinning and chorioretinal changes in these persons, simple fundus examination may miss subtle retinal pathologies. OCT is an accurate tool which can localize such anatomical changes. It seems to be the paraclinical test of choice for highly myopic eyes."}
{"text": "Cancer cells have altered metabolism, with an increased rate of glucose uptake, increased glycolysis, and due to the Warburg phenomenon, increased production of biomass (amino acids and nucleic acids) as metabolic byproducts. Association of these metabolic changes with breast cancer subtype and tumor gene expression has not been evaluated, nor is it well understood what biological processes and characteristics are most important in driving altered metabolic state in breast cancer.Thirty-four breast tumors and six samples of cancer-adjacent normal tissue were analyzed by liquid and gas chromatography (LC/GC) mass spectrometry (MS) to determine the expression of 379 metabolites. The same tissues were also used to perform gene expression microarrays and the resulting gene expression profiles were used to identify tumor subtype. These data combined with clinical tumor characteristics were evaluated in association with metabolic phenotype. To complement these analyses of human tissues, in vitro assays using human breast cancer cells alone and in coculture with cancer-associated fibroblasts (CAFs) were performed to study glucose uptake and utilization.Unsupervised cluster analysis on all metabolites resulted in two main clusters, with differences in the prevalence of aggressive tumor subtypes in each cluster. Characteristic of the Warburg phenomenon, four groups of metabolites showed differential levels between the two tumor clusters: amino acids, sugars, nucleic acids, and citric acid (TCA) cycle metabolites. Normal breast tissue samples were similar to less aggressive tumors with low biomass production and decreased levels of glycolysis/TCA byproducts. Parallel to these results in human tissues, glucose uptake was increased in basal-like breast cancer cells when they were cocultured with fibroblasts, but less aggressive luminal-fibroblast cultures did not show increased glucose uptake. Rather, in luminal cocultures, the fibroblasts appeared to suppress glucose uptake. Glucose utilization (oxidation and glycogen synthesis) was also higher in basal-like mono- and cocultures compared to luminal cultures. Consistent with these findings that the stroma influences metabolic phenotype, tumors that had active wound response gene expression had the more aggressive, Warburg-like metabolic profile.We observed distinct metabolic profiles associated with more aggressive breast cancer tumors. Based both on the observed patterns of glucose uptake and utilization in cocultures, and on the association between wound response activation and metabolic profile, these metabolic signatures appear to be influenced by multiple factors, including the stroma. These data suggest that integration of genomic and metabolic data provide insights for better understanding a Warburg effect in human breast cancer that may be regulated by the stroma."}
{"text": "Visual hallucinations (VH) represent one of the core features in discriminating dementia with Lewy bodies (DLB) from Alzheimer\u2019s Disease (AD). Previous studies reported that in DLB patients functional alterations of the parieto-occipital regions were correlated with the presence of VH. The aim of our study was to assess whether morphological changes in specific cortical regions of DLB could be related to the presence and severity of VH. We performed a cortical thickness analysis on magnetic resonance imaging data in a cohort including 18 DLB patients, 15 AD patients and 14 healthy control subjects. Relatively to DLB group, correlation analysis between the cortical thickness and the Neuropsychiatric Inventory (NPI) hallucination item scores was also performed. Cortical thickness was reduced bilaterally in DLB compared to controls in the pericalcarine and lingual gyri, cuneus, precuneus, superior parietal gyrus. Cortical thinning was found bilaterally in AD compared to controls in temporal cortex including the superior and middle temporal gyrus, part of inferior temporal cortex, temporal pole and insula. Inferior parietal and supramarginal gyri were also affected bilaterally in AD as compared to controls. The comparison between DLB and AD evidenced cortical thinning in DLB group in the right posterior regions including superior parietal gyrus, precuneus, cuneus, pericalcarine and lingual gyri. Furthermore, the correlation analysis between cortical thickness and NPI hallucination item scores showed that the structural alteration in the dorsal visual regions including superior parietal gyrus and precuneus closely correlated with the occurrence and severity of VH. We suggest that structural changes in key regions of the dorsal visual network may play a crucial role in the physiopathology of VH in DLB patients. Dementia with Lewy bodies (DLB) is the second most common form of dementia in the elderly after Alzheimer\u2019s Disease (AD). Despite the precise nosological relationship between DLB and AD remains uncertain, persistent visual hallucinations (VH) along with fluctuations in cognitive function and parkinsonism represent the core feature in discriminating DLB from AD and other dementias The physiopathology underlying VH in DLB is not well understood. Causative models for complex VH have suggested that the origin of this deficit may be related to a range of pathological alterations affecting both the dorsal visual stream, specialized for visuo-spatial attention and location, and the ventral visual stream, designated to object recognition In this context, structural Magnetic Resonance Imaging (MRI) could be a powerful tool to investigate the aetiology of core symptoms in DLB. To date, several studies by using voxel-based morphometry (VBM) found widespread cortical sites of grey matter atrophy in DLB patients compared to healthy controls Cortical thickness approach allows to perform cortical parcellation and to measure with great reliability the pathological thinning of the cortical grey matter. By measuring a real physical quantity that is much easier to interpret and to localize in comparison to the three-dimensional VBM, cortical thickness methods provide a better localization of structural changes because the smoothing procedure is performed on a two-dimensional manifold which reduces morphological artefacts due to ageing and pathological processes Despite the potential advantage of cortical thickness analysis, to date this approach has not been applied to DLB patients.In the present study, we performed cortical thickness analysis to verify the presence of cortical grey matter damage related to VH in DLB patients. To this aim, firstly, we compared DLB patients respect to healthy controls. Subsequently, we included a comparison against AD groups to exclude possible pathologic alterations arising as a result of a dementia process per se and not specific to DLB pathology. Finally, relatively to DLB group, we performed a correlation analysis between the cortical thickness and the Neuropsychiatric Inventory (NPI) hallucination item scores to highlight the cortical regions which were effectively related to the occurrence and severity of VH.The study was approved by the Institutional and Ethics Committee of the University \u201cG. d\u2019Annunzio\u201d Chieti-Pescara (ID#157801). All procedures were conducted according to the Declaration of Helsinki and subsequent revisions All patients underwent MRI scan within six months before the inclusion in the study and dopaminergic presynaptic ligand ioflupane SPECT (DAT scan).Global tests of cognition included Clinical Dementia Rating (CDR), Mini Mental State Examination (MMSE), Dementia Rating scale-2 (DRS-2) Exclusion criteria were uncontrolled hypertension, myocardial ischemia, peripheral vascular disease and chronic kidney.1-Weighted Turbo Field-Echo sequence was carried out. Participants with images characterized by motion artefacts were excluded from the analysis.All acquisitions were carried out with a Philips Achieva 3 T scanner equipped with 8-channel receiver coil. After scout and reference sequences, a 3-dimensional T1-weighted image was estimated at each vertex across the brain surface using Freesurfer software package (http://surfer.nmr.mgh.harvard.edu). This method has been previously described in detail by Fischl and Dale Cortical thickness on TCortical brain regions affected by cortical thinning were classified by using the Desikan-Killiany Atlas integrated in FreeSurfer.SPSS version 14.0 was used for statistical analysis. Analysis of variance (ANOVA) among groups and Tukey\u2019s HSD post-hoc test was performed on demographic and clinical data. Chi-squared test was carried out for gender.For each hemisphere, comparison among groups was performed by using general linear model (GLM), including cortical thickness as dependent factor and group as independent factor. MMSE, CAF and UPDRS scores were included as covariates.https://surfer.nmr.mgh.harvard.edu/fswiki/FsgdFormat).FreeSurfer processing stream was used to assess the pairwise differences among groups was used to individuate statistically significant regions where NPI hallucination item scores and thickness were correlated. MMSE, CAF, UPDRS scores were included as nuisance factors.In DLB group, QDEC . Next, SPSS version 14.0 was used for statistical computation and MMSE, CAF and UPDRS scores were included as nuisance factors.To perform partial correlations between NPI hallucination item scores and mean cortical thickness values in the posterior regions which were affected significantly in DLB in comparison with AD, the mean cortical thickness values were extracted from each region of interest (defined by Desikan-Killiany Atlas) by using \u201caparcstats2table\u201d command line, in cortical thickness between DLB and age-matched healthy controls. Cortical thickness was reduced in the posterior regions of DLB. Specifically, pericalcarine, lingual gyri, cuneus precuneus and superior parietal gyrus were affected bilaterally. panel B shows regional differences (corrected p<0.05) in cortical thickness between DLB and AD. Cortical thickness was reduced in DLB compared to AD in the right posterior regions including superior parietal gyrus, precuneus, cuneus, pericalcarine and lingual gyri.With the present MRI study, we have evidenced that DLB patients are characterized by marked cortical thinning in posterior regions when compared with AD and age-matched healthy controls.Posterior cortical regions play a critical role in the visual information processing, and their damage was related to recurrent VH in DLB patients Consistently with neuroimaging Although previous studies reported abnormalities related to VH in DLB or Parkinson\u2019s Disease (PD) patients compared to control groups Additionally, despite both the dorsal and ventral attention networks were affected in DLB as compared to controls and AD, the correlation analysis between cortical thickness and NPI hallucination item scores, suggested a greater involvement of the dorsal attention regions including superior parietal gyrus and precuneus in the occurrence and severity of VH in DLB.The superior parietal region is implicated in visuo-spatial working memory Precuneus acts in concert with the parietal regions, elaborating information about motor imagery and more abstract mental imagery tasks Despite impairment of dorsal stream is well defined in DLB patients, the ventral stream resulted to be affected in both AD and DLB as compared to controls. However a different distribution of grey matter loss along the ventral pathway was found in DLB and AD. Specifically, cortical thinning in lingual and pericalcarine giri was observed in DLB, whereas a marked and diffuse cortical thinning was found in the mesial temporal cortex in AD. This latter structural alteration could be linked to greater memory impairment affecting AD patients and it is in accordance with previous morphometric studies According to previous reports from our group Different models have suggested a central role of posterior regions in manifestation of VH"}
{"text": "Client-owned pet dogs represent exceptional translational models for advancement of Cancer Research, as they reflects the complex heterogeneity observed in human cancer. We have recently shown that a genetic vaccine targeting dog telomerase (dTERT) and based on Ad/DNA-EGT technology can induce strong cell-mediated immune responses against this tumor antigen and increase overall survival of dogs affected by B-cell lymphosarcoma (LSA) in comparison with historical controls when combined with COP chemotherapy regimen. Here, we have conducted a double arm clinical trial with an extended number of LSA patients, measured the antigen-specific immune response and evaluated potential toxic effects of the immunotherapy along with a follow up of patients survival for three years and half. The immune response was measured by ELISPOT. The expression of dTERT was quantified by quantitative PCR. Changes in hematological parameters, local/systemic toxicity or organic dysfunction and fever were monitored over time during the treatment. dTERT-specific cell mediated immune responses were induced in almost all treated animals. No adverse effects were observed in any dog patient that underwent treatment. The overall survival time of vaccine/COP treated dogs was significantly increased over the COP-only treated cohort . There was a significant association between dTERT expression levels in LSA cells and overall survival (OS) among vaccinated patients. In conclusion, Ad/DNA-EGT-based cancer vaccine against dTERT in combination with COP chemotherapy is safe and significantly prolongs the survival of LSA canine patients. These data confirm the therapeutic efficacy of dTERT vaccine and support the evaluation of this approach for other cancer types as well as the translation of this approach to human clinical trials."}
{"text": "Optimizing productivity and growth of recombinant Chinese hamster ovary (CHO) cells requires insight and intervention in regulatory processes. This is to some extent accomplished by several 'omics' approaches. However, many questions remain unanswered and bioprocess development is therefore still partially empirical. In this regard, the analysis of DNA methylation as one of the earliest cellular regulatory levels is increasingly gaining importance. This epigenetic process is known to influence transcriptional events when it occurs at specific genomic regions with high CpG frequencies, called CpG islands (CGIs). Being methylated, CGIs attract proteins with methyl-DNA binding domains (MBD proteins) that in turn can interact with chromatin modifying complexes, thereby leading to a transcriptionally inactive state of the associated gene . In CHO Based on the genomic and transcriptomic information available for CHO cells ,5, 21,992+, MAPK and Wnt signalling systems were comprised within the latter group and showed a large coverage by differentially methylated components. 48 hours upon butyrate addition the number of differential methylations decreased by about 90 %. COBRA analysis of the Wnt responsive myc proto-oncogene protein-like gene showed clearly detectable cleavage products 24 hours upon butyrate addition, that completely vanished another 24 hours later (Figure Butyrate treated CHO DP-12 cultures stopped proliferating and decreasing viabilities could be detected 24 hours upon addition of the SCFA Figure . Simultar Figure , confirmOur first genome-wide screening for differential DNA methylation in CHO cells shows that the epigenetic response upon butyrate treatment seems to be highly dynamic and reversible. This was confirmed by applying the bisulfite-based single-gene method COBRA to analyze a region of the myc proto-oncogene protein-like gene. Furthermore, detection of differential methylation before butyrate addition indicates that heterogeneity in DNA methylation occurs even if cells originated from the same preculture and were treated identically. This occurrence of differentially methylated genes in parallel cultivations strongly fosters the hypothesis that the culture history influences final process outcomes . It unde"}
{"text": "Sensory cortex often undergoes population activity fluctuations due to attentional modulations and arousal changes, but activity fluctuations can also be generated intrinsically. The mechanisms that underlie these spontaneous activity fluctuations are unknown, in particular whether they arise from common inputs or more active neuronal processes. We measured the activity of tens of V1 neurons simultaneously in monkeys stimulated with oriented visual stimuli, and found that the tuning curves (TCs) of orientation selective neurons spontaneously underwent shifts and multiplicative scalings proportional to population activity while their widths remained constant Based on this observed TC activity dependence, we constructed a precise statistical model featuring Poisson-like firing, shifts and gain modulation. The model not only accounted for neuronal co-variability but also approached the performance of state-of-art decoding methods. Surprisingly, we found that decoding performance on sensory stimuli increased with population activity, despite the fact that the stimulus was identical. Therefore, spontaneous population activity fluctuations display highly non-random features, boosting TCs by shifts and multiplicative factors that gate information processing.We found that TCs are shifted and scaled by a multiplicative factor proportional to mean population activity Figure . The amoThe observed boosting properties of TCs motivated us to build a statistical model with Poisson-like neurons that includes a multiplicative scaling factor (PS). We observed that the effect of population activity on TCs is not purely multiplicative, and we introduced therefore a shift (PSS). Our models approached the performance of state-of-art decoding techniques and provided higher accuracy than other tested decoders based on population vector and independent Poisson neurons. Experimental methods are as in ."}
{"text": "Diverse therapeutic strategies for food allergy are under investigation including food allergen-specific and non-specific approaches. Allergen-specific approaches include immunotherapy with native food allergens, immunotherapy with mutated recombinant allergens, and diets containing extensively heated milk or egg. Native allergen immunotherapy can be administered via oral, sublingual, subcutaneous, or epicutaneous route. Oral immunotherapy trials with native food allergens such as milk, peanut, or egg reported that approximately 50-75% of the treated subjects reached and tolerated the maintenance dose. Failure of desensitization occurred in about 10-20% of the treated subjects and might be associated with the most severe and likely permanent food allergy phenotype, as opposed to the successful desensitization and tolerance that might be associated with a transient clinical phenotype and higher chances of spontaneous resolution of food allergy. Food allergens can be altered to decrease their allergenicity and lower the risk of acute adverse reactions. Immunotherapy with mutated recombinant peanut proteins, which have decreased IgE-binding activity, co-administered within heat-killed E.coli to generate maximum immune response had a strong protective effect in the mouse model of peanut anaphylaxis. This vaccine is being currently evaluated in the phase I clinical trials in adults with peanut allergy. Heating and processing changes food protein conformation and affects how food proteins are digested and transported via the gut barrier. Extensively heated (baked) milk and egg are tolerated by approximately 70% of the milk or egg allergic children. Diets containing extensively heated (baked) milk and egg represent an alternative approach to food oral immunotherapy and are already changing the paradigm of strict dietary avoidance for food-allergic patients."}
{"text": "We construct a state-and-transition model for mammals in tropical savannas in northern Australia to synthesize ecological knowledge and understand mammalian declines. We aimed to validate the existence of alternative mammal assemblage states similar to those in arid Australian grasslands, and to speculate on transition triggers. Based on the arid grassland model, we hypothesized that assemblages are partitioned across rainfall gradients and between substrates. We also predicted that assemblages typical of arid regions in boom periods would be prevalent in savannas with higher and more regular rainfall. Data from eight mammal surveys from the Kimberley region, Western Australia (1994 to 2011) were collated. Survey sites were partitioned across rainfall zones and habitats. Data allowed us to identify three assemblage states: State 0:- low numbers of mammals, State II:- dominated by omnivorous rodents and State III:- dominated by rodents and larger marsupials. Unlike arid grasslands, assemblage dominance by insectivorous dasyurids (State I) did not occur in savannas. Mammal assemblages were partitioned across rainfall zones and between substrates as predicted, but\u2014unlike arid regions\u2014were not related strongly to yearly rainfall. Mammal assemblage composition showed high regional stability, probably related to high annual rainfall and predictable wet season resource pulses. As a consequence, we speculate that perpetually booming assemblages in savannas allow top-down control of the ecosystem, with suppression of introduced cats by the dingo, the region's top predator. Under conditions of low or erratic productivity, imposed increasingly by intense fire regimes and introduced herbivore grazing, dingoes may not limit impacts of cats on native mammals. These interacting factors may explain contemporary declines of savanna mammals as well as historical declines in arid Australia. The cat-ecosystem productivity hypothesis raised here differs from the already-articulated cat-habitat structure hypothesis for mammal declines, and we suggest approaches for explicit testing of transition triggers for competing hypotheses. The processes that drive fluctuations in population size and community composition have long been a source of fascination for ecologists, and gaining a general understanding of their identity and effects remains an enduring goal. Although some emphasis has been placed on the influence of intrinsic factors, such as social interactions, in driving species' dynamics In many systems, the interplay between bottom-up and top-down forces can lead to the existence of alternative states that are characterized by different dominant species or species-groups State-and-transition models were initially developed to assist in managing non-equilibrial rangeland systems Here, we apply state-and-transition modelling to synthesize knowledge about native mammal assemblages in the Kimberley region of northern Australia and explore factors that might drive them. This region is of considerable conservation concern: populations of many mammal species are declining across the northern Australian savannas, conceivably towards irreversible regional or total extinctions. Worldwide, about a quarter of all mammal species are threatened with extinction; about 38% of land mammals suffer from habitat loss associated with diversion of natural resources to benefit humans, and 16% are at risk from hunting or harvesting Although mammal declines elsewhere in Australia have received considerable attention Sminthopsis macroura, Pseudomys desertor, Rattus villosissimus, Mus musculus) and functional groups (particularly insectivorous dasyurids and omnivorous rodents).We use a recently described model from central Australia There are two key differences between central Australian arid grassland assemblages and those of the Kimberley's tropical savannas: (1) The former are now largely devoid of medium-sized mammals (e.g. peramelids) whereas all medium-sized mammals persist in the tropical savannas, albeit in most cases, with greatly reduced ranges It is important that state-and-transition models be testable annual rainfall,rocky versus non-rocky savannas, andthe abundance and representation of particular species and taxonomic or functional groups.Because of the importance of antecedent rainfall in driving patterns of mammalian abundance and composition through time, we predicted also that inter-annual differences in rainfall would lead to shifts between states. Rainfall, and thus productivity, is predictable in the Kimberley but not in central Australia, where erratic rainfall drives ephemeral pulses of productivity. In consequence, we predicted further that Kimberley mammal assemblages would be more stable and exist in higher states than those in central Australia. We use our results to generate hypotheses about the key factors that prompt shifts between assemblage states and hence further our understanding of the threats to the Kimberley mammal faunas. These hypotheses also can be extended to, and tested in, other tropical savanna areas.4 grasses dominating the ground layer The Kimberley region is in the far north west of Australia and represents the Western Australian component of Torresian habitats. It has a tropical monsoonal climate with rain falling mostly during the summer from November to April. Annual rainfall ranges from 1400 mm on the far north coast to <400 mm along the semi-arid southern boundary . AlthougTo classify mammal assemblage states, we collated data from 229 survey sites in savanna across all the major Kimberley bioregions All survey data presented here consist of one-off site surveys. Where repeat site surveys occurred, we maintained temporal independence by choosing just one survey at random to represent that site. As different rainfall regions and savanna habitats provide the potential conditions needed to drive different states and transitions, we considered this space-for-time approach to be appropriate.This study makes use of data from eight separate mammal fauna surveys with differing methodologies and trap effort per site . DespiteAnalyses were performed on individual species and also on pre-defined functional groups , terrestrial omnivorous rodents (Muridae), arboreal rodents, large marsupials (>150 g) including dasyurid predators, bandicoots (peramelids), possums , and small macropods (macropodids <2000 g)). We compared species and taxonomic/functional groups in terms of their abundance, measured here as percentage trap success for each survey. We tested for potential under-estimation of small dasyurids among surveys by separately analyzing trap records from pitfall traps based on the rationale that pitfall traps are the most effective method for estimating the abundance of small dasyurids in arid grassland surveys The hypothesis that species and mammal groups differ in abundance among rainfall zones and between rocky and non-rocky savannas was tested using Kruskal-Wallis tests. This non-parametric test was chosen due to inequality of sample sizes and non-normality of the survey data, which had many zero values. The effect of fluctuations in annual rainfall within rainfall zones/savanna types was tested using regressions of trap success over previous wet season rainfall. Differences among mammal assemblages across rainfall zones and savanna habitats were explored using Bray Curtis ordinations, with the Sorensen dissimilarity distance used to calculate separation between surveys. A non-parametric multi-response permutation procedure (MRPP) was used to test for differences among predefined rainfall zone and savanna habitat (rocky and non-rocky) groups. We used PC-ORD 4 for ordinations and MINITAB 14 for all statistical analyses.Zyzomys argurus, Pseudomys nanus, Rattus tunneyi and P. delicatulus. The next most prominent group comprised large dasyurid predators , with 0.95% trap success. Small insectivorous dasyurids were relatively rare and yielded a total trap success of only 0.09%. Other groups represented in the surveys included bandicoots (0.58%) and arboreal rodents (0.43%). The low trap success rate for macropods and possums (<0.2%) probably reflects ineffective sampling rather than low numbers as these animals are not often trapped even where locally numerous.After removal of data from sites sampled more than once, we recorded a total of 5138 mammals from 71,016 trap nights (mean trap success 7.24%) . The larCanis lupus dingo and feral cats Felis catus were abundant. Dingoes were frequently observed and recorded in the high and medium rainfall zones during surveys . Similarly, cats are present throughout the Kimberley Although not recorded by trapping, dingoes P. delicatulus, P. nanus) were more numerous in low rainfall zones and non-rocky savannas, while others were most abundant in high rainfall rocky savannas showed variable responses to rainfall and habitat. Some rodent species , the bandicoot Isoodon auratus and arboreal rodents occurred only in surveys in the high rainfall zone , including rodents and small dasyurids, were captured using pitfall traps irrespective of rainfall zone . RodentsIn individual surveys, 17% of sites had no mammals (State 0), 2% were dominated by insectivorous dasyurids (State I), 37% were dominated by omnivorous rodents (State II) and 44% had a significant component of large mammals in addition to omnivorous rodents (State III). Surveys yielding zero mammals (State 0) were unusual in high (8% of surveys) and medium (0%) rainfall rocky savannas but more common in non-rocky savannas and in low rainfall rocky savannas (32%). Small dasyurids (State I) dominated assemblages in 1% of high rainfall rocky savannas, and in 5% and 10% of rocky and non-rocky sites in the low rainfall zone. Rodents dominated assemblages (State II) in medium rainfall non-rocky (73%), low rainfall rocky (63%) and low rainfall non-rocky (71%) savannas. State II assemblages were also common in medium rainfall rocky (25%) and high rainfall non-rocky savannas (38%), but less so (6%) in high rainfall rocky savannas. State III assemblages with large CWR mammals (>150 g) were restricted to high rainfall or rocky savannas, with 84% and 75% of surveys yielding these assemblages in high and medium rainfall rocky savannas, and 40% in high rainfall non-rocky savannas.Z. argurus and P. desertor and on non-rocky substrates (sand plains and open non-rocky savannas) by P. nanus, P. delicatulus and R. tunneyi. These species differ from their arid zone counterparts where State II assemblages are dominated by Notomys alexis and Pseudomys hermannsburgensis (Letnic and Dickman 2010). Finally, surveys in the high rainfall zone conformed to State III arid zone assemblages, with rodents and marsupial groups including predatory dasyurids dominating. State III assemblages were dominated by rodents and the large dasyurid predator Dasyurus hallucatus on rocky substrates. State III assemblages also included bandicoots (Isoodon macrourus and I. auratus), arboreal rodents (Mesembriomys macrurus and Conilurus penicillatus) and infrequently trapped possums (e.g. Wyulda squamicaudata) and small macropods . The latter groups, comprising CWR mammals, have become extinct since European settlement in central Australian grasslands This study confirms the existence of alternative assemblage states for mammals in tropical savannas of the Kimberley region. A proposed model depicting these states is shown in Sminthopsis macroura, S. virginiae, Planigale ingrami, P. maculata and Pseudantechinus ningbing occurred throughout Kimberley. However, they never occurred at high abundance, nor were they ever more common than other mammal groups. In contrast, arid assemblages are often dominated by small dasyurids (i.e. State I) A key difference between the arid zone assemblages described by Letnic and Dickman D. hallucatus, P. tapoafata), bandicoots and arboreal rodents have generally been restricted to high rainfall savannas in the Kimberley and Top End regions since the 1980s The assemblages described here correspond closely with previous reports on mammals in the Kimberley savannas Key transition triggers for changes in mammal assemblage state in central Australian grasslands are rainfall events that drive ephemeral pulses of primary production, and wildfires, drought, grazing by introduced herbivores and predation by introduced predators (cats and foxes) D. hallucatus) Despite the predictability of these patterns, assemblage states were not fixed; for example, State II assemblages sometimes occurred in the high rainfall zone and State III assemblages in the medium rainfall zone. Several other studies have also documented changes in assemblage states at particular sites over time High regional stability among assemblages of Kimberley savanna mammals in response to inter-annual differences in rainfall suggests that transitions there are governed differently from those in central Australian grasslands. Because savanna productivity is generally relatively high due to higher rainfall than in more arid regions, factors that effect downward state transitions may assume more importance in driving assemblage changes. Such factors operating in the savannas may also explain the relatively low abundance of mammals in most Kimberley assemblages relative to those in the arid grasslands during periods of population irruption Predation by introduced cats and foxes drives mammal assemblages towards lower states in arid regions Of the predators in the Kimberley savannas, dingoes are most likely to have a top-predator role and to influence mammal assemblage states. Ecological theory and many empirical observations show that where resource pulses are regular, as in the Kimberley relative to the arid zone, predators often maintain higher and more stable populations and can then exert strong regulatory effects on prey If dingoes act as \u2018biodiversity regulators\u2019 As in the conceptual model for arid Australian assemblages, fire regimes and introduced herbivores have major influences on assemblages of savanna mammals Arid zone mammals typically occur as State 0 or State I assemblages for long periods until shifted up by large but infrequent flooding rains The cat-ecosystem productivity hypothesis posited here, and depicted in"}
{"text": "It has been previously shown that loss of consciousness is associated with a breakdown of dominating fronto-parietal feedback connectivity as assessed by electroencephalogram (EEG) recordings. Structure and strength of network connectivity may change over time. Aim of the current study is to investigate cortico-cortical connectivity at different time intervals during consciousness and unconsciousness. For this purpose, EEG symbolic transfer entropy (STEn) was calculated to indicate cortico-cortical information transfer at different transfer times.The study was performed in 15 male volunteers. 29-channel EEG was recorded during consciousness and propofol-induced unconsciousness. EEG data were analyzed by STEn, which quantifies intensity and directionality of the mutual information flow between two EEG channels. STEn was computed over fronto-parietal channel pair combinations to analyze changes of intercortical directional connectivity. Feedback and feedforward connectivity was calculated for transfer times from 25 ms to 250 ms in 5 ms steps. Transfer times leading to maximum directed interaction were identified to detect changes of cortical information transfer induced by unconsciousness (p<0.05).The current analyses show that fronto-parietal connectivity is a non-static phenomenon. Maximum detected interaction occurs at decreased transfer times during propofol-induced unconsciousness . Strength of maximum feedback interaction decreases during unconsciousness (p\u200a=\u200a0.026), while no effect of propofol was observed on feedforward interaction. During both consciousness and unconsciousness, intensity of fronto-parietal interaction fluctuates with increasing transfer times.Non-stationarity of directional connectivity may play a functional role for cortical network communication as it shows characteristic changes during propofol-induced unconsciousness. Altered states of consciousness are associated with changes in directional (effective) and functional connectivity within a fronto-parietal network. This is observed as a common phenomenon during anesthesia, vegetative states and sleep Recent studies show that functional connectivity of cerebral areas is not a static phenomenon, but shows spontaneous fluctuations over time However, so far, fluctuations of neuronal network connectivity have been shown for functional connectivity as measured by functional magnetic resonance imaging (fMRI). The current study evaluates whether directional cortical connectivity as measured by electroencephalogram (EEG) may also show fluctuations, but in the range of milliseconds Fifteen healthy male volunteers participated after approval by the university's ethics committee and informed written consent. The study was conducted in the department of anesthesiology of the Technische Universit\u00e4t M\u00fcnchen, Germany. Standard monitoring parameters and 29-channel EEG were continuously recorded with a sampling rate of 5 kHz using BrainAmp electroencephalographic amplifier and BrainVision Recorder data acquisition software. Propofol was administered by a target controlled infusion pump . Subjects received propofol in stepwise increasing concentrations until loss of consciousness occurred, which was defined clinically when subjects stopped following the investigator's instruction to squeeze his hand. TCI concentration at this point was maintained for 10 minutes to allow equilibration. EEG was recorded without drug application and during propofol-induced unconsciousness (10 minutes). Basic artifact detection and average reference were performed on EEG recordings.In existing EEG data of propofol-induced unconsciousness we applied EEG analysis within the framework of an information-theoretic approach allowing a model-free exploration of directed interactions between frontal (process X) and parietal (process Y) electrodes. For this purpose, EEG symbolic transfer entropy (STEn) was calculated For calculation, STEn analyzes consecutive sequences For frontal (x) and parietal (y) EEG this indicates feedforward parietal \u2192 frontal projections between parietal and frontal electrodes . STEn was computed over fronto-parietal channel pair combinations at consciousness and propofol-induced unconsciousness using one artifact free EEG signal of 10 s length for each subject . Acording to the signal length criterion Values of STEn may indicate spurious interdependencies in the EEG caused by spectral changes. To address this question, surrogates from the electroencephalographic signals were derived by maintaining the spectral amplitudes and randomising the phase non-parametric STEn showed consistent results even in different setups, e.g. embedding parameters, electrode montage Further studies with different anesthetics and altered states of consciousness are required to clarify some open points. Unconsciousness was induced by propofol. Therefore, it remains an open question, whether the detected results are a propofol-specific phenomenon or reflect characteristics of unconsciousness in general. The small number of subjects and low spatial resolution of the fronto-parietal network analyzed in EEG represent further limitations. Method inherent issues can not be fully excluded. Estimation of transfer times as performed in the present analysis may also include intrinsic prediction within one area In conclusion, our results indicate that cortical information transfer is not a static process but fluctuates periodically. Fluctuations of directional connectivity seem to reflect an intrinsic phenomenon of the brain to energetically optimize cortical communication. Characteristically, fluctuations are changed during propofol-induced unconsciousness towards faster information transfer. At the same time, the amount of parieto-frontal feedforward projections is not reduced during unconsciousness, while fronto-parietal feedback interactions are reduced. Both the inhibition of feedback connectivity and the altered fluctuation of information transfer during propofol administration are proposed as functional correlates of loss of consciousness."}
{"text": "Quality of Life (QoL) data from oncology trials may have missing data which cannot be assumed to be missing completely at random (MCAR) . IgnorinWe searched MEDLINE (2002-2012) to identify oncology trials reporting longitudinal analysis of QOL data. The appropriateness of the analysis was reviewed and trials reporting QOL as primary/secondary endpoint were assessed for reporting quality using the CONSORT extension for PROs .69 RCTs reporting longitudinal QOL analyses were identified. 29 (42%) use an analysis to account for the nature of the missing data. Methods varied widely, eg pattern-mixture models, conditional linear models, QTWiST, joint longitudinal models, generalised estimating equations, selection models and Markov models. Fourteen papers used more than one method check the robustness of their results.In order for QOL data to adequately inform clinical decision-making the correct analysis needs to be performed. Statistical methods ignoring the missing data were found to over-estimate QOL but it was rare for the significance of QOL differences between treatments to change. A strategy for appropriate analysis of QOL data will be presented using case studies to highlight where ignoring informative missing data could alter the conclusions regarding treatment differences."}
{"text": "Progressive increase of temperatures as well as longer seasonal drought periods revealed by climate studies correspond to fast environmental changes that forest species face with their actual genetic background. Natural selective processes cannot develop an adaptive response within this time frame. Thus the capability of forest tree species to adapt to the new environments will depend on their genetic background, but also rely on their phenotypic plasticity. Several reports have shown the involvement of epigenetic modifiers as the basis of the phenotypic plasticity, and in particular to the adaptation to abiotic stresses. DNA methylation (methylation of cytosine residues)is one the most important epigenetic modification in eukaryotes. Itis involved in specific biological processes such as gene transcription regulation, gene silencing, mobile element control or genome imprinting.Therefore, there is a great interest in analyzing cytosine methylation levels and distribution within the genome.HpaII and MspI are isoschizomers that are frequently used to detect cytosine methylation. HpaII cannot cleave if one or both cytosines are fully methylated (in both strands), whereas MspI cleaves C5mCGG but not 5mCCGG sequences). For each sample, MSAP analysis is performed using both EcoRI/HpaII and EcoRI/MspI digested samples. Comparative analysis between EcoRI/HpaII and EcoRI/MspI fragment patterns allows the identification of two types of polymorphisms: (1) \u201cMethylation-insensitive polymorphisms\u201d that are associated with genetic variability and will show common EcoRI/HpaII and EcoRI/MspI profiles among samples; and (2) \u201cMethylation-sensitive polymorphisms\u201d that are associated with epigenetic variability and detected as amplified fragments differing in their presence or absence or in their intensity between EcoRI/HpaII and EcoRI/MspI patterns of the same sample. Thus, full methylation of the internal cytosine at the assayed CCGG sites will be associated with fragments detected in EcoRI/MspI pattern which are absent or less intense in EcoRI/HpaII profile. Hemi-methylation of the external cytosine will be associated with fragments observed in EcoRI/HpaII pattern which are absent in EcoRI/MspI profile.In order to analyze methylation-sensitive anonymous CCGG restriction sites we used MSAP technique (Methylation-Sensitive Amplified Polymorphism), an AFLP-based technique for the analysis of cytosine methylation. The technique is based on the use of isoschizomers that show differential cleavage sensitivity to cytosine methylation. Fagus sp.) and gymnosperm (Pinus sp.) species.We have optimized DNA methylation analysis for two forest tree species, including both angiosperm (Pinus pinea L. a specie which is characterized by a low genetic variability and high level of phenotypic plasticity. Representative populations spanning the whole distribution of this specie within Spanish geography were chosen for this study, including coastal and interior populations. MSAP patterns from vegetative propagated trees were compared among and within populations. Percentage of methylation-sensitive polymorphisms was calculated and selective markers were identified.The set-up of the MSAP technology has allowed study intra-specific variability of DNA methylation in Fagus sylvatica L. in response to water deficit we analyzed two populations of beech from Spain and Sweden which differ in the response to water stress. Patterns of DNA methylation clearly differed between populations. Although the rate of DNA methylation was similar between irrigated and non-irrigated trees in each polpulation after AMOVA, some specific MSAPs associated with water stress response were identified.To test a possible role of DNA methylation in the plasticity of"}
{"text": "DNase I hypersensitivity (DHS) combined with next generation sequencing (DNase-seq) is an efficient way of observing, in a single experiment, the genome-wide chromatin effects associated with the binding of multiple transcription factors. Using quantitative contrasts of DHS before and after estrogen and androgen stimulation in breast and prostate cancer cell lines, we have shown that differential DHS can accurately predict hormone induced transcription factor binding. Despite its effectiveness, the DHS assay can vary significantly depending on the experimental parameters. To increase the robustness of this assay, we have systematically evaluated two major parameters, digestion level and fragment size. We found that while there is a broad range of suitable digestion level, over-digestion dramatically decreases the efficiency of detecting DHS regions. More interestingly, we found that different fragment sizes capture distinct chromatin elements, and thus represent different chromatin structures. We were able to classify different combinations of estrogen receptor coregulators that resulted in different local chromatin structures."}
{"text": "Aging is worldwide recognized as a dominant risk factor for most forms of cardiovascular disease -3. HowevIn adult and elderly humans, high levels of physical activity preserve the protective role of preinfarction angina against in-hospital mortality and cardiogenic shock after myocardial infarction. More recent data indicate that higher levels of physical activity performed before primary coronary angioplasty may independently predict the reduction of early and late cardiac mortality in older infarcted patients . Accordi"}
{"text": "Mitotic chromosome motions have recently been correlated with electrostatic forces, but a lingering \"molecular cell biology\" paradigm persists, proposing binding and release proteins or molecular geometries for force generation.Pole-facing kinetochore plates manifest positive charges and interact with negatively charged microtubule ends providing the motive force for poleward chromosome motions by classical electrostatics. This conceptual scheme explains dynamic tracking/coupling of kinetochores to microtubules and the simultaneous depolymerization of kinetochore microtubules as poleward force is generated.We question here why cells would prefer complex molecular mechanisms to move chromosomes when direct electrostatic interactions between known bound charge distributions can accomplish the same task much more simply. Molecular mechanisms underlying mitosis, particularly those associated with directed chromosome movement during the cell cycle, have been pursued intensely over the past two decades with no clear picture emerging--or is there? Recent experiments identify positively charged kinetochore-associated molecules that likely interact with negatively charged microtubule ends to generate electrostatic-dependent poleward forces that drive chromosome motion . This coIndeed, current thought on mitotic motions is shifting from a molecular to a more electrostatics-based framework -3, and psic] attempted to explain chromosome motions by nanoscale electrostatics and unnecessary sophistry...\" [Perhaps the most surprising part of this story is the untimely resistance to classical electrostatics by the cell biology community. For example, critiques including \"...groundless speculations in which the authors [stry...\" , and reqstry...\" suggest stry...\" ,2, and istry...\" and redustry...\" .To gain perspective on this subject, it may be instructive to consider the problem of cell division in an evolutionary context, and more specifically in an ancestral cell that lacked \"modern\" molecular machinery. Clearly, cells have been dividing since the origin of life, and the mechanisms underlying this fundamental process in modern cells are likely derived from some ancestral state--just like other cellular processes were likely derived from ancestral, catalytic RNAs that were later supplemented with supporting proteins. In a simple cell, all chromosome movements during mitosis are readily explained by electrostatic interactions between core components of the system , without the requirement for supplemental protein machinery -6. Why tOur current bottleneck in understanding mitotic chromosome movements seems reminiscent of another challenging question in our imperfect scientific history, namely the self-imposed constraints of ancient Greek astronomers in trying to explain geocentric planetary motions with perfect circles. Indeed, layers of epicycles were incorporated into an increasingly complex scheme of integrated circles that was \"understood\" by only the best natural philosophers of the time. It took ~2,000 years of scientific work by Brahe, Galileo, Kepler and Newton to achieve the simplicity of a modern theory based on a different conceptual scheme, i.e., elliptical orbits in a heliocentric solar system.Twenty years ago, Guenter Albrecht-Buehler lamented the view of many cell biologists that \"molecular analysis of cellular functions\" is the only acceptable approach to cell biology , yet thiThe authors declare that they have no competing interests.DHS made intellectual contributions and drafted the manuscript. LJG conceived the study. All authors read and approved the final manuscript."}
{"text": "We conducted a qualitative study to gain insight into the high retention rate and variable outcomes achieved in the 3-year PODOSA (Prevention of Diabetes and Obesity in South Asians) family-based cluster randomised controlled trial of a dietitian-delivered lifestyle modification intervention.We interviewed 21 trial participants and family volunteers following trial completion. Purposive sampling ensured representation of the diversity within the trial population. Data were thematically analysed. Findings were shared with trial dietiticans once the trial had closed.Many participants were aware of their family history of diabetes and attracted by the availability of information and monitoring. Offering home or clinic-based interventions, communication in the participant's chosen language(s) and excellent relationships between participants and dieticians contributed to retention. Adaptations in food choices were accommodated by participants, although community and faith based considerations made consistent adherence challenging. Participants found increasing their level of physical activity difficult given other demands, including long working hours, physically demanding employment and domestic commitments.Undertaking qualitative research allowed in-depth insight into participation, retention and adherence in the PODOSA trial. The main benefit participants sought was information regarding diabetes. Home-based interventions and continuity in dieticians were included in trial design, but it was not anticipated that these relationships would contribute so greatly to retention. Adaptations in food choices were not felt to be an extra burden upon participants but were made more difficult due to cultural considerations. Increasing levels of physical activity were felt to be an additional burden, again augmented by cultural considerations."}
{"text": "Rodent models of heterotopic cardiac transplantation are important for gaining a better understanding of heart allograft rejection. This study compared a working heart (WkHt) transplant model, which have developed by our laboratory, with the traditional non-working heart (Non-WkHt) model using cardiac MRI (CMRI) and pathological evaluation. Our results indicate that the physiological hemodynamic loading significantly impacts graft immune cell infiltration and myocardial function. Our WkHt transplant model with intact pulmonary circulation, retains hemodynamic loading close to that of native heart, and is thus more appropriate for both functional and immunological studies, especially for developing the clinically relevant CMRI techniques for comprehensive evaluation of the heart graft.The traditional heterotopic heart transplantation rodent model ,2 lacks WkHt model: En bloc of graft heart and lung was transplanted into the recipient abdomen. Graft aorta and superior vena cava (SVC) were anastomosed with recipient abdominal aorta and inferior vena cava (IVC), respectively.,4 Non-WkAlthough isograft hearts from both models had strong heart beats and normal ECG, they exhibited very different cardiac functions revealed by CMRI Fig.. The WkHOur results indicate that hemodymamic loading significantly impacts the graft status. The WkHt transplant model, with intact pulmonary circulation, retains physiological conditions close to that of the native heart, and therefore is more appropriate for functional and immunological studies, especially for developing the clinically relevant CMRI techniques for comprehensive evaluation of the heart graft.This study is supported by grants from the National Institutes of Health (P41EB001977 and R01HL-081349)."}
{"text": "Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) is a common chemotherapeutic regimen for advanced colorectal cancer. Here, we present a case of interstitial lung disease associated with FOLFOX therapy.A 74-year-old man with a history of metastatic colorectal cancer was admitted with a four week history of progressive dyspnoea and evidence of severe respiratory failure. He had recently completed six cycles of FOLFOX chemotherapy in the months prior to presentation. Investigations did not reveal convincing evidence of infection or pulmonary embolism. CT chest demonstrated widespread pulmonary infiltrates and interlobular septal thickening. The patient was commenced on both broad spectrum antibiotic therapy and high dose corticosteroid treatment however his respiratory failure continued to progress. The patient died four days after admission due to progressive respiratory failure. Subsequent post-mortem examination demonstrated evidence of diffuse alveolar damage without evidence of tumour infiltration, infection or pulmonary embolism.Although infrequent, pulmonary toxicity can occur in association with FOLFOX therapy. Cessation of therapy and prompt initiation of corticosteroids may improve outcomes. Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) is an effective chemotherapeutic regimen for advanced colorectal cancer, improving survival with acceptable tolerability and side effect profile.A 74-year-old man with a history of metastatic colorectal cancer was admitted with a four week history of progressive dyspnoea and haemoptysis. He had undergone a right hemicolectomy three and a half years previously for a Duke\u2019s A colorectal cancer. Three years post resection, a large single liver metastasis was identified with no other evidence of metastatic disease on PET scanning. CT examination of the chest at the time demonstrated only mild emphysematous changes .The patient was commenced on FOLFOX chemotherapy and underwent six cycles from October to December 2008. A re-staging CT scan in January 2009 demonstrated progressive malignant disease with multiple new metastases within the liver. Chest imaging at this time revealed bilateral peripheral subpleural reticular changes and interlobular septal thickening without evidence of overt lung metastases . No chanThe patient subsequently presented in early February 2009 with four weeks of worsening dyspnoea and haemoptysis. His Creactive protein level was moderately elevated although white cell count and differential were normal. Arterial blood gases demonstrated severe type I respiratory failure. CT pulmonary angiogram excluded pulmonary embolism but demonstrated new patchy infiltrates with interlobular septal thickening . Sputum He was commenced on empirical broad spectrum antibiotics and high dose intravenous corticosteroid therapy. His respiratory failure worsened and after discussion with both the patient and his family, mechanical ventilation was not administered. The patient died four days after admission from progressive respiratory failure.Post-mortem examination did not demonstrate evidence of an infective aetiology on staining and culture of fresh specimens. There was also no evidence of emboli, thrombus or malignant infiltration within the lungs. Histological examination demonstrated widespread generalised changes within both lungs, with oedema, intra-alveolar haemorrhage and fibrin deposition along with interstitial and intraluminal fibroblastic proliferation without mature fibrosis. These findings were consistent with diffuse alveolar damage.Diffuse alveolar damage (DAD) is a common histopathological finding in patients with ARDS and is commonly associated with infections (both respiratory and systemic). It is more frequently seen in immunocompromised patients. Although drug reactions are a relatively uncommon cause of DAD, chemotherapeutic agents are overrepresented as potential precipitants. Mortality following histologically proven DAD obtained from surgical lung biopsy has been reported to be greater than 50%.7et al. demonstrated improved response rate, median time to progression and overall survival in patients with advanced colorectal cancer treated with FOLFOX in comparison to a regimen utilising Irinotecan instead of Oxaliplatin.17Oxaliplatin, in combination with 5-fluorouracil and leucovorin (FOLFOX) has been shown to be an effective regimen for the treatment of advanced colorectal cancer.Although pulmonary toxicity from FOLFOX appears to be an uncommon and apparently idiosyncratic effect of therapy, this case highlights the importance of clinicians being aware of this potentially fatal complication and the importance of regular follow-up.Given the temporal relationship between the use of FOLFOX and the onset of radiological changes and clinical symptoms, we believe that FOLFOX is the likely precipitant in this case. Whilst this appears to be an uncommon adverse effect, early recognition may allow prompt cessation of FOLFOX therapy and initiation of systemic corticosteroids, and this has the potential to improve outcomes for such patients."}
{"text": "Batrachochytrium dendrobatidis - Bd) are major drivers of amphibian declines worldwide. Habitat loss regulates host-pathogen interactions by altering biotic and abiotic factors directly linked to both host and pathogen fitness. Therefore, studies investigating the links between natural vegetation and chytridiomycosis require integrative approaches to control for the multitude of possible interactions of biological and environmental variables in spatial epidemiology. In this study, we quantified Bd infection dynamics across a gradient of natural vegetation and microclimates, looking for causal associations between vegetation cover, multiple microclimatic variables, and pathogen prevalence and infection intensity. To minimize the effects of host diversity in our analyses, we sampled amphibian populations in the Adirondack Mountains of New York State, a region with relatively high single-host dominance. We sampled permanent ponds for anurans, focusing on populations of the habitat generalist frog Lithobates clamitans, and recorded various biotic and abiotic factors that potentially affect host-pathogen interactions: natural vegetation, canopy density, water temperature, and host population and community attributes. We screened for important explanatory variables of Bd infections and used path analyses to statistically test for the strength of cascading effects linking vegetation cover, microclimate, and Bd parameters. We found that canopy density, natural vegetation, and daily average water temperature were the best predictors of Bd. High canopy density resulted in lower water temperature, which in turn predicted higher Bd prevalence and infection intensity. Our results confirm that microclimatic shifts arising from changes in natural vegetation play an important role in Bd spatial epidemiology, with areas of closed canopy favoring Bd. Given increasing rates of anthropogenic habitat modification and the resulting declines in temperate and tropical frogs, understanding how vegetation cover and disease interact is critical for predicting Bd spread and developing appropriate management tools for wild populations.Habitat loss and chytridiomycosis (a disease caused by the chytrid fungus Anthropogenically driven habitat change has important implications for host-pathogen interactions, because even slight changes in environmental conditions can modify numerous biotic and abiotic factors that influence these interactions Batrachochytrium dendrobatidis (Bd), for instance, is more prevalent and occurs at higher infection intensities in pristine tropical forests compared to disturbed habitats Bd-induced amphibian declines Shifts in microclimate and changes in host community structure across gradients of habitat alteration play important roles in amphibian epidemiology Bd, thus limiting pathogen growth and persistence Bd persistence in these environments From the host's perspective, immune responses usually decrease as a result of the multiple effects of habitat alteration Bd in populations of the common Green Frog (Lithobates clamitans) across a gradient of natural vegetation and microclimate. We sampled frogs in the southern Adirondack Park, New York State, a region with relatively low amphibian diversity and high dominance of this habitat generalist host Bd in amphibians and (ii) test for causal associations linking vegetation cover and microclimate with both Bd prevalence and infection intensity. Combined, these goals may elucidate whether vegetation and microclimate modulate disease risk in temperate amphibian populations affected by anthropogenic habitat change.Here, we examined the infection dynamics of Bd is enzootic and widespread in the northeastern U.S. Bd growth in this region Lithobates clamitans, Ranidae), the locally dominant amphibian host species. Green Frogs breed in permanent ponds during the boreal spring and summer, and typically spend most of the time at the shallow banks of water bodies \u22121. We recorded body weight (g) for each captured individual and screened post-metamorphic frogs with sterile swabs to quantify Bd prevalence and infection intensity (average of 16.6 L. clamitans per site). We tested samples for Bd in singlicate using Taqman qPCR Bd in each sample. This protocol maximizes amplification efficiencies by diluting extracts to reduce inhibition in environmental samples. For calculations of Bd prevalence, we categorized individuals as Bd-positive when their qPCR showed an infection load of greater than or equal to one g.e. Bd prevalence as the percentage of infected individuals and Bd infection intensity as average number of g.e. per population.We sampled anuran populations in the Adirondack Park of the State of New York . This region is heavily forested with elements representative of temperate and boreal forests \u22121) as a proxy for host population density. We specifically chose this study system because of its relatively low species diversity and high single host species dominance. These community attributes allow us to test hypothesis about the roles of microclimate in disease dynamics without the potential effects of complex host community structure. Nonetheless, we recorded host community diversity , and we reported the model with the highest goodness-of-fit for each run. We also used CAR to test for associations of natural vegetation with host population and community attributes .To control for the effects of spatial autocorrelation among ponds, we analyzed our data using conditional autoregressions (CAR). We used CAR to test the relationship of each explanatory variable with Bd infection parameters. Because canopy density may be a better proxy for microclimate than our actual temperature records from a single data logger per pond, we tested an alternative path diagram in which canopy density directly affected Bd infection parameters. We compared goodness-of-fit among models using Expected Cross-validation Index (ECVI), an AIC-based index. We conducted CAR using Spatial Analysis in Macroecology v4.0 We used path analyses to statistically test for the strength of unidirectional cascading effects linking natural vegetation, canopy density, water temperature, and Bd at all study sites with mean prevalence of 24.25%\u00b116.41 SD and mean infection intensities of 29.36\u00b1151.60 SD, reaching a maximum load of 1063.23 g.e. in our focal species without observed mortalities. Canopy density was the best predictor of Bd prevalence in L. clamitans , maximum daily average temp. , minimum daily average temp. ], and natural vegetation . We found no significant relationships between Bd prevalence and average body weight, capture rate, elevation, host community diversity, or overall host community biomass.We detected Bd infection intensity. Canopy density best predicted Bd infection intensities , maximum daily average temp. , minimum daily average temp. ], natural vegetation , average body weight , and capture rate were also significant predictors of Bd infection intensity in L. clamitans. Similar to prevalence, we found no direct associations of Bd infection intensity with elevation, host community diversity, or overall host community biomass.We found similar results for Bd prevalence and infection intensity, our model selection identified three key environmental factors: canopy density, natural vegetation, and daily average water temperature and infection intensity underscores the dominance of the focal species across this landscape . The amount of natural vegetation surrounding our sampling ponds did not significantly predict host population and community attributes; namely host average body weight , host capture rate , overall host community biomass , species richness , and host diversity .The high evenness and low diversity among our sampling ponds . Although these species may help maintain Bd throughout the cold months, it is unlikely that they have a strong effect on disease dynamics later in the season, because they spend long periods of time away from water bodies Bd growth Bd infections in the wild Bd prevalence and infection intensity in temperate amphibian populations by modulating shade and associated microclimatic patterns, and that host community structure plays at most a minor role in our study system.The effects of habitat loss and forest fragmentation on host-pathogen interactions are varied Bd prevalence and infection intensity were environmental variables associated with vegetation cover and microclimate in Pennsylvania showed that the proportion of leaf-litter and vegetation in the pond substrate correlated positively with Bd prevalence and infection intensity Bd transmission by providing substrates for Bd growth. Alternatively, leaf-litter may be an indicator of canopy cover and total degree of shade, which are potentially the true drivers of higher Bd levels in natural forest habitats. Similarly, in Costa Rica and Australia, localities with little to no canopy cover may provide amphibians with a refuge from Bd-induced extinction Bd year round (above 69%) Bd infections by environmental factors is a general phenomenon, and that these environmental controls linking natural vegetation to Bd dynamics are similar in tropical and temperate amphibian communities.The best predictors of mate see . The amontensity . A studyBd growth and persistence in both host and the environment, and (ii) by changing host's ability to fight and clear Bd through thermoregulation. The growth rate of Bd in the laboratory is strongly temperature-dependent, with an optimum climatic envelope ranging between 17\u201325\u00b0C and reduced persistence at temperatures above 28\u00b0C Bd growth may have been limited during some periods in our highest-temperature ponds. In fact, in four of our ponds 40.85\u00b114.42% SD of water temperature records were above 25\u00b0C during the study period. Our data closely match the association between Bd infections and temperature found by Raffel et al. Bd infection intensities and prevalence at sites with average water temperatures above 23\u00b0C. In the State of Maine, USA, Bd infections were lower during the peak of the summer than in spring and fall, presumably because water temperatures often exceeded the optimal temperature range for Bd growth Bd-infected frogs were largely absent from sites where spring water exceeded 25\u00b0C Bd strain showed that pathogen growth in vitro is hampered by short exposures to high temperatures that would typically be available to frogs at basking sites Bd infections Bd infection and transmission in open habitats Bd loads Bd infection intensity and frog survival were unrelated to water temperature Microclimate can affect amphibian disease risk in two ways by (i) regulating Bd system are larger than the effects imposed by density-dependent forces that typically predict prevalence and infection intensity in other temperate amphibians Bd infection intensity, potentially indicating density-dependent controls; however, this effect was marginal and capture rate was not a significant predictor of Bd when considered together with environmental factors in model selection. The potential effect of density on Bd was not linked to forest cover because we did not detect a significant effect of natural vegetation on host capture rate. Pathogen build-up to lethal infection intensities is more likely to occur in dense populations, under conditions that promote continuous reinfection of the hosts Our results indicate that the small-scale effects of vegetation and microclimate on our host-Bd susceptibility Bd prevalence and infection intensities. One potential explanation is that disease risk drops with age in response to host-acquired immunity, as repeated exposure to a given pathogen increases host resistance Bd infection intensity when considered independently, this parameter became a weak predictor when considering other environmental variables in the analysis. This weak effect of host body weight on Bd infection coupled with the fact that vegetation cover had no influence on host capture rate is an indication that, in our study system, habitat change has a larger influence on pathogen fitness than on host fitness. This result suggests that our focal species is highly resistant to Bd regardless of microclimate and vegetation. In fact, L. clamitans persists with a local Bd strain in the laboratory within optimal Bd grow temperatures Earlier studies in both tropical and temperate zones have found ontogenetic differences in Bd infections in both temperate and tropical systems Bd epidemics Bd resistance or tolerance could be a useful tool for assisted reintroductions in the wild Bd is most prevalent. With the high rate of anthropogenic modification to temperate and tropical forests, understanding how vegetation cover and disease interact is critical for predicting Bd spread and developing appropriate management tools for wild populations. Our results indicate that species-specific in situ management strategies will need to consider fine-scale microclimatic factors to safeguard Bd-susceptible species with narrow geographic distributions We have shown that disturbances to natural forest habitats reduce Table S1Model selection for environmental and biological variables influencing Batrachochytrium dendrobatidis (Bd) prevalence and infection intensity in populations of Lithobates clamitans in the Adirondack region, New York, USA.(DOCX)Click here for additional data file."}
{"text": "This study intends to develop a physiologic thumbprint for nonconvulsive seizures (NCSz) after acute brain injury. Abnormal electrographic brain activity including NCSz is common after acute brain injury and is associated with poor outcome. Mechanisms underlying this phenomenon are poorly understood but in animals periods of inadequate perfusion during seizures have been documented. In the present study we hope to gain better understanding of the relationship between abnormal electrographic patterns and brain homeostasis in patients with subarachnoid hemorrhage (SAH).2), regional cerebral blood flow (rCBF), and intracranial pressure monitoring; 69% (n = 36) also with intracortical EEG . Each minute of EEG was categorized separately into non-ictal, on the ictal-interictal continuum (including periodic discharges at 2 Hz or faster), or seizures. We identified seizure onsets on ICE recordings and extracted the physiologic monitoring data 30 minutes pre and post seizure onset. Physiologic profiles based on standard error of the means plots were generated using high-frequency time series physiologic measurements and interpreted by visual analysis.Between June 2006 and June 2010, 51 poor-grade SAH patients underwent multimodality monitoring with microdialysis, brain oxygen tension of patients with ICE recordings . NCSz were preceded by an increase in rCBF starting 15 minutes prior to onset of depth NCSz that stayed elevated throughout the observation period. Heart rate, mean arterial, intracranial, and cerebral perfusion pressures were elevated surrounding NCSZ. There was a small transient drop in PbtOThese findings confirm in comatose human beings that NCSz detected by ICE are associated with hyperemia, increased metabolism, and possibly brain tissue hypoxia, which serve as surrogates for secondary brain injury. Future research should implement novel approaches for ICU time-series data analysis, evaluate surface seizures, and utilize other surrogates of brain metabolism such as microdialysis."}
{"text": "Groin infections resulting in arterial bleeding due to bacterial vessel destruction are a severe challenge in vascular surgery. Patients with them most often present as emergencies and therefore need individualized reconstruction solutions.Case 1 is a 67-year-old man with infectious bleeding after an autologous reconstruction of the femoral bifurcation with greater saphenous vein due to infection of a bovine pericard patch after thrombendarterectomy. Case 2 is a 35-year-old male drug addict and had severe femoral bleeding and infection after repeated intravenous and intra-arterial substance abuse. Both patients were treated with an autologous obturator bypass of the superficial femoral vein. We review the current literature and highlight our therapeutic concept of this clinical entity.Treatment should include systemic antibiotic medication, surgical control of the infectious site, revascularization and soft tissue repair. An extra-anatomical obturator bypass with autologous superficial femoral vein should be considered as the safest revascularization procedure in infections caused by highly pathogenic bacteria. Severe groin infections with inguinal blood vessel destruction may be caused by intravenous substance abuse, radiation scars, transfemoral interventions and, most commonly, infection of prosthetic vascular implants (incidence 2% to 18%). ComplicStaphylococcus aureus (MRSA) superinfection of an inguinal lymphatic fistula. For surgical control of bleeding, orthotopic revascularization with iliacofemoral and iliacoprofundal greater saphenous vein interposition and resection of the xenogenic patch material was performed, accompanied by systemic MRSA-specific antibiotic treatment. Three weeks later rebleeding occurred due to an infectious arterial pseudoaneurysm. Intra-operative findings revealed complete erosion of the profundal venous graft anastomosis or severe claudication-7. Witho% or seveThe obturator bypass, with primary patency rates of up to 76% after 2 years, has proven to be feasible in a few small clinical series with a considerable risk of late prosthetic graft infection remaining,3,4,9-11Streptococcus in this report. With proven susceptibility of several native and prosthetic materials to MRSA and rising clinical incidence, femoral vein obturator bypass is the safest revascularization procedure with the best long-term results[To the best of our best knowledge, investigators of only one clinical series have reported the use of obturator bypass fashioned from autologous superficial femoral vein at infection sites. We ther results.Pseudomonas aeruginosa and Group B Streptococcus. It should be considered the primary treatment option by vascular surgeons confronted with this problem, especially in young patients.The extra-anatomic obturator bypass with femoral vein is a safe and feasible revascularization procedure in patients with severe groin infections and highly pathogenic bacteria such as MRSA, Written informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests and did not receive any payment from industrial partners.RK, CB, CT and AB performed surgery on the patients and were responsible for postoperative intensive medicine care. UL performed vascular graft infection studies in mice and was a major contributor in writing the manuscript. All authors read and approved the final manuscript."}
{"text": "This case study followed one adolescent patient who underwent bilateral deep brain stimulation of the centromedian parafascicular complex (CM-Pf) for debilitating, treatment refractory Tourette's syndrome for a period of 1.5 years. Neurocognitive testing showed no significant changes between baseline and follow-up assessments. Psychiatric assessment revealed positive outcomes in overall adaptive functioning and reduction in psychotropic medication load in this patient. Furthermore, despite significant baseline psychiatric comorbidity, this patient reported no suicidal ideation following electrode implantation. Deep brain stimulation is increasingly being used in children and adolescents. This case reports on the positive neurologic and neuropsychiatric outcome of an adolescent male with bilateral CM-Pf stimulation. Tourette syndrome (TS) is a chronic, childhood onset neuropsychiatric disorder, which occurs in approximately one percent of the general population, consists of motor tics and at least one vocal tic lasting longer than one year . Tic symHigh-frequency (above 100\u2009Hz) deep brain stimulation (DBS) is being increasingly used as an efficacious treatment modality in patients with severe TS complicated by behavioral and psychiatric comorbidity that is refractory to first and second line treatment . Here, wA 17-year-old left-handed male with severe Tourette's syndrome, attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD) was evaluated by pediatric neuropsychology and child psychiatry prior to the date of electrode implantation for DBS for treatment of refractory tic symptoms. The patient was treated with bilateral centromedian parafascicular complex (CM-Pf) stimulation and was followed for 1.5 years. Preoperative neuropsychometric testing was noteworthy for borderline general intellectual functioning and commensurate academic achievement . CognitiPreoperative psychiatric evaluation demonstrated severe psychosocial impairment related to treatment refractory Tourette's syndrome. Social impairment was associated with significant amounts of missed school and anxiety related to tics. Attempts to garner employment were hampered with being overwhelmed by his neurologic symptoms. Past psychiatric history was significant for three prior psychiatric hospitalizations, all occurring within the context of managing a complicated psychotropic medication regimen, and treatment approach for comorbid psychiatric conditions . InpatiePostoperative neuropsychometric testing revealed general cognitive functioning that had remained stable across time . The patPostoperative psychiatric evaluation was noteworthy for significant functional and psychosocial gains. No concerns for suicidal or self-injurious thoughts or actions were noted. The patient's psychotropic medication load was also significantly reduced . ImproveThis case report focused on the neurocognitive and psychosocial outcomes in an adolescent male who had received DBS for severe refractory Tourette's syndrome followed for 1.5 years. This patient demonstrated no significant changes in his follow-up psychometric testing and reported significant improvement in psychosocial functioning postoperatively. He was able to decrease his psychotropic medication load during follow-up psychiatric assessments and did not report any suicidal ideation throughout the course of treatment. DBS is being increasingly used for treatment-refractory TS in adults and is an important emerging treatment modality of treatment-refractory TS within the pediatric population . Thus faCase reports documenting long-term treatment outcomes in both adults and adolescents with severe refractory TS using DBS have yielded mixed results with regards to improved psychosocial functioning and overall quality of life. Stimulation of the globus pallidus internus (GPi) was shown to be beneficial in one adolescent boy with severe TS and comorbid OCD and anxiety but had little therapeutic benefit in another patient with similar tic severity, but lacking comorbid psychiatric conditions , 7. AckeIn a larger prospective cohort study, Porta and colleagues documented improvement in tic symptoms, as well as improvement in neuropsychiatric symptoms without cognitive decline in a 24-month followup of 15/18 patients who underwent bilateral thalamic stimulation [Given the ongoing need for awareness of cognitive and psychiatric outcomes in adolescent patients who have undergone DBS treatment, we specifically focused on the neurocognitive and psychosocial outcomes in an adolescent male who had received DBS for severe refractory TS . This ca"}
{"text": "Acute variceal bleeding continues to be associated with significant mortality. Current standard of care combines hemodynamic stabilization, antibiotic prophylaxis, pharmacological agents, and endoscopic treatment. Rescue therapies using balloon tamponade or transjugular intrahepatic portosystemic shunt are implemented when first-line therapy fails. Rescue therapies have many limitations and are contraindicated in some cases. Placement of fully covered self-expandable metallic stent is a promising therapeutic technique that can be used to control bleeding in cases of refractory esophageal bleeding as an alternative to balloon tamponade. These stents can be left in place for as long as two weeks, allowing for improvement in liver function and institution of a more definitive treatment. Acute variceal bleeding continues to be associated with significant mortality. Recently published randomized controlled trials have shown that mortality from acute variceal bleeding has decreased over the past two decades from 42% to 15%, but this figure is still remarkably high [Balloon tamponade (BT) using Sengstaken-Blakemore tube used to be the primary therapy prior to the availability of endoscopic methods. Sengstaken-Blakemore tube, was first described in 1950 , is a muSurgical management for bleeding esophageal varices falls into two categories: shunt and nonshunt procedures. Nonshunt procedures include esophageal transection and gastroesophageal devascularization. Shunt procedure is classified into selective shunts such as splenorenal shunts, partial shunts such as calibrated small-diameter portacaval shunts, and nonselective shunts such as portacaval shunts. Surgical procedures are used less frequently in the era of advanced endoscopic therapy, TIPS, and liver transplant. However, surgical intervention remains an important and effective treatment modality in selected patients . Distal TIPS is an intrahepatic shunt that is placed using a percutaneous approach. It connects the hepatic vein and intrahepatic branch of portal vein using an expandable metallic stent with a diameter of 8 to 12\u2009mm. TIPS was introduced as an alternative to surgery in the 1990s and has replaced surgical shunts in most centers . CurrentThe previously listed limitations of the current rescue therapies have led to the continued search for other methods as rescue therapy for refractory esophageal variceal bleeding.Self-expandable metal stents (SEMSs) are increasingly used in treatment of esophageal obstruction, stricture, leak, perforation, and tracheoesophageal fistula . AnecdotThe initial pilot study by Hubmann et al. in 2006 reported the use of SEMS in 20 patients with massive ongoing esophageal variceal bleeding . All patHubmann et al. published their extended series of 39 patients with massive ongoing esophageal variceal bleeding despite prior use of endoscopic or pharmacological therapy . ResultsWright et al. reported their experience using the SX-Ella Danis stent in ten patients with variceal bleeding and contraindications to TIPS insertion or balloon tamponade . The patDech\u00eane et al. recently reported their experience using SEMS in 8 patients with refractory esophageal variceal bleeding events . One patStandard fully covered SEMSs have also been used successfully for the management of esophageal tears caused by Sengstaken-Blakemore tube or banding. These applications further confirm the important role of SEMS in the successful management of iatrogenic esophageal injuries , 26, 27.Limited data suggests that specially designed SEMS (SX-Ella Danis stent) can effectively stop refractory bleeding from esophageal varices . This stStent placement requires appropriate training and expertise. Gastric varices will not be adequately compressed by the stent and persistent variceal bleeding after stent placement should raise the suspicion for presence of bleeding gastric varices. Appropriate precautions to prevent aspiration are needed since the stent is positioned at the gastroesophageal junction. Distal stent migration into the stomach was observed frequently but was not associated with apparent complications. Stent-related compression of the left main bronchus was reported in one patient and was treated successfully with stent removal , 28. No Current rescue therapies for bleeding esophageal varices are effective in stopping the bleeding in the majority of patients . In some"}
{"text": "Pragmatic trials of treatment pathways can require patient awareness of treatment allocation in order to better represent clinical reality, for example when concordance with a treatment has an important effect on outcome. Conversely, masking of treating clinicians to allocation group can be impossible when full clinical assessment requires knowledge of the current treatments, resources do not permit separate teams for treatment and assessment or when such duplication of clinician contact might affect an outcome such as patient experience.The LiGHT trial is a 718 subject multi-centre 6-year NIHR-funded study of two treatment pathways for glaucoma with outcome measures of health related quality of life and cost effectiveness. We aimed to minimise variation in aspects of clinical behaviour that might introduce bias by affecting either of these outcomes.Custom-written decision support software permits real-time decision-making using analysis of multiple clinical measures made by masked observers: optic disc analysis, visual field assessment and intra-ocular pressure measurements. Treatment targets are objectively defined according to disease severity criteria. Target attainment accounts for known measurement uncertainties.A treatment algorithm based on robust, published criteria determines clinical decisions that influence cost or patient experience .Where objective criteria for clinical decisions exist, it is possible to balance the competing demands of reducing bias with protocol-driven escalation criteria with a pragmatic \u2018real-world\u2019 approach to therapeutic choices permitting variation in clinical practice, in a manner acceptable to clinicians recruiting into an unmasked pragmatic trial."}
{"text": "Picea rubens) populations at high elevation sites in Southern Appalachians to anthropogenic sulfate depositions. Red spruce seedlings are more sensitive to drought and cold stresses elicited by exposure to anthropogenic sulphate air pollution, than old trees. Genetic variation in seedlings and young trees was significantly reduced in heavily polluted stands. Several candidate genes involved in cold acclimation and calcium metabolism demonstrated signatures of selection corresponding with sulfate pollution levels. SNP allele frequencies at one gene involved in calcium metabolism demonstrated directional selection in response to anthropogenic sulfate deposition in red spruce growing at severely polluted high elevation sites, which corresponds well with the putative role of this gene in adaptation to acidification stress. Unlike range-wide experimental designs (e.g. the popular FST outlier test) and nucleotide diversity-based association studies, our within-population testing approach disentangled the confounding effects of geographic variation and demography from the genetic effects of recent selection.Rapid environmental changes, such as anthropogenic air pollution, can create significant evolutionary pressures on populations, species and ecosystems. Evolutionary processes occurring in natural populations at very short time scales, especially in response to human-induced environmental changes, are not well understood. Confounding effects of geographic variation and demography cannot be easily separated from signatures of recent selection in natural populations. We investigated the genetic response of declining red spruce ("}
{"text": "The goal of enhanced nutrition in critically ill patients is to improve outcome by reducing lean tissue wasting. However, such effect has not been proven. This study aimed to assess the effect of early administration of parenteral nutrition (PN) on muscle volume and composition by repeated quantitative computer tomography (qCT).We performed a preplanned substudy of a randomized controlled trial (EPaNIC) that compared early initiation of PN when enteral nutrition was insufficient (early PN) with tolerating a pronounced nutritional deficit for 1 week in the ICU (late PN) [Critical illness evoked substantial loss of femoral muscle volume in 1 week, irrespective of the nutritional regimen. Early PN reduced the quality of the muscle tissue, as reflected by the attenuation, revealing increased intramuscular water/lipid content. Early PN also increased the volume of adipose tissue islets within the femoral muscle compartment. These changes in skeletal muscle integrity correlated with caloric intake. In the abdominal muscle compartments, changes were similar, albeit smaller. Femoral and abdominal subcutaneous adipose tissue compartments were unaffected by disease and nutritional strategy.Early PN did not prevent the pronounced wasting of skeletal muscle observed over the first week of critical illness. Moreover, early PN increased the amount of adipose tissue within the muscle compartments."}
{"text": "Varanus komodoensis). The growth of 400 individual Komodo dragons was measured in a capture-mark-recapture study at ten sites on four islands in eastern Indonesia, from 2002 to 2010. Generalized Additive Mixed Models (GAMMs) and information-theoretic methods were used to examine how growth rates varied with size, age and sex, and across and within islands in relation to site-specific prey availability, lizard population density and inbreeding coefficients. Growth trajectories differed significantly with size and between sexes, indicating different energy allocation tactics and overall costs associated with reproduction. This leads to disparities in maximum body sizes and longevity. Spatial variation in growth was strongly supported by a curvilinear density-dependent growth model with highest growth rates occurring at intermediate population densities. Sex-specific trade-offs in growth underpin key differences in Komodo dragon life-history including evidence for high costs of reproduction in females. Further, inverse density-dependent growth may have profound effects on individual and population level processes that influence the demography of this species.Somatic growth patterns represent a major component of organismal fitness and may vary among sexes and populations due to genetic and environmental processes leading to profound differences in life-history and demography. This study considered the ontogenic, sex-specific and spatial dynamics of somatic growth patterns in ten populations of the world\u2019s largest lizard the Komodo dragon ( Somatic growth patterns represent a major component of an organism\u2019s life-history Sex-specific growth variation must occur to result in sexual size dimorphism (SSD), reflecting different tactics and requirements for energy acquisition and investment between maximum female and male body size Across a species distribution growth rates influencing life history and demography can vary considerably due to an interaction between genetic and environmental regulation Several issues have hindered understanding of the causes of individual growth rate variation in animals, and particularly ectotherms that experience indeterminant growth. First, most growth rate models do not accommodate potential polyphasic growth Varanus komodoensis; 300 cm snout-vent-length and 87 kg body mass). Data were collected from marked individuals from 2002\u20132010, with the aim to evaluate individual, sex-specific and spatial patterns in somatic growth. It was assumed that several energy allocation trade-offs may alter investment in growth in Komodo dragons during life-history changes including distinct transitions in habitat use, sex related growth differences pre- and post-maturation, and aging, that may occur in long-lived apex predators such as this, which have very low mortality due to predation . Each of these phenomena could result in polyphasic growth trajectories involving growth \u201clags\u201d and \u201cspurts\u201d across ontogeny. As this sort of pattern may not be possible to model with the use of standard growth models such as the von Bertalanffy growth function in this species was addressed. Such pronounced SSD must entail different tactics and requirements for energy acquisition and investment The final aim considered spatial variation; looking at differences in ecological, demographic and genetic factors on the islands that may account for differences in growth patterns among sites. Dragon body size varies dramatically between islands, with the presence of dwarf and giant forms in part suggesting spatial variation in growth. For Komodo dragons potential variation in growth could be mediated by differences in prey availability Rusa timorensis), feral pig (Sus scrofa) and water buffalo The Komodo dragon is endemic to five islands in eastern Indonesia, with four island populations in Komodo National Park and several fragmented populations on Flores 2 Komodo Island); Loh Baru (Lba), Loh Buaya (Lbu), Loh Dasami (Lda) and Loh Tongker (Lto) ; and one site on each of the islands of Gili Motang and Nusa Kode . Only two of 1062 marked Komodo dragons moved between any of the sites during the course of the study and hence the ten sites are considered discrete closed populations.To evaluate growth patterns in Komodo dragons, a capture-mark-recapture (CMR) study was undertaken at ten sites on four islands in Komodo National Park , eastern Indonesia , during Dragons were captured in a trapping grid at each site using aluminium box traps and noose poles, and were uniquely marked with passive integrated transponder (PIT) tags . Further details of the capture program are outlined elsewhere Absolute growth rates were calculated from growth records for each individual sampled using snout-vent-length as the dependent variable, and included negative and zero growth rates because animals can shrink in size due to senescence or in response to extreme resource limitation A two-stage statistical modelling approach was used to model somatic growth Size-specific growth rates were modelled as a function of snout-vent-length using a GAMM t- and F-ratio tests The mgcv package Size frequency distributions were constructed for all male and female lizards using the SVL obtained at the first capture event. Using sex-specific age-at-size equations we predicted the mean age for each individual at first capture. To evaluate if male and female size and predicted age distributions differed significantly we performed Kolmogorov-Smirnov tests in program R is) (see methods below for determination of site estimates for each covariate). The four candidate models, including a null model, were fitted again using a GAMM approach in the mgcv package w), considering the strength of evidence that the candidate model is the best model for the data Four competing models were conceived involving three putative covariates; population density, prey availability, and level of inbreeding Faecal counts were conducted annually from 2003\u20132010 (i.e. late dry season) at each site, with faeces of Timor deer and water buffalo counted within circular plots on 150 m transects in each site. Hand-held GPS units were used to locate transect line starting points, and ungulate faeces were counted within 30 sample plots placed at 5 m intervals along each transect. Between 20 and 41 transects were randomly positioned and orientated at each site, providing a total of 308 transects with a total length of 45.50 km. Faecal counts of both species show positive relationships with actual density estimates derived from distance sampling V. komodoensis genetic microsatellite data sampled from eight sites is) were calculated using Genetix 4.01 is values to a frequency distribution of fixation indices obtained after 10,000 permutations of alleles.Estimates of site-specific inbreeding coefficients were obtained predominantly from previously analysed This Research was authorized under successive collaborative research memorandums of understanding (MOU), first (2002\u20132007) between Zoological Society of San Diego, The Nature Conservancy and the Indonesian Department of Forest Protection and Nature Conservation (PHKA), and second (2008\u20132015) under MOUs between the Komodo Survival Program and PHKA. Animal experimental ethics committee approval was obtained from the University of Melbourne (under Permit 0911162.1).Growth measurements were obtained from 400 individually marked Komodo dragons refer to capturedThe estimated size-specific growth function for Komodo dragons was polyphasic with highest growth rate at the juvenile stage , and incComparing the estimated size-specific growth curves of both sexes however,The estimated size-at-age growth curves indicate that males and females are of similar size until \u223c7 years , after wThe estimated age-specific growth function indicateMale and female lizards exhibited significantly different frequency distributions in body size with males exhibiting substantially larger body sizes than females exhibited: distinct sex-based differences in growth trajectories, suggesting altered energy allocation tactics with different life-stages; and spatial variability in growth rates, due to population density-dependent processes.Somatic growth dynamics of individuals and populations can have profound consequences for fitness, life-history and demography In species with indeterminate growth, where females have higher energy costs for reproduction, they must allocate nearly all energy investment from growth to reproduction after maturity ; whereas males may typically invest considerably less to ensure reproductive success increases with body size The largest females tend to be in poor body condition due to extended periods of fasting whilst nest-guarding. Males in comparison appear to live longer presumably aided by lower reproductive costs and an absence of predation conferring higher male survival. A consequence of these sex related differences appears to be large differences in the age of maturity and also maximum longevity estimates . Female Significant variation in mean growth rates was evident among sites and islands . SupportWith size-specific growth variation among sites and islands, it would be worthwhile to detect specific habitats with distinct environmental or genetic differences in dragon growth trajectories that underpin life-history traits such as maximum body size, longevity and vital rates. Vast geographic variation in phenotypic traits are recognised in various intra- and inter-specific studies of sea turtles Our study shows that across ontogeny somatic growth of Komodo dragons is polyphasic in males, yet not in females, as a consequence of differences in energy allocation tactics regarding the onset of reproduction, which also result in an extreme contrast in longevity between sexes. This vast difference in life-span likely has a significant effect on population sex ratios, which in turn could be increasing sexual size dimorphism (SSD) within this species. In future it would be interesting to compare how SSD may vary between populations in regards to demographics and environmental quality Figure S1Mean growth year index as a predictor for growth rate in Komodo dragons. Year index was one covariate in the fitted generalized additive mixed model (GAMM). Dotted lines represent the 95% confidence interval for the fitted values.(TIF)Click here for additional data file.Figure S2Spatial variation in growth rates in Komodo dragons. Mean growth rates (cm SVL/yr) for each site indicate spatial variation in growth among sites and islands. Error bars are standard errors of site mean growth rates.(TIF)Click here for additional data file.Methods S1(DOCX)Click here for additional data file.Methods S2Methods & Results.(DOCX)Click here for additional data file.Table S1(DOCX)Click here for additional data file.Table S2(DOCX)Click here for additional data file."}
{"text": "Dear Editor,The study named \u201cThe role of myocardial perfusion gated SPECT study in women with coronary artery disease\u201d reveals some current and important issues in diagnosing myocardial ischemia in women . BecauseOn the other hand the evaluation criterion for diagnosing ischemia seems controversial in the study. The question is that: \u201cDo the left ventricular (LV) wall motion abnormality and decreased systolic thickening at the segment with reduced perfusion in gated SPECT study necessarily show true ischemia as it is expressed in the study?This approach considers that wall motion abnormality and perfusion defects occur exactly at the same time in CAD stages, but as it is known, wall motion abnormalities follow quite a bit later after the perfusion defects appear. Myocardial hypoperfusion is first seen in ischemic cascade, and followed by decrease in metabolic activity, relaxation impairment (diastolic dysfunction), reduction in contractility (systolic dysfunction), global LV dysfunction, ECG changes and angina pectoris, respectively . So, theMore importantly, because the imaging begins 30-60 minutes after the radiopharmaceutical injection, stress\u2013gated images with Tc-99m MIBI show stress perfusion at the time of injection, but LV function at the time of acquisition. Snapper et al. demonstrated that the combination of a perfusion defect with normal wall motion and thickening in the same segment on stress-gated MIBI images was associated with a high positive predictive value (96%) for detecting ischemia. They concluded that the diagnosis of ischemia could be made confidently in patients with normal wall thickening in a segment with perfusion defect. The lack of wall thickening was found less specific, because only 40% of the cases with perfusion defects and wall motion abnormalities showed reversibility on rest perfusion imaging . Thus, tFinally, the criterion mentioned in the study could be entirely true and supporting if all the subjects had been shown to have reversible defect (ischemia), but some patients are reported to have myocardial infarction. So the criterion might include myocardial scar in patients with fix defect (particularly when the presence of metabolic activation on the defect related with hibernation was excluded). In the routine evaluation of gated SPECT studies, wall motion abnormality and/or systolic thickening at the same segment with fixed defect primarily indicates myocardial scar. So, the inclusion criterion that the authors used in the study constitutes a great limitation for drawing true conclusions about ischemia and/or infarct without making some comparisons between post-stress and rest end-systolic and end-diastolic volumes or measuring LVEF differences together with the wall motion abnormalities.The evaluation criteria to differentiate ischemia, infarct and soft tissue attenuation artifacts in stress-rest gated SPECT imaging may be simply summarized as below:1. Normal perfusion with no wall motion abnormality or TID: Normal2. Normal perfusion with wall motion abnormality or TID: Stunning (and/or multivessel disease?).3. Reversible ischemia with no wall motion abnormality, TID or reduced LVEF in stress-gated images: Ischemia.4. Reversible ischemia with wall motion abnormality, TID or reduced LVEF in stress-gated images: Severe ischemia with increased cardiac event rate.5. Fixed defect with normal wall motion or wall thickening: Soft tissue attenuation artifact.6. Fixed defect with wall motion or wall thickening abnormality: Myocardial scar."}
{"text": "Cryopreservation and transplantation of ovarian tissue is one option for re-establishing ovarian function, but optimal conditions for graft sustainment and follicular survival are still considered experimental. The present study aims to analyze the effect of FSH treatment on the resting follicle pool in fresh and cryopreserved primate ovarian tissues following xenografting.Ovarian tissues from adult marmosets were grafted freshly or following cryopreservation to ovarectomized nude mice treated with FSH 25 IU twice daily post transplantation or left untreated as controls. Grafts were retrieved 2 or 4 weeks after transplantation to evaluate the number and morphological appearance of follicles.Early start of FSH treatment within 1 week following transplantation partly prevents primordial follicle loss in fresh and frozen-thawed tissues, whereas after a 3 weeks time interval this effect is present only in fresh tissues. A similar positive effect of early, but not later FSH treatment on primary follicles is seen in fresh tissues compared to only marginal effects in frozen-thawed tissues. The percentage of morphologically normal follicles is generally increased in FSH treated tissues, whereas the percentage of primary follicles over all primordial and primary follicles is increased by FSH only in freshly-grafted tissues.FSH treatment alleviates depletion of the resting follicle pool and promotes normal follicular morphology both in freshly and frozen-thawed grafted tissues. In previously cryopreserved tissues, applying to most of the tissues intended for clinical use in fertility preservation attempts, its positive effect on primordial follicle numbers and potential graft sustainment is dependent on an early start of treatment within one week of transplantation. Increasing cancer survival rates and awareness of fertility as a quality of life issue in long-term cancer survivors have fuelled the growing demand for fertility preservation in recent years . In femain vitro study has confirmed equal effectiveness of human recombinant FSH compared to marmoset FSH on the marmoset FSH receptor . Grafting duration has no influence on mean primordial follicle numbers compared to untreated tissues but not at 4 weeks and frozen-thawed (29.9+/\u22122.9%) ovarian tissues. In freshly grafted tissues, these proportions decrease significantly after transplantation and then remain stable over time , but not FSH-treated tissues (p=0.411; Figure\u2009The size of the resting follicle pool determines the ovarian reserve of an individual and correlates with graft sustainment after restoration of fertility by ovarian tissue cryopreservation and transplantation. Assessment of ovarian reserve following ovarian tissue transplantation is challenging when using established markers and indicates high variability between patients . Besidesnd week of transplantation. In freshly but not in frozen-thawed grafted tissues, a positive effect of FSH treatment on primordial follicle number was also observed if the start of treatment was postponed to 3 weeks post transplantation. As we have previously documented in the marmoset [in vitro co-culture system had previously been described for other non-human primates [Enhanced follicular depletion through FSH effects during ovarian stimulation has anecdotally been reported in the human , but conmarmoset , and othmarmoset ,33,34, cprimates . In humaprimates , thus enprimates , and forprimates , suggestWhen started after a prolonged grafting period of frozen tissues, FSH negatively influences primordial follicle numbers that are already low and most likely at this point reflect manifestation of preceding tissue damages due to cryopreservation. Since primary follicle numbers are increased in these tissues, the reduction in the primordial follicle pool may additionally mirror the beginning of follicular recruitment becoming apparent in already low primordial follicle numbers. However in fresh tissues, baseline values of follicle numbers are higher also after a prolonged grafting period, and FSH treatment following early or at a later point in time after transplantation prevents primordial follicle loss. This is in agreement with viability studies on fresh and frozen ovarian tissue resulting in significantly reduced viability when applying a slow-freezing protocol .per se on follicle pool dynamics and primary follicle activation in adult and prepubertal ovarian tissues [Proportional analysis of primary and primordial follicle number can indicate initiation of follicular growth, and for xenografted human ovarian tissue the influence of cryopreservation and timi tissues . This co tissues . As the FSH treatment alleviates depletion of the resting follicle pool and promotes normal follicular morphology both in freshly and frozen-thawed grafted tissues. In previously cryopreserved tissues, applying to most of the tissues intended for clinical use in fertility preservation attempts, its positive effect on primordial follicle numbers and potential graft sustainment is dependent on an early start of treatment within one week of transplantation. Whereas in fresh tissues FSH treatment following xenografting results in a higher percentage of primary over all un-advanced follicles, this appears to be largely independent of FSH in frozen-thawed tissues.All authors declare that they have no competing interests.VVS and BS designed the study, analyzed and interpreted the results and drafted the manuscript. RC performed the experiments and analyzed the results. EN and LK participated in the study design, helped in the acquisition of funding and critically reviewed the manuscript. RO helped to perform statistical analysis and with the drafting of the manuscript. All authors read and approved the final manuscript."}
{"text": "Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disorder, while Becker muscular dystrophy (BMD) is milder muscle disease . Both arThe exon skipping approach uses antisense oligonucleotides (AONs) to induce skipping of targeted exons during pre-mRNA splicing, with the aim of reading frame restoration, converting of the severe DMD into the milder BMD phenotype . This apAfter promising results in cultured cells and animal models where AON treatment allowed in dystrophin restoration (reviewed in ), a firsTowards systemic application, studies in animal models revealed that dystrophic muscles facilitated uptake of 2OMePS AONs and that subcutaneous delivery was feasible . In a suIn parallel, preclinical studies to further optimise treatment regimens are in progress as well as clinical trials for additional exons for exon 44 skipping . Trials are planned for exon 45 and 53 skipping .The mutation specificity of the approach poses challenges to drug development regulations. A concerted effort of academic researchers, industry, regulators and patients is needed to adapt regulations to enable application of these personalised medicine approaches to rare diseases."}
{"text": "Olfactory dysfunction develops in many neurodegenerative diseases, and is an early feature of the most common neurodegenerative disorder, Alzheimer's disease (AD).Here we compared olfactory function prospectively in cohorts of patents with PCA and typical AD (tAD). Neuroanatomical associations of odour identification were assessed using voxel-based morphometry (VBM). We hypothesised that PCA would be associated with olfactory impairment qualitatively similar to tAD, but less severe ; and that deficits of odour identification in both syndromes correlate with grey matter loss in anteromedial temporal and inferior frontal lobes.6\u201310Fifteen patients fulfilling consensus criteria for PCA,supplementary table S1). Further details about the behavioural assessments are in online supplementary material.All subjects had a comprehensive general neuropsychological assessment which corroborated the clinical impression in both disease groups (see online supplementary table S2) before identifying it; and target-foil choices were name-picture combinations rather than odour names alone, to maximise available response cues. Group differences were assessed using analysis of variance (ANOVA) or \u03c72 tests (Stata V.12.1), adjusting for cognitive severity, verbal processing measures, age and gender.Olfactory processing was assessed using the 40-item, four-alternative-forced-choice University of Pennsylvania Smell Identification Test (UPSIT: British version).http://www.fil.ion.ucl.ac.uk/spm) following previously described procedures . Linear regression was used to examine voxel-wise associations between regional grey matter volume and odour identification performance (age-normed and gender-normed percentile score) across the combined patient cohort, within the PCA subgroup, and between syndromic subgroups, incorporating syndromic group, mini-mental state examination (MMSE) score and total intracranial volume as covariates. Statistical parametric maps were assessed thresholded over the whole brain volume and after multiple-comparisons correction over small volumes of interest specified in our prior anatomical hypotheses.Twelve patients with PCA and eight patients with tAD had T1-weighted volumetric magnetic resonance (MR) brain images acquired on a 3.0T Siemens Trio scanner. VBM was performed using SPM8 . Based on published UPSIT norms,supplementary table S1). An error analysis of individual odour items in the identification test revealed a qualitatively similar profile of errors across all groups (see online supplementary figure S2).For both patient groups, mean odour categorisation and identification raw scores were significantly lower than the HC group . Across the combined patient cohort, performance on the odour identification task was positively associated with regional grey matter volume in right entorhinal cortex and parahippocampal gyrus . At a more lenient threshold (p<0.001 uncorrected over the whole brain volume), additional associations were present in more distributed, predominantly right-sided cerebral areas, including hippocampus, posterior inferior temporal gyrus/sulcus, temporo-parieto-occipital junction and premotor cortex (see online supplementary table S3). Similar grey matter associations of odour identification performance were identified for the PCA subgroup alone . Direct comparison between the PCA and tAD subgroups revealed no significant between-group differences in regional grey matter correlations of olfactory performance.Statistical parametric maps of significant regional grey matter associations of odour identification performance are displayed in Here we have demonstrated deficits of odour identification and categorisation in patients with PCA relative to HCs. A similar proportion around 30%) of patients with PCA and tAD in this study had an absolute deficit of odour identification referenced to published age and gender norms and taking account of associated cognitive impairment. Olfactory impairment was similar quantitatively and qualitatively in the PCA and tAD groups. To the extent that PCA manifests underlying AD, the findings imply that olfactory impairment is a hallmark of AD pathology. It is noteworthy that only a minority of patients in both phenotypical groups here reported olfactory symptoms, suggesting that in many cases olfactory impairment is \u2018subclinical\u2019. Mean corrected odour identification scores were higher than categorisation scores in the HC and PCA groups: this unexpected finding might hold clues to the cognitive organisation of olfactory knowledge or the cognitive strategies engaged by these tests, and would warrant further study in larger populations. Odour identification tasks tend to be cognitively demanding and therefore potentially susceptible to executive and attentional deficits that accompany AD.0% of pat13The deficit of odour identification identified here was associated with regional grey matter volume in a cerebral network focussed on the right anteromedial temporal lobe. The most robust neuroanatomical associations occurred in parahippocampal gyrus and entorhinal cortex: areas linked to odour identification in healthy human subjects.This study has several limitations that suggest directions for future work. We did not assess perceptual encoding of odours: it will be important to compare associative and perceptual olfactory functions directly, to assess the extent to which these different factors contribute to olfactory impairment in AD. The patient groups studied here were relatively small: there is a need to extend the work to larger patient cohorts spanning other AD phenotypes and in direct comparison with other neurodegenerative pathologies."}
{"text": "After publication of our work , we notiThe authors declare no competing interests.JL and DM designed research; JL carried out phylogenetic analyses, and JL and DM wrote the manuscript. Both authors read and approved the final version."}
{"text": "Microscopic Colitis (MC) is characterized by chronic watery diarrhea, grossly normal appearing colonic mucosa during conventional white light endoscopy, and biopsy showing microscopic inflammation. We report a case of collagenous colitis with gross endoscopic findings. A 71-year-old female with past medical history of coronary artery disease, carotid artery disease, hypertension, and diabetes mellitus type 2 was being evaluated for recurrent intermittent diarrhea. Patient denied any abdominal pain, weight loss, or any blood in stool. Patient was not on any medications and lab work was within normal limits. Colonoscopy was required to further evaluate patient's diarrhea. Colonoscopy revealed multiple scattered segments throughout the colon with increased nodularity and loss of vascular markings in the hepatic flexure, descending colon and cecum Figures . These fMicroscopic examination showed lymphocytic colitis with marked thickening of the superficial collagen table consistent with collagenous colitis. The submucosal collagen was dense and paucicellular with several entrapped lymphocytes and capillaries (red arrow). The lamina propria displays an increase in eosinophils, plasma cells, and lymphocytes (black arrow) .Microscopic Colitis (MC) is characterized by chronic watery diarrhea, grossly normal appearing colonic mucosa during conventional white light endoscopy, and biopsy showing microscopic inflammation. It accounts for 4%\u201313% of patients evaluated for chronic diarrhea and divided into lymphocytic and collagenous colitis . CertainAlthough identical clinically, both types of colitis have distinct microscopic findings. Lymphocytic colitis is characterized by intraepithelial lymphocytosis while collagenous colitis is diagnosed by thickening of subepithelial collagen layer of more than 10 micrometer [By definition colonic mucosa has a normal appearance in MC. Yet distinct endoscopic findings, particularly for collagenous colitis, have been described in the literature. These findings include alteration of mucosal vascular pattern, mucosal abnormalities such as red spots, increased mucosal nodularity, or textural alteration, and pseudomembranes . Recent advance in endoscopy may enhance the ability to detect MC. A newly developed post processing light filters such as i-Scan helps to enhance the visualization of mucosal pattern and vascular architecture. Chromoendoscopy using indigocarmine dye sprays may show a mosaic pattern of mucosa in lymphocytic colitis and a nodular, grooved pattern in collagenous colitis . These nMicroscopic Colitis is traditionally known to have normal colonic mucosa on endoscopy. Recent advance in endoscopic techniques has shown that various mucosal abnormalities such as alteration of mucosal vascular pattern and increased mucosal nodularity are associated with MC. These newer techniques will allow us to get targeted biopsy, which will increase the yield of endoscopic diagnosis of MC."}
{"text": "Borrelia burgdorferi infection. Little has been published in the medical literature about patients with chronic Lyme disease or their relationships with healthcare providers. The objective of this study was to gain insights into the health beliefs and experiences of patients with chronic Lyme disease.Chronic Lyme disease is a term that describes a constellation of persistent symptoms in patients who may or may not have serologic evidence of This was a qualitative, descriptive study in which face-to-face in-depth interviews were conducted with patients who were diagnosed with or self-identify as having chronic Lyme disease. Patients were recruited through Connecticut-based Lyme disease mailing lists and support groups. A coding structure was developed using an iterative process. Transcribed interviews were coded using Atlas.ti software and analyzed for emergent topics and themes. Interviews were conducted until thematic saturation was achieved.A total of 12 interviews were conducted. Four major themes emerged. Patients reported: (1) diminished health status associated with chronic Lyme disease; (2) concerns about persistence of symptoms ; (3) two divergent types of physician-patient relationships ; and (4) seeking and receiving unconventional care .Our findings show that patients report a marked decrease in health status associated with chronic Lyme disease and are often unsatisfied with care in conventional settings. Negative experiences with providers were associated with reports of dismissive, patronizing, or condescending attitudes. Positive experiences were associated with providers reported to be attentive, optimistic, and supportive. Patient-centered approaches that acknowledge suffering and focus on continuity of care and symptomatic relief may result in increased patient satisfaction."}
{"text": "Increasing the use of pharmacotherapies for alcohol dependence has the potential to improve patient outcomes and reduce health-care costs by reducing hospital admissions. This randomized controlled trial (RCT) evaluated the cost-effectiveness of tailored mailed feedback on general practitioner (GP) prescribing for alcohol dependence and alcohol-related hospital admissions. General practitioners (N = 115) in 10 communities randomized to the experimental arm of the Alcohol Action in Rural Communities (AARC) project received tailored mailed feedback on their prescribing of acamprosate and naltrexone. Segmented regression analysis examined the impact of the intervention relative to GPs\u2019 prescribing and inpatient hospital admissions for alcohol dependence in those communities. Incremental cost-effectiveness ratios were estimated to compare costs per additional prescription written and costs per inpatient admission averted. Trend analysis showed GPs significantly increased their prescribing of acamprosate and significantly decreased their prescribing of naltrexone . Rates of alcohol-related inpatient admissions for alcohol dependence decreased significantly in the experimental group compared with the control group . Similar to evidence showing SBI can improve patient outcomes, this study showed mailed tailored feedback to GPs achieved cost-effective increases in their prescribing of acamprosate, with a subsequent and plausibly causal reduction in inpatient hospital admissions for alcohol dependence. Demonstrating the capacity of brief intervention in primary-care settings to reduce demand for tertiary care services appears to be a promising direction for the SBI field. A large-scale RCT of the cost benefit of tailored feedback to GPs appears warranted."}
{"text": "We used ecologic niche modeling of outbreaks and sporadic cases of filovirus-associated hemorrhagic fever (HF) to provide a large-scale perspective on the geographic and ecologic distributions of Ebola and Marburg viruses. We predicted that filovirus would occur across the Afrotropics: Ebola HF in the humid rain forests of central and western Africa, and Marburg HF in the drier and more open areas of central and eastern Africa. Most of the predicted geographic extent of Ebola HF has been observed; Marburg HF has the potential to occur farther south and east. Ecologic conditions appropriate for Ebola HF are also present in Southeast Asia and the Philippines, where Ebola Reston is hypothesized to be distributed. This first large-scale ecologic analysis provides a framework for a more informed search for taxa that could constitute the natural reservoir for this virus family. Mononegavirales, family Filoviridae) are unknown potential reservoirs, including bats, rodents, arthropods, and plants to the nearest 0.001\u00b0. Although assigned geographic coordinates may not fix the exposure point precisely, they represent our best guess as to its position and are likely to be representative of the coarse-scale ecologic conditions. Distributional data for filovirus-associated HF occurrences in hominids were accumulated from the literature . Occurrehttp://www.lifemapper.org/desktopgarp/). In general, GARP focuses on modeling ecologic niches (the conjunction of ecologic conditions wherein a species can maintain populations without immigration) Ecologic niches and potential geographic distributions were modeled by using the Genetic Algorithm for Rule-set Prediction (GARP) (Occurrence points are divided evenly into training (for model building) and test datasets. GARP works in an iterative process of rule selection, evaluation, testing, and incorporation or rejection: a method is chosen from a set of possibilities and applied to the training data to develop or evolve a rule. Predictive accuracy is evaluated on the basis of the test data. Rules may evolve in ways that mimic DNA evolution . Change in predictive accuracy between iterations is used to evaluate whether particular rules should be incorporated into the model; the algorithm runs 1,000 iterations or until convergence. Model quality was evaluated through independent test dataset reserved prior to modeling; a chi-square test was used to compare observed success in predicting the distribution of test points with that expected under a random model .http://edcdaac.usgs.gov/gtopo30/hydro/), and climate characteristics, including daily temperature range; mean annual precipitation; maximum, minimum, and mean annual temperatures; solar radiation; frost days; wet days; and vapor pressure . These coverages are worldwide and provide a consistent view of ecologic variation across regions studied. GARP\u2019s predictive ability has been tested under diverse circumstances . The resulting dataset represents unique combinations of environments and predictions; its attributes table provides the model prediction for all environmental combinations to permit visualization of ecologic variation. We also compared ecologic conditions inside and outside of the modeled Ebola HF distribution within 11 regularly spaced circular windows (radius 50 km); comparisons were summarized through Mann-Whitney U-statistics, permitting a nonparametric visualization of the strength of association of each ecologic dimension with the range limit.-7). Although subsequent modeling was done without subsetting to maximize occurrence data, these preliminary results nonetheless indicated excellent predictivity of our distributional hypoptheses. The geographic distribution of filovirus disease spreads generally across the humid Afrotropics A. OutlieFiloviridae in general , a complementary distributional area was predicted D. Marbur Sequential omission of Ebola virus species from analyses provided a view of ecologic similarity of species Inspection of niche models of Ebola HF occurrences (Marburg HF excluded) in ecologic space provided Distributional limits are complex results of multiple causal agents. A species is seldom limited on all sides by a single factor; rather, distributional limits are the combined result of many such factors. Inspection of the ecologic dimensions coincident with modeled geographic limits of Ebola HF occurrences showed s Given the mysterious origin of Ebola Reston virus A. ProjecThe ecologic niche characteristics reconstructed for filovirus species disease outbreaks coincided closely with phylogenetic patterns in the group , GARP predictions will be overly large. Jackknife manipulations (systematic omission of ecologic dimensions to assess sensitivity to coverage density) can, to some degree, help in assessing sensitivity to coverage completeness Detailed understanding of the geography and ecology of filovirus HF outbreaks represents an underexplored avenue of investigation regarding natural transmission cycles of filoviruses. We assembled available information regarding filovirus HF outbreaks and used various analytical tools to arrive at a detailed understanding of geography and ecology of filovirus disease occurrences. Consequently, we can now assemble criteria by which potential reservoir taxa might be judged. If one assumes a fair degree of host specificity in this host-parasite system, patterns of codistribution and cophylogeny can be expected. Hence, criteria include the following: 1) African Ebola virus reservoirs would be distributed principally in evergreen broadleaf forest; 2) the main focus of the geographic distribution of the reservoir(s) would be in the Congo Basin; 3) a disjunct distributional area would be present in West Africa; 4) a related taxon in eastern Africa would range in more arid habitats; 5) the reservoir would belong to a clade more broadly distributed across Africa and Southeast Asia. Assessment of potential reservoir taxa by using these criteria has begun , with the idea of eventually testing hypotheses of host associations through ecologic niche comparison methods"}
{"text": "Most pathogenesis studies focus on pathogen virulence attributes that mediate host colonization, toxicity, or immune evasion. Some studies focus on how pathogens employ active mechanisms to acquire essential nutrients such as iron and vitamins from the host by producing siderophores or avidins. In order to prevent pathogen nutrient acquisition, host cells employ a process called nutritional immunity to sequester these nutrients, particularly iron, from invading pathogens How and where do intracellular pathogens obtain sufficient amounts of energy and nutrients to support their replication? Pathogens may either parasitize existing energy stores or manipulate the host cell to create usable energy and anabolic precursor metabolites. Several recent studies have identified the host AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) kinases as two important regulators of cellular metabolism whose activities are often altered during infection. However, the AMPK/mTOR pathway also regulates autophagy, which can destroy cytosolic pathogens. While the evasion of autophagy by pathogens is well appreciated, recent work suggests that both the AMPK/mTOR pathway and autophagy itself can provide intracellular metabolites that support intracellular pathogen replication.During times of limited nutrient availability, intracellular ATP levels fall, with a corresponding increase in AMP levels. Within eukaryotic cells the increased AMP\u2236ATP ratio induces AMPK activity, which in turn initiates a series of signaling events that stimulate energy and nutrient acquisition In order to achieve optimal levels of proliferation, many pathogens must manipulate activity of AMPK and mTOR. Interestingly, several viral pathogens have evolved strategies that allow for the induction of both AMPK and mTOR activity. For example, infection with human cytomegalovirus (HCMV) increases both AMPK and mTOR activity Simian virus 40 (SV40) infection also stimulates both AMPK and mTOR activity. SV40 small T antigen is both necessary and sufficient for AMPK activation Mycobacterium tuberculosis and Chlamydia trachomatis utilize fatty acids derived from lipid droplets Enveloped viruses require host lipids to generate the virion membrane. Activated mTOR stimulates fatty acid and lipid synthesis, and therefore could prove beneficial for virus assembly. In fact, host lipid metabolism is essential for the hepatitis C virus (HCV) life cycle and is highly regulated during infection AMPK activation also inhibits the replication of several arboviruses, including Rift Valley fever virus (RVFV) Leishmania donovani amastigotes (the parasitic form that grows inside macrophages) preferentially generate energy through fatty acid oxidation and amino acid catabolism L. donovani acquires fatty acids and amino acids from the infected host cell. Consistent with this finding, transcriptomic analysis of macrophages infected with the related parasite Leishmania major suggests that infected cells increase glucose transport, glycolysis, and starch degradation Leishmania alters host metabolic processes, a reasonable hypothesis is that intracellular Leishmania activates AMPK to benefit parasite replication. Activated AMPK could stimulate increased glucose utilization and autophagy, thus creating elevated levels of anabolic precursor pools for parasite growth. Parasite replication requires the Leishmania protein GP63, which cleaves and inactivates mTOR to reduce type I interferon production, thus AMPK activation could further benefit parasite replication by inhibiting mTOR It takes a lot of energy to make hundreds, thousands, or potentially millions of new parasites, bacteria, or viruses. It seems logical that intracellular pathogens that undergo significant intracellular growth would activate AMPK due to the energetic demands placed on the infected cell. Activation of AMPK could provide several benefits for intracellular pathogens. The increased glucose uptake, glycolysis, and fatty acid breakdown would increase available intracellular energy and nutrient pools needed for pathogen replication. For example, Francisella tularensis growth is impaired in autophagy-deficient host cells. Bacterial growth was restored in autophagy-deficient cells by supplying the infected cells with excess pyruvate or amino acids. Since F. tularensis replicates within the cytosol of host cells, our results suggest that intracellular F. tularensis uses autophagy to increase cytosolic nutrient pools that support bacterial growth F. tularensis avoids engulfment by classical autophagosomes Autophagy is an essential cellular process that recycles cellular constituents from macromolecular complexes under conditions of nutrient stress. As discussed above, autophagy is positively regulated by AMPK and negatively regulated by mTOR. However, autophagy also functions as a host defense mechanism that destroys intracellular pathogens through a process termed xenophagy. While generally viewed as detrimental for intracellular pathogens, some bacteria and viruses use autophagosomes as a replicative niche AMPK and mTOR are critical regulators of host cell metabolism making them logical targets for manipulation by invading pathogens. The energetic burden of the host cell to create hundreds or more pathogens should deplete cellular ATP levels, thus activating AMPK. AMPK induction stimulates host processes to produce energy and nutrients that the pathogen could then steal from the host. This idea suggests AMPK activation may be a common theme among infection by successful intracellular pathogens. On the other hand, mTOR signaling stimulates protein and lipid synthesis, which could be beneficial for many viral pathogens; whereas mTOR modulation is likely less important for free-living bacteria pathogens and parasites that supply their own biosynthetic and translation machinery. Identifying what nutrient sources are required for intracellular growth and how host metabolic signaling is manipulated by infection is being investigated in viral pathogenesis, yet remains poorly understood in bacterial and parasitic pathogenesis.Manipulating host metabolism is an attractive approach to controlling infection as targeting the host rather than the pathogen should considerably reduce the ability of pathogens to develop drug resistance. Several drugs already in clinical use target the AMPK or mTOR kinases to treat diseases such as cancer and diabetes. The studies described above suggest that these drugs may have additional uses in treating infections with intracellular pathogens. As our understanding of pathogen manipulation of host metabolism grows, it may also be possible to develop inhibitors of specific host metabolic pathways hijacked by intracellular pathogens. Identifying the essential nutrients required for intracellular pathogen proliferation and the host pathways manipulated to acquire these nutrients will be a significant step in understanding the requirements for viral, bacterial, and parasitic pathogenesis and identifying new targets for novel therapeutics."}
{"text": "Poecilia parae, a colour polymorphic fish, exhibit five distinct phenotypes: drab-coloured (immaculata), striped (parae), structural-coloured (blue) and carotenoid-based red and yellow morphs. Previous work indicates that immaculata males employ a sneaker strategy, whereas the red and yellow morphs exploit female preferences for carotenoid-based colours. Mating strategies favouring the maintenance of the other morphs remain to be determined. Here, we report the role of agonistic male-male interactions in influencing female mating preferences and male mating success, and in facilitating the evolution of AMSs.Intense competition for access to females can lead to males exploiting different components of sexual selection, and result in the evolution of alternative mating strategies (AMSs). Males of P. parae morphs during indirect and direct interactions with sexually receptive females. Two morphs, parae and yellow, use aggression to enhance their mating success by 1) directly monopolizing access to females, and 2) modifying female preferences after winning agonistic encounters. Conversely, we found that the success of the drab-coloured immaculata morph, which specializes in a sneak copulation strategy, relies in its ability to circumvent both male aggression and female choice when facing all but yellow males.Our study reveals variation in aggressiveness among Strong directional selection is expected to deplete genetic variation, yet many species show striking genetically-based polymorphisms. Most studies evoke frequency dependent selection to explain the persistence of such variation. Consistent with a growing body of evidence, our findings suggest that a complex form of balancing selection may alternatively explain the evolution and maintenance of AMSs in a colour polymorphic fish. In particular, this study demonstrates that intrasexual competition results in phenotypically distinct males exhibiting clear differences in their levels of aggression to exclude potential sexual rivals. By being dominant, the more aggressive males are able to circumvent female mating preferences for attractive males, whereas another male type incorporates subordinate behaviours that allow them to circumvent male aggression and female mating preferences. Together, these and previous results indicate that exploiting different aspects of social interactions may allow males to evolve distinct mating strategies and thus the long term maintenance of polymorphisms within populations. Intense sexual selection can lead to competing males evolving alternative ways to obtain fertilizations, thereby enhancing their reproductive success . In geneUta stansburiana), males have evolved AMSs and the relative fitness of each strategy fluctuates depending on the frequency of the competing strategies from one generation to the next )A and MB representing total proportion of time spent with male A or B, respectively, positive values of this index (MA - MB) would indicate a preference for male A and negative values a preference for male B. To determine whether there was a switch in female mating preferences after observing male-male interactions, we subtracted the post-male competition preference score from the pre-male competition preference score . We determined if females switched or enhanced their mate preferences between trials using a paired t-test. Preference scores were arcsine transformed to meet the assumptions of parametric tests into two categories: aggressions received and initiated. Both categories (aggressions received and initiated) were analysed using Kruskal-Wallis non-parametric ANOVAs. To determine which morphs were attacked less and attacked more, we ran multiple comparisons of mean ranks. We also performed Kruskal-Wallis non-parametric ANOVAs and multiple comparisons of mean ranks to analyse aggressions received and initiated during the open aquarium experiments. To compare whether there were differences in the number of attacks performed by males during direct and indirect interactions with females, we used a Mann-Whitney test. Finally, the difference in number of gained or lost copulations to the competitors was analysed with Wilcoxon matched pair tests. All data sets were tested for normality and analysed with STATISTICAJLHG conceived the study, carried out the experiments, analysed the results and drafted the manuscript in partial fulfilment of a doctoral degree at Syracuse University, New York (USA). JACU contributed to the study design, supervised the study, edited and revised the manuscript critically. Both authors have read and approved the final manuscript.This file includes: Table A1 with additional information of the standard body lengths (mm) of males used during the experiments. Table A2 presents a brief description of aggressive behaviours commonly displayed by males of Poecilia parae. Figure A1 presents a simplified view of the experimental settings.Click here for file"}
{"text": "In this article, we review studies of astrocytic-neuronal interactions and their effects on the activity of oxytocin (OXT) neurons within the magnocellular hypothalamo-neurohypophysial system. Previous work over several decades has shown that withdrawal of astrocyte processes increases OXT neuron excitability in the hypothalamic supraoptic nucleus (SON) during lactation. However, chronically disabling astrocyte withdrawal does not significantly affect the functioning of OXT neurons during suckling. Nevertheless, acute changes in a cytoskeletal element of astrocytes, glial fibrillary acidic protein (GFAP), occur in concert with changes in OXT neuronal activity during suckling. Here, we compare these changes in GFAP and related proteins with chronic changes that persist throughout lactation. During lactation, a decrease in GFAP levels accompanies retraction of astrocyte processes surrounding OXT neurons in the SON, resulting from high extracellular levels of OXT. During the initial stage of suckling, acute increases in OXT levels further strengthen this GFAP reduction and facilitate the retraction of astrocyte processes. This change, in turn, facilitates burst discharges of OXT neurons and leads to a transient increase in excitatory neurochemicals. This transient neurochemical surge acts to reverse GFAP expression and results in postburst inhibition of OXT neurons. The acute changes in astrocyte GFAP levels seen during suckling likely recur periodically, accompanied by rhythmic changes in glutamate metabolism, water transport, gliotransmitter release, and spatial relationships between astrocytes and OXT neurons. In the neurohypophysis, astrocyte retraction and reversal with accompanying GFAP plasticity also likely occur during lactation and suckling, which facilitates OXT release coordinated with its action in the SON. These studies of the dynamic interactions that occur between astrocytes and OXT neurons mediated by GFAP extend our understanding of astrocyte functions within the central nervous system."}
{"text": "The emergence of spontaneous bursting events in developing neuronal networks likely depends on the evolving network connectivity. Theoretical models have shown that hierarchical network structures embedding clusters of strongly inter-connected neurons are optimal for initiating and sustaining spontaneous activity . It is cTo test this we chronically manipulated activity-dependent structural plasticity by inhibition of protein kinase C (PKC) in developing networks of cortical neurons in vitro. Previous studies showed that PKC inhibition in developing cerebellum promotes dendritic outgrowth and arborization of Purkinje cells and impairs pruning of climbing fibers. We found that developmental inhibition of PKC in cortical cell cultures increased dendritic outgrowth, impaired neurite fasciculation and clustering and abolished network pruning. This resulted in more homogeneous and potentially better connected networks fig. . As a re"}
{"text": "This study investigated procedural errors made during root canal preparation using stainless steel and nickel-titanium (NiTi) instruments by undergraduate students, using two diagnostic imaging methods.n=20; group 1: K-Flexofile, group 2: K3, and group 3: BioRace). The root canals were filled with gutta-percha and AH Plus. Periapical radiographs and cone beam computed tomography (CBCT) images were obtained to detect procedural errors made by undergraduate students during root canal preparation. Two examiners evaluated the presence or absence of fractured instruments, perforations and canal transportations. The agreement between observers was assessed using the kappa coefficient. The Kolmogorov-Smirnov, Fisher exact, ANOVA and Tukey tests were used for statistical analysis. The level of significance was set at 5%.Sixty human molars were divided into three groups (There were no significant differences in detecting procedural errors between two- and three-dimensional diagnostic imaging methods. There were no significant differences in procedural errors between stainless steel and NiTi instruments. Mean preparation time was recorded in minutes, and results were significantly different between the three groups. NiTi instruments had the lowest mean preparation time.Both periapical radiographs and CBCT identified procedural errors, however, three-dimensional images offered more diagnostic resources. The frequency of procedural errors was low for any of the endodontic instruments despite being used by inexperienced operators. Centralizing ability and apical transportation were not influenced by mechanical motion or type of instrument used. Hartmann et al. . Further research should investigate new concepts and technologies that raise opportunities for discussion, reflection and changes in the scientific world.The frequency of procedural errors during the preparation of canals of maxillary and mandibular molars using stainless steel and NiTi instruments was low regardless of diagnostic imaging method when used by inexperienced operators."}
{"text": "Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also develop defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but, to date, has not been reported in patients with Cartilage-hair hypoplasia.To describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency and evaluate treatment options.In a retrospective, observational study, we collected clinical data on 21 patients with CHH in order to identify and further characterize individuals with granulomatous inflammation.Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) developed epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti Tumor necrosis factor alpha monoclonal antibody therapy in 3 of these patients led to significant regression of granulomas. However, one treated patient developed fatal progressive multifocal leukoencephalopathy due to the JC polyomavirus. In two patients, immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas.To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although Tumor necrosis factor alpha antagonists may effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients."}
{"text": "DNA methylation may play a role in the etiology of neuropsychiatric disorders through abnormal genomic methylation patterns regulating genes involved in brain development or physiology. In this study we explored the DNA methylation profile of depression in the prefrontal cortex because converging evidence from brain imaging and postmortem studies has implicated this region in depression neuropathology.et al., doi: 10.4161/epi.6.11.17876). Overall, these data represent relatively unbiased coverage of the genome, including CpG-rich domains such as CpG islands and repetitive elements.In order to better understand both the wild type genomic DNA methylation patterns and aberrant methylation events occurring in disease states we profiled DNA methylation patterns in human postmortem brains of 12 depressed and non-psychiatric controls using the methylation mapping and paired-end sequencing (Methyl-MAPS) method. Methyl-MAPS is an enzymatic-base method that can delineate the methylation status of greater than 80% of CpG sites genome-wide across all RefSeq annotated genes, but significant variations were detected proximal to the TSS (referred to as \u201cCpG island shores\u201d). We observed statistically significant methylation loss in CpG island shores in depressed cases compared to controls. These findings were replicated in purified neuronal cell populations. Using an independent sample of depressed cases and matched non-psychiatric controls, we isolated neuronal nuclei from the dorsal prefrontal cortex of 11 depressed cases and 11 controls. Due to limited quantities of neuronal DNA typically obtained from isolation of nuclei using fluorescence-activated cell sorting, we used the Illumina HumanMethylation450 BeadChip. DNA methylation differences in CpG island shores revealed that, of the CpG dinucleotides with significant methylation differences, >95% showed loss of methylation in depressed brains. The underlying mechanism involved in the loss of methylation in depression psychopathology is unclear. However, the global 5-hydroxymethylcytosine levels in neuronal DNA from the same sample specimens also showed a loss of hydroxymethylation in depressed brains compared to controls. Although these data were not statistically significant, they revealed an important trend in loss of hydroxymethylation and the possible mechanism for DNA demethylation in brains of depressed patients. Gene ontology analysis of genes with significant methylation differences (primarily loss of methylation) in depressed vs. controls identified a number of cellular functions. Of note, the fourth most significant gene set identified was involved in programmed cell death and 74% of the genes in this set were associated with neuronal cell death. These changes in methylation dynamics suggest a possible mechanism linking neuronal cell death associated with oxidative stress and inflammation in the depressed brain."}
{"text": "This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics, and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.Poly(ADP-ribose) polymerase (Parp) is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose) chains (known as PARylation). Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis, and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on Breast cancer is an epidemic afflicting approximately one out of every nine women and gemcitabine showed improved overall survival of varying degrees of homology , all of whom use NAD+ as a substrate to catalyze the addition of ADP-ribose moieties onto target proteins locus glycohydrolase (known as Parg). Parg catabolizes ADP-ribose polymers synthesized by Parp-1. This enzymatic activity has been demonstrated to impair Parp-mediated chromatin remodeling In addition to histone H1 removal, Parp-1 configures chromatin through modification of proteins involved in remodeling and organizing chromatin structure. PARylation generally results in protein activation, but can also result in functional suppression of chromatin remodelers. For example, PARylation is inhibitory to the function of the repressive remodeling complex Iswi , together with histone deacetylases (Hdacs), results in a repressive complex, inactivating the transcription of genes involved in cardiomyocyte differentiation through deacetylation of histones .Finally, we propose that Parg represents an attractive therapeutic target Figure . The undParp-1 is an important activator of transcription and probably plays an important role in promoting transcription of tumor suppress genes. Therefore, we postulate Parp inhibitors may actually have pro-oncogenic effects on some cell populations. But, what is the impact of inhibiting Parg on these same processes? While the overall impact of Parg on gene regulation remains unclear at this time, it has been shown that Parg can block Parp-1 mediated chromatin remodeling and transcriptional activation in specific circumstances. Therefore, we speculate Parg inhibition might heighten the effects of PARylation, thus promoting the transcription of tumor suppressor genes. Further, in cancer cells having defects in the PARylation pathway such as aberrantly dePARylated Ctcf, Parg inhibition might serve to correct these deficiencies.in vivo (Marienfeld et al., in vitro data showing growth inhibitory activity of Parg inhibition or knockdown in multiple types of cancer (Fauzee et al., Supporting these rationale for Parg inhibition being a novel approach for anti-cancer therapy are several reports indicating Parg inhibition has potent anti-tumor effects against cholangiocarinoma The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Acute liver failure related to hepatitis B infection may occur after acute HBV infection or during an exacerbation (flare) of a chronic HBV infection. The condition is associated with a very high morbidity and mortality rate.We present the diagnosis and management difficulties of a four-case series admitted to our clinic during the last year, with severe acute liver failure, with encephalopathy that required medical management, intensive care and organ support, including artificial extracorporeal liver support.In the presence of acute liver failure and serological evidence of hepatitis B viral infection, differentiating between acute infection and exacerbation (flare) of chronic infections remains a challenge. Mortality rates remain high inspite of recent medical advance."}
{"text": "NATbox: Network Analysis Toolbox in the language R that houses a battery of BSL algorithms in conjunction with suitable statistical tools for modelling FRs in the form of acyclic networks from gene expression profiles and their subsequent analysis.There has been recent interest in capturing the functional relationships (FRs) from high-throughput assays using suitable computational techniques. FRs elucidate the working of genes in concert as a system as opposed to independent entities hence may provide preliminary insights into biological pathways and signalling mechanisms. Bayesian structure learning (BSL) techniques and its extensions have been used successfully for modelling FRs from expression profiles. Such techniques are especially useful in discovering undocumented FRs, investigating non-canonical signalling mechanisms and cross-talk between pathways. The objective of the present study is to develop a graphical user interface (GUI), i) impute missing observations in the given data (ii) model FRs and network structure from gene expression profiles using a battery of BSL algorithms and identify robust dependencies using a bootstrap procedure, (iii) present the FRs in the form of acyclic graphs for visualization and investigate its topological properties using network analysis metrics, (iv) retrieve FRs of interest from published literature. Subsequently, use these FRs as structural priors in BSL (v) enhance scalability of BSL across high-dimensional data by parallelizing the bootstrap routines.NATbox is a menu-driven open-source GUI implemented in the R statistical language for modelling and analysis of FRs from gene expression profiles. It provides options to (http://bioinformatics.ualr.edu/natboxWiki/index.php/Main_Page.NATbox provides a menu-driven GUI for modelling and analysis of FRs from gene expression profiles. By incorporating readily available functions from existing R-packages, it minimizes redundancy and improves reproducibility, transparency and sustainability, characteristic of open-source environments. NATbox is especially suited for interdisciplinary researchers and biologists with minimal programming experience and would like to use systems biology approaches without delving into the algorithmic aspects. The GUI provides appropriate parameter recommendations for the various menu options including default parameter choices for the user. NATbox can also prove to be a useful demonstration and teaching tool in graduate and undergraduate course in systems biology. It has been tested successfully under Windows and Linux operating systems. The source code along with installation instructions and accompanying tutorial can be found at Classical biological experiments have focused on understanding changes in the expression of single genes across distinct biological states. Such differential gene expression analyses while useful may not provide sufficient insight into their interactions or functional relationships (FRs). Understanding FRs is crucial as genes work in concert as a system as opposed to independent entities. On a related note, phenotype formation is mediated by pathways comprising of complex interactions between several genes as opposed to a single gene. Recent development of high-throughput assays in conjunction with sophisticated computational tools has enabled modelling such interactions and gain system-level understanding.Several commercial and non-commercial software packages have been developed in the past for modelling gene interactions. Ontology-based packages ,2 that rBayesian structure learning (BSL) techniques have beehttp://bioinformatics.ualr.edu/natboxWiki/index.php/Main_Page.Several open-source packages are available for BSL and can be used to model gene networks -13. Howei) determine missing values in a given data using the functions LLSimpute, also implemented in the R-package pcamethods [ii) Learn acyclic network structure using BSL routines from the R-package deal [dynamicGraph [iii) identify what the author term as 1st order network structure using a resampling procedure and (iv) reconstruct coherent sub-regulatory networks using an extended version of the algorithm CODENSE [Prior to a detailed description of NATbox functionalities, we briefly review those of a closely related package BNArray which waamethods (ii) Leaage deal . SubsequmicGraph (iii) id CODENSE . In the The comparisons are also enclosed under Table i. GUI: NATbox provides a convenient menu-driven graphical user interface (GUI) developed using Tcl/Tk for modelling and analysis of gene expression networks. This has to be contrasted with BNArray [ BNArray , which iii. Input/output: The input data in NATbox is assumed to be in tab-delimited text format, similar to that of BNArray. In NATbox, the rows of the input file represent independent experiments whereas the columns represent the names of the genes. However, in BNArray the rows represent the genes of interest and the columns represent their expression across experiments. Unlike NATbox, BNArray does not specify whether the experiments need to be independent or dependent.iii. Missing values: Gene expression profiles often have missing values. For instance, in microarray data such missing values are common and may be attributed to experimental artefact, improper hybridization and non-specific binding of the probes. It is prudent to use suitable statistical techniques to accommodate such data sets rather than discard them. NATbox provides an option to determine missing values using nearest-neighbour averaging approach (menu: File), impute.knn (R-package impute) which has been found to perform well for high-dimensional data sets [LLSImpute) [pcamethods).ata sets . BNArraySImpute) algorithiv. Functional relationships: NATbox provides the option to model functional relationships using a battery of Bayesian structure learning techniques from the R-package (bnlearn) [menu: Bayesian Networks). It is important to note that they model the network structure solely from the joint probability distribution in the absence of explicit temporal information. The tab-delimited input data should be in the form of a matrix where the columns represents the number of genes, and rows the number of repeated (independent) experiments. Each element in the matrix represents the expression value of that gene in a given experiment.bnlearn) : GS is b\u2022 Incremental Association Markov Blanket Algorithm (IAMB) : IAMB is\u2022 Fast Incremental Association Markov Blanket Algorithm (Fast-IAMB) : Fast-IA\u2022 Interleaved Incremental Association Markov Blanket Algorithm (Inter-IAMB) : Inter-I\u2022 Max-Min Parents Children Algorithm (MMPC) : MMPC ismutual information, mutual information for Gaussian distributed data, fast mutual information, Pearson's \u03c72, Akaike information criterion) as well as numerical/continuous distributions are provided. NATbox also provides an interface to the search and score algorithm from bnlearn. HC searches the model space and retrieves the best model using a scoring criterion which is also provided. Several choices of scoring criterion are provided for categorical/discrete and numerical/continuous distributions (Gaussian posterior density). Each BSL technique works under implicit assumptions and may result in spurious conclusions when these assumptions are violated. NATbox provides a battery of BSL techniques to alleviate such concerns. For instance, constraint-based techniques can be affected by sample sizes and are sensitive to initial results of the conditional independence tests. Search and score algorithms can result in local optima, hence may benefit from multiple random restarts unlike constraint-based approaches.Several choices of conditional independence tests for categorical/discrete are deemed robust. Bootstrap procedures can be computationally demanding for high-dimensional data sets. Search and score techniques such as hill-climbing implicitly require several random restarts during the confidence estimation. NATbox provides an option to parallelize bootstrapping across multiprocessor or multi-core processor by invoking the appropriate routines from the R-package SNOW (Simple Network Of Workstations) [nfidence of an edtations) . Such patations) is shown\u03b8 > 0.8) on the acyclic graph learned from the given data, Fig. dynamicGraph [The results of the bootstrap are written onto a tab-delimited file. An option is also provided for highlighting the robust FRs (micGraph for visuwhitelisting (include) and blacklisting (exclude) FRs. Such priors impose constraints on the network structure which implicitly rely on prior knowledge and needs to be chosen prudently in order to avoid bias during learning. However, a proper choice can alleviate uncertainty and improve accuracy of the conclusions. A text retrieval interface is provided for identifying structural priors and can be useful for investigating well-established signalling mechanisms.In addition, NATbox GUI also provides options for incorporating structural priors in BSL by vi. Network analysis metrics: BSL techniques are useful in inferring the cause-effect relationships and network structure from the gene expression profiles. However, they provide no insight into the network's topological properties. NATbox incorporates social network analysis metrics and motif finder from the package (igraph) [menu: Network Analysis Metrics) for investigating the topological properties of the networks generated using BSL techniques. Such metrics can be especially useful in investigating large networks. The input is assumed to be a binary adjacency matrix of the network constructed using BSL with ones and zeros representing the presence/absence of an edge respectively. Since BSL results in directed acyclic graphs, the corresponding binary adjacency matrix need not be symmetric. The centrality measures along with their respective parameter options are provided for the user. A detailed discussion of these centrality measures are deferred to [igraph [igraph package incorporated into NATBox also provides option to save the acyclic network in formats compatible with Cytoscape [(igraph) under . The user has the option to input the (a) pairs of gene names (co-occurrence) of interest through the GUI or (b) upload a two-column matrix of FRs of interest or those identified as robust by the bootstrap procedure. For well-documented studies, an integrated approach that incorporates the results from the Text Retrieval in justifying the choice of whitelisted (include) and/or blacklisted (edges) in BSL. The Text Retrieval results are in html format, with a list of PUBMED identifiers hyper-linking to the respective abstracts/articles in PUBMED. The results of text retrieval on gene expression data from [ata from is showni) expand the choice of structure learning algorithms including dynamic bayesian networks (ii) improve statistical inference of the network features (ii) parallelization of the implemented routines across multi-core and multi-processor machines of BSL functions as well as bootstrapping (iii) provide a web-interface so as to obviate the need for local installation of the toolbox (iv) enhance text retrieval so as to accommodate advanced text mining approaches.Modelling and analysis of gene expression networks is an area of active research. Several tools have been proposed in the literature for the same. Recently, Bayesian structure learning (BSL) techniques in conjunction with high throughput assays were used successfully to capture functional relationships. Existing packages may demand the user to have considerable programming expertise. NATbox provides a convenient menu-driven GUI along with appropriate parameter recommendations including default parameter choices for modelling and analysis of gene expression networks. It incorporates diverse functionalities from existing R-packages. This in turn encourages transparency and reproducibility, characteristic of open-source environment. NATbox can also be used as a teaching and demonstration tool for graduate courses in systems biology. Immediate future enhancements to the toolbox include (The authors declare that they have no competing interests.bnlearn package and was involved in trouble shooting the Bayesian structure learning routines. RN wrote the manuscript.SSC and MAB implemented the toolbox under RN's guidance. MS developed the"}
{"text": "Patients after fractures become more and more immobile. Necessary stimuli decrease further. It comes to progressive deconditioning, whereby the vicious circle is complete, because it results in decreasing muscle cross-sectional area as well as bone strength. Accordingly, therapy concepts have to focus on maintenance and increasing muscle force and power. An established method is intensive resistance exercise training aimed to hypertrophy. Also the training program must ensure that forces reach the minimal effective strain and leads to bone remodelling. High-load resistance exercises effectively increase muscle and bone at the same time.Bone and muscle are dynamic tissues. Muscle adapts to stimuli above thresholds (energetic emptying > exhaustion). Wolff\u2019s law states that structural bone adaptation is driven by the experienced bone strains. Osteocytes within our bones regulate bone formation and degradation in response to mechanical stimuli. The largest strains emerge from muscle contractions. A lot of diseases are associated with secondary muscle weakness (sarcopenia) and reduced bone density (osteoporosis). Both deficits cause an increase in fall incidence. About every 4"}
{"text": "Yersinia pestis, are highly variable in their response to plague ranging from near deterministic extinction to a low probability of extinction despite persistent infection . Much of the work to understand this variability has focused on specific host characteristics, such as population size and resistance, and their role in determining plague dynamics. Here, however, we advance the idea that the relative importance of alternative transmission routes may vary causing shifts from epizootic to enzootic dynamics. We present a model that incorporates host and flea ecology with multiple transmission hypotheses to study how transmission shifts determine population responses to plague. Our results suggest enzootic persistence relies on infection of an off-host flea reservoir and epizootics rely on transiently maintained flea infection loads through repeated infectious feeds by fleas. In either case, early-phase transmission by fleas has been observed in laboratory studies, and we show that it is capable of driving plague dynamics at the population level. Sensitivity analysis of model parameters revealed that host characteristics vary in importance depending on transmission dynamics, suggesting that host ecology may scale differently through different transmission routes enabling prediction of population responses in a more robust way than using either host characteristics or transmission shifts alone.Host populations for the plague bacterium, Yersinia pestis, remains a public health concern because of its high virulence in multiple mammal species, including humans, and its role in past pandemics in humans. Despite its historical importance and the continued threat of human cases, plague is primarily a disease of rodents and their fleas. Consequently, humans are at greatest risk of exposure to Y. pestis during plague epizootics when rodent hosts die in large numbers increasing potential exposures to sick or dead animals and infectious fleas Plague, caused by the bacterium However, rodent species show high variability in their population-level response to plague infection, and the mechanisms that determine outbreak conditions are not fully understood. The variability in host response can be compartmentalized into two classes: either enzootic or epizootic . This classification enables predictions that can be based on observable intra-population dynamics rather than invoking landscape-level maintenance mechanisms involving the interaction of plague dynamics in multiple species Rhombomys opimus) in Kazakhstan, show high levels of prolonged resistance , rarely survive plague infection Previous research on plague dynamics depended on observation of host characteristics to differentiate between epizootic and enzootic populations. For example, enzootic hosts, such as great gerbils allows for the maintenance of infection levels in fleas and increases infectious duration for early-phase transmission Y. pestis has survived in carcasses and soil for several days under both field and laboratory conditions Experimentally studying transmission routes in natural systems is nearly impossible, but laboratory experiments have identified effective transmission routes that could also affect population responses to plague infection. In particular, early-phase transmission by un-blocked fleas has been shown to be a viable alternative to blocked-flea transmission in several flea species under laboratory conditions Y. pestis dynamics that incorporates three routes of plague transmission: 1) the booster-feed infection cycle; 2) the build-up of infectious, questing fleas; and 3) contact with carcass-derived material. We parameterize the model for an epizootic host, the black-tailed prairie dog, and for an enzootic host, the California ground squirrel (Spermophilus beecheyi). We sequentially remove or reduce each transmission route to understand how the influence of each route may vary between characteristic epizootic and enzootic hosts. We also use sensitivity analysis of model parameters to quantify the importance of transmission routes across a broader range of species and to explore how previously identified host characteristics interact with transmission to improve prediction of plague dynamics.In order to simultaneously consider how multiple transmission routes interact to determine plague dynamics, we present a general model of We developed an ordinary differential equation (ODE) model consisting of both host and flea submodels causing fleas to transition to EP stage 2 , while the infectious, questing flea reservoir increases almost throughout . InfectiSystematic removal of transmission routes helped provide a clearer picture of each in plague dynamics, especially for epizootic behavior . For thea, was positively correlated with enzootic probability but had little effect on extinction probability. Increasing transmission efficiency from EP2, L\u03b2, increased extinction probability as did an increase in the transition rate between EP1 and EP2 for fleas taking non-infectious blood meals, E\u03b8.Our multi-parameter sensitivity analysis was consistent with the relative importance of transmission routes described above and revealed that model results were sensitive to parameters influential to both the booster-feed infection cycle and the infectious, questing flea reservoir ; Fig. 3.\u03d5, and shorter host exposure periods . However, increased host resistance, p, and increased host carry capacity, K, served to decrease epizootic behavior. In contrast, enzootic probability was increased by increasing host carrying capacity and declined with higher rates of resistance loss, shorter host exposure periods, and decreasing host connectance . Sensitivities that are not reported were not significant.Population responses to plague infection were also sensitive to several host parameters in the model . Among tOur model produced characteristic enzootic and epizootic behaviors, and model behaviors for our specific parameterizations were consistent with empirical observations of plague activity in the hosts they were based on, black-tailed prairie dogs and California ground squirrels. The agreement with natural systems highlights our ability to reliably compare the shifting roles of transmission routes in creating each dynamic. In particular, the booster-feed infection cycle is primarily responsible for epizootic behavior. While laboratory experiments have demonstrated that the booster feed infection cycle results in the maintenance of infection levels in fleas B; Our sensitivity analysis supports the role of shifting transmission dynamics in determining plague dynamics in the host population. We found that epizootic behavior was strongly affected by flea characteristics that determine both the strength and turnover rate of the booster-feed infection cycle, while enzootic potential was strongly influenced by flea questing efficiency adding support to the involvement of a flea reservoir in the maintenance of plague at the population level While the flea reservoir may be important in connecting spatially distinct groups of hosts, we also hypothesize that questing fleas may act as a bridge in enzootics, connecting temporally separated pools of susceptible hosts generated from a resistant refuge. This endogenously derived temporal bridge contrasts with more traditionally hypothesized exogenous sources of re-infection. Bat rabies virus may display a similar endogenous bridging mechanism by entering a quiescent state during host hibernation, thus creating a bridge between birth pulses that refresh the susceptible pool Most of the previous research on the variability in population responses to plague infection has focused on host traits, and our sensitivity analysis confirmed some of these observations, particularly the importance of host resistance and population size as observed in Asian great gerbils However, while our analysis confirms previous observations on the role of host characteristics in determining disease dynamics, it is important to note that these traits do not act independently of transmission routes to determine population response and thus, the effects of host traits may depend on the specific transmission routes operating. For example, we found that increasing host carrying capacity generally increased enzootic potential in our sensitivity analysis. However, our specific results for prairie dogs and California ground squirrels exhibited the opposite of the expected responses with black-tailed prairie dogs having larger population sizes but higher probabilities of extinction. Here, knowledge of transmission shifts may be more informative. Specifically, the importance of booster-feeds in epizootics, a transmission route that relies on continued contact between hosts and fleas, may create a situation where increasing host abundance leads to large epizootic potential that cannot be maintained. This is in contrast to enzootic hosts where an endogenous bridging mechanism like infectious, questing fleas overcomes issues of host limitation. The maintenance of infection potential in a flea reservoir may also alter the traditionally hypothesized role of resistance in promoting enzootics. In this case, resistance may primarily be important in avoiding epizootics and becomes important in promoting enzootics only when infectious, questing fleas dominate transmission. Thus, host and flea characteristics may scale up through transmission routes allowing for more robust predictions than when considering either host or flea characteristics alone.Figure S1Flow chart for the host sub model. The three transmission routes included in the model are highlighted: booster-feed infection cycle (blue), infectious, questing flea reservoir (green), and infectious carcasses (orange).(TIF)Click here for additional data file.Figure S2Flow chart for the flea submodel. The relationship between the booster-feed infection cycle (blue) and infectious flea reservoir (green) is highlighted.(TIF)Click here for additional data file.Table S1Alternate flea parameter values. Parameter values for the prairie dog flea O. tuberculata cynomuris. Other flea species are provided for comparison.(DOC)Click here for additional data file.Text S1Alternate flea submodel which prevents the buildup of infectious, questing fleas.(DOC)Click here for additional data file.Text S2Parameter fitting and estimation.(DOC)Click here for additional data file.Text S3Detailed prairie dog and California ground squirrel model outputs.(DOC)Click here for additional data file."}
{"text": "Urobatis halleri, as a model species. First, we examined the effects of temperature on vertebral elemental incorporation . Second, we tested the relationship between water and subsequent vertebral elemental composition by manipulating dissolved barium concentrations . We also evaluated the influence of natural variation in growth rate on elemental incorporation for both experiments. Finally, we examined the accuracy of classifying individuals to known environmental histories (temperature and barium treatments) using vertebral elemental composition. Temperature had strong, negative effects on the uptake of magnesium (DMg) and barium (DBa) and positively influenced manganese (DMn) incorporation. Temperature-dependent responses were not observed for lithium and strontium. Vertebral Ba/Ca was positively correlated with ambient Ba/Ca. Partition coefficients (DBa) revealed increased discrimination of barium in response to increased dissolved barium concentrations. There were no significant relationships between elemental incorporation and somatic growth or vertebral precipitation rates for any elements except Zn. Relationships between somatic growth rate and DZn were, however, inconsistent and inconclusive. Variation in the vertebral elemental signatures of U. halleri reliably distinguished individual rays from each treatment based on temperature (85%) and Ba exposure (96%) history. These results support the assumption that vertebral elemental composition reflects the environmental conditions during deposition and validates the use of vertebral elemental signatures as natural markers in an elasmobranch. Vertebral elemental analysis is a promising tool for the study of elasmobranch population structure, movement, and habitat use.Differences in the chemical composition of calcified skeletal structures have proven useful for reconstructing the environmental history of many marine species. However, the extent to which ambient environmental conditions can be inferred from the elemental signatures within the vertebrae of elasmobranchs has not been evaluated. To assess the relationship between water and vertebral elemental composition, we conducted two laboratory studies using round stingrays, The trace and minor elemental composition of biomineralized structures can provide insight into the environmental conditions in which the elements were deposited. Elemental assays of coral skeletons and foraminifera tests, for example, have been commonly applied as surrogates of past climatic or oceanographic conditions \u20133. RecenThe most widespread and expanding application of elemental markers in biomineralized structures has occurred using the otoliths of fishes ,5. OtoliThe elemental composition of biogenic calcified structures is not a simple reflection of environmental conditions. A variety of physiological barriers and processes are encountered as elements are taken up from the water through the gills or intestine, transferred through the blood plasma, and eventually incorporated into biomineralized structures . PhysiolSharks, skates, and rays (elasmobranchs) are cartilaginous fishes that lack otoliths. Elasmobranch skeletons are composed of mineralized cartilage, an impure (non-stochiometric) form of carbonated calcium phosphate (hydroxyapatite) . Like thChemical analyses of elasmobranch vertebrae to date have been predominately directed toward age validation ,27 and dUrobatis halleri, as a model species. We manipulated environmental concentrations of barium (Ba) to determine the extent to which vertebral elemental ratios reflect the ambient environment. Finally, we evaluated the utility of these elemental markers to distinguish the environmental history experienced by individual rays using multivariate classification models. These experiments allowed us to test the following hypotheses: (i) elemental incorporation in vertebrae is mediated by water temperature; (ii) vertebral Ba to calcium ratios (Ba/Ca) reflects water Ba/Ca; (iii) growth rate does not significantly influence vertebral elemental composition; and (iv) vertebral elemental markers can distinguish individuals based on differences in environmental history. This investigation represents the first attempt to evaluate the utility of vertebral chemistry as potential records of environmental history in elasmobranchs.Key assumptions regarding vertebral elemental incorporation in relation to the physical and chemical environment must be evaluated before broader ecological questions and hypotheses can be addressed using naturally occurring elemental markers in elasmobranchs. We quantified the effects of temperature and growth rate on vertebral elemental incorporation through controlled laboratory studies using the round stingray, This investigation was conducted with a permit from the California Department of Fish and Game (803099-01) and in strict accordance with guidelines established by the American Fisheries Society and National Institutes of Health for the use of fishes in research. Experimental protocol was approved by Oregon State University\u2019s Institutional Animal Care and Use Committee (3783).Urobatis halleri, is a benthic, live-bearing elasmobranch that occurs in estuaries and nearshore coastal soft bottom habitats from Panama to Eureka, California, USA ) experiment.Correlations (r) between partition coefficients (DThe number (n) of round rays included in growth rate estimates, observed range of individual somatic growth rates (mm disc width month-1), and vertebral precipitation rates (\u03bcm radius month-1) are reported for each treatment. Significant p-values are indicated by bold font.(PDF)Click here for additional data file."}
{"text": "Vascular injury represents less than 1% of all injuries, but deserves special attention because of its severe complications. Amputation or retention of a painful functionless limb is the most untoward result of severe vascular injury or inadequate treatmet. Thus, vascular injury needs a judicious and multidimensional approach.This retrospective study was done to asess the outcome of minor modifications of the methodology of extremity fasciotomy by making it liberal with respect to incision and definition.Out of 55 patients in 2008, 45 patients (Group A) had either no fasciotomy or limited primary fasciotomy, 10 patients (Group B) had primary liberal fasciotomy. Another group from 2008 onwards had undergone primary liberal fasciotomy in all the 45 patients (Group C).In group A, we had 5 amputations and one death. In group B, there were no amputations or deaths and from group C, we had one amputation and no deaths.Blunt and distal traumatic vascular injury of the extremities and its repair should always combined with primary liberal fasciotomy, which although increases manageable morbidity, avoids disability . Vascular injury represents less than 1% of all injuries, but deserves special attention because of their severe complications. Amputation or retention of a painful functionless limb is the most untoward result of severe vascular injury or inadequate treatment, so vascular injury needs a judicious and multidimensional approach. Patients with pain out of proportion to injury, pain upon passive stretching, sensory changes, weakness or parasthesia after vascular repair indicate vascular compromise due to compartment syndrome and need immediate fasciotomy. Popliteal artery injuries continue to result in maximum limb loss, possibility due to use of limited fasciotomy.This study was done to assess the outcome of minor modifications of the methodology of extremity fasciotomy by making it liberal with respect to incision and definition.We studied 55 patients in 2008 with firearm or splinter vascular injuries of extremities; 45 patients (Group A) underwent different methods of vascular repair either without primary fasciotomy or with limited fasciotomy. Only 10 patients (Group B) had liberal primary fasciotomy. After 2008 to date, we treated 45 patients (Group C) with different types of vascular injuries, by different reparatory methods all of which received primary liberal fasciotomy.Assessment included emergency work-up: clinical examination, CBC, KFT, ECG, chest x-ray, USG abdomen, color flow Doppler, blood grouping and cross-matching; only 6 patients were subjected to pre-operative angiography.Vascular repair was done by primary end-to-end anastomosis or reverse sephanous vein graft either without fasciotomy or with varied limits of fasciotomy.Limited fasciotomy included superficial incision with inadequately cut deep fascia, isolated compartment fasciotomy, inadequate length of fasciotomy not passing across proximal and distal joints. Liberal fasciotomy included cutting through skin, deep fascia as well as outer covering of underlying exposed muscles (epimysium), till muscle pouts out. Oozing blood from muscle indicates adequate blood flow through the repaired vessel as well as adequacy of fasciotomy, thus it has therapeutic as well as diagnostic importance. Checking muscle viability with low voltage electric cautery stimulation. Confirming muscle viability helps in adequate debridement to prevent infective complications of dead tissue.We use S-shaped incision both at elbow and popliteal fossa, closure of this incision does not cause any constricting effect, while in case of liberal primary fasciotomy, the same incision is extended. The repaired vessel is loosely covered either by surrounding fat or muscle to prevent desiccation of the vessel. Curved fasciotomy incisions decompress the maximum area of the extremity and avoids superficial venous injury.Ensure muscle pouting along fasciotomy wound. All-compartmental fasciotomy is better than isolated-compartment fasciotomy. Dressings should not be tight. Avoid entrapment of adventitia in the anastomotic suture line.Passing a Fogarty catheter damages endothelium and increases tendency of thrombosis, thus anticoagulation is recommended.From group A, we had 5 amputations and one death (death due to infective complications of gangrene followed by DIC - despite that the limb was amputated); from group B we had no complications and from group C one amputation and no deaths were recorded; 12 patients from group A needed either extension of fasciotomy or secondary fasciotomy.Most of the patients with liberal primary fasciotomy need care by a plastic surgeon. But 25% patients were discharged and referred to their respective primary health care centers for regular dressings and admitted subsequently for split-thickness skin grafting with favorable results.All those patients with primary liberal fasciotomy even with borderline muscle viability at the time of primary vascular repair had the least amputation rate. There was no significant increase in infection rate. Soaked dressings were changed regularly. One significant complication with primary liberal fasciotomy was pain which needed short interval analgesics. Also changing dressings in these patients was time consuming and significantly painful which demanded extra patience by patient as well as attending resident. These patients have long lasting paresthesia at graft site with varied presentation. Patients in high dependency units with no or limited fasciotomy obscured signs of compartment syndrome due to liberal use of analgesics. Delayed or revised fasciotomy in these patients helped to a very limited extent, and in the long run gave a functionally disabled limb with chronic pain in saved limbs.Delayed fasciotomy, revision fasciotomy and disability due to amputation/vegetative limb or chronic limb parasthesia all have a very strong psychological impact in contrast to less morbidity associated with primary liberal fasciotomy.In patients with primary liberal fasiotomy crossing knee and ankle in lower limb, elbow and wrist in upper limb with cutting some fibers of reticulum at ankle or wrist appreciably improved blood flow. Any vascular injury associated with blunt trauma limb, fracture, venous injury, longer duration of ischemia; below knee/elbow vascular repair needed primary liberal fasciotomy whether the patient had a tense compartment at the time of vascular repair or not.Extensive soakage from fasciotomy wound needs frequent change of dressings, which is painful and cumbersome for patient. Frequent analgesics make patients apprehensive. Painful postural changes and difficulty in assuming comfortable postures effects sleep. Longer hospital stay is uncomfortable.Compartment syndrome is a surgical emergency characterized by raised pressure in an unyielding osteofascial compartment caused by trauma, revascularization, myocyte edema after ischemia-reperfusion injury, or resuscitation -4. The cBlunt and distal traumatic vascular injury of extremities and its repair should be combined with primary liberal fasciotomy, which may although increase manageable morbidity, will avoid lifelong disability. No fasciotomy can be acceptable when chances of compartment syndrome are absolutely nil; however, limited fasciotomy is absolutely discouraged in favor of primary liberal fasciotomy."}
{"text": "The autonomic nervous system (ANS) and innate immunity are intimately linked. Heart rate variability (HRV) analysis is a widely employed method to assess cardiac ANS activity, and changes in HRV indices may correlate with inflammatory markers. Here, we investigated whether baseline HRV predicts the innate immune response. Second, we investigated whether the magnitude of the inflammatory response correlated with HRV alterations.Escherichia coli O:113). Of these, 12 healthy volunteers were administered LPS again 2 weeks later. HRV was determined at baseline (just prior to LPS administration) and hourly thereafter until 8 hours post LPS. Plasma cytokine levels were determined at various time points.Forty healthy volunteers received a single intravenous bolus of 2 ng/kg endotoxin (lipopolysaccharide (LPS), derived from Baseline HRV indices did not correlate with the magnitude of the LPS-induced inflammatory response. Despite large alterations in HRV following LPS administration, the extent of the inflammatory response did not correlate with the magnitude of HRV changes. In subjects that were administered LPS twice, inflammatory cytokines were markedly attenuated following the second LPS administration, while LPS-induced HRV alterations were similar. See Figure HRV indices do not predict the innate immune response in a standardized model of systemic inflammation. The innate immune response results in HRV changes; however, no correlations with inflammatory cytokines were observed. These findings suggest that cardiac ANS activity may not reflect ANS outflow to other organs involved in the innate immune response. Furthermore, the magnitude of endotoxemia-related HRV changes does not reflect the extent of the inflammatory response."}
{"text": "An asymptomatic issueless young staff nurse underwent pre-employment health screening and USG abdomen showed multiple hypodense lesions in liver. Further screening with whole body positron emission tomography-computed tomography (PET-CT) scan showed significantly FDG avid mass involving most of the right lobe of liver with multiple large FDG avid lymph nodal metastases. Unsuspected focal abnormal, FDG avid, hyperdense mural nodule was seen in uterus, which is the site of primary. With the advent of sophisticated medical instrumentation in the diagnostic workup for malignancies, detailed investigations fail to reveal the primary site of origin for a subset of patients with metastatic carcinoma. This is often referred to as Carcinoma of Unknown Primary (CUP) or occult primary malignancy.The exact incidence of CUP in the United States is not precisely known, but it is definitely underreported. Its actual incidence is most probably between 2 and 6%. In 15\u201325Clinical presentation of cancer of unknown primary origin is extremely variable and depends on the extent and type of organ involvement. Investigations are usually guided by any positive findings on initial evaluation. Patients have early dissemination of their cancer without symptoms at the primary site. The symptoms often depend on the site of metastases, like ascites may be the initial presentation in a patient with a GI or an ovarian malignancy, etc.The patient was an issueless, 32-year-old staff nurse undergoing pre-employment health checkup. USG abdomen showed a large heterogenous lobulated mass with predominant hypoechogenicity suggestive of possible atypical hemangioma or possible evolving abscess. Magnetic resonance imaging (MRI) of abdomen showed a large heterogenous enhancing hypodense lesion with altered signal intensity with a large exophytic component in the right lobe of liver suggestive of possible hepatic adenoma/atypical hemangioma/possible neoplasm. Fine needle aspiration cytology (FNAC) followed by trucut biopsy was suggestive of possible metastatic rhabdomyosarcoma.18F FDG (Fluoro Deoxyglucose) intravenously in euglycemic status. After 1 hour, the patient was imaged. Images showed large hypodense, significantly FDG avid, non-enhancing mass involving most of the right lobe of liver [Standard Uptake Value (SUV) max 30 g/ml]. Multiple large FDG avid, left axillary, porta hepatic, celiac and retropancreatic lymph nodal metastases were also present. Portal vein was seen encased by the tumor at porta hepatis. Inferior venacava was obstructed below the liver and collateralized via azygos and hemiazygous system. [Whole body positron emission tomography-computed tomography (PET-CT) scan was done using 8 mCi on system. . Inferio system. .The patient underwent further pelvic USG and was biopsy proven. The patient was started on chemotherapy and is doing well for the past 6 months. Follow-up CT of abdomen showed recession in size of liver metastases.Rhabdomyosarcoma is primarily a disease affecting children; it rarely affects adults. Common sites of involvement are the head and neck 28%), extremities 24%), and genitourinary tract (18%).8%, extre Uterine %, and geMost uterine sarcomas fall into the category of leiomyosarcoma, endometrial stromal sarcoma, or undifferentiated sarcoma.5 MetastaRhabdomyosarcoma is subdivided into three general types histologically as follows.Embryonal rhabdomyosarcoma: This usually occurs in head and neck locations with small round or oval tumor cells and a finely granular eosinophilic cytoplasm. Well-differentiated tumors demonstrate elongated, strap-shaped or tadpole-shaped rhabdomyoblasts.Alveolar rhabdomyosarcoma is the next variety comprising relatively small, poorly differentiated round and oval cells aggregated into irregular clusters or nests separated by fibrous septa. An occasional variant, referred to as the botryoid type, shows a diffuse myxoid or mucoid matrix with thinly scattered primitive mesenchymal cells. The characteristic feature of this type is a peripheral zone of increased cellularity, sometimes known as the \u201ccambium layer.\u201dPleomorphic rhabdomyosarcoma shows randomly arranged eosinophilic cells with considerable variation in cell size and shape, as well as variation in nuclear size and shape. The pleomorphic cells are often admixed with small, primitive mesenchymal cells. This tumor is often so undifferentiated that the identification of the cell of origin is difficult or impossible. Positive immunostains for desmin and myoglobin are helpful as in our case.Regardless of the histologic subtype, special stains are often quite useful for differentiating rhabdomyosarcoma from other neoplasms. The trichrome stain is especially useful because it colors rhabdomyoblasts bright red while myofilaments and cross-striations have fuchsinophilic properties, also highlighted by PTAH (deep purple color). Myxoid stroma may be positive for hyaluronidase with acid mucopolysaccharide staining, although many other tumors also have positive stroma with these stains. The most418F FDG PET-CT is an important screening tool for the evaluation of unknown primaries as well as for staging and follow-up of several malignancies.[In patients with metastatic disease, prognosis is poor with a 5-year event-free survival rate of less than 30%. 18F FDG gnancies.8 FDG PETOur patient was unique, as she was a young asymptomatic lady presenting with multiple large liver and nodal secondaries, which is relatively an uncommon site for metastases. The patient had no previous history of menorrhagia or metrorrhagia as usually expected in uterine rhabdomyosarcomas. Incidentally detected mural nodule in uterus helped in finding the site of hidden primary malignancy."}
{"text": "We compared the difference in left atrial tissue remodeling (LATR) pre-ablation and post-ablation lesion characteristics between three methods for electrical isolation of pulmonary veins routinely done to treat paroxysmal atrial fibrillation (PAF).Patients presenting with PAF who qualified for a cryo, PVAC or SRF ablation were prospectively followed. DE-MRI of the left atrium (LA) was performed prior to and three months post procedure. The degree of LATR is reported as a percentage of the total LA area.37 patients were included in this study. Six patients underwent an ablation using PVAC catheter, SRF catheter was used in 14 patients, and 17 patients underwent a cryoballoon ablation. Pre-ablation LATR was comparable in all three cohorts (Figure From our preliminary results, PVAC ablation appears to result in lesser scar formation as compared to Cryo and SRF ablation. The greater recurrence in patients with low scar post-ablation suggests the need to implement an adequate ablation strategy that results in greater scar to maximize successful outcomes. DE-MRI is an appropriate method to compare lesion formation induced by different ablations strategies.None."}
{"text": "Two variants with evidence of association with higher endometrial cancer grade (p-trend<10\u20136) have been selected for validation in independent sample sets. These SNPs are located in or near genes not previously reported to be involved in cancer aetiology or prognosis and, if confirmed, would represent novel gene targets. Neither of these SNPs fall into the top 1500 SNPs prioritised for validation of association with risk. Results to date suggest that genetic alleles associated with prognostic features, such as cancer grade, may be distinct from those associated with predisposition. GWAS analysis of tumour prognostic features is thus likely to improve understanding of biological pathways influencing outcome for endometrial cancer patients.Endometrial cancer is the most commonly diagnosed gynaecological cancer. Although endometrioid endometrial cancer (80% of cases) generally carries a good prognosis, some patients with this tumour subtype relapse within two years. Identifying genetic variants associated with prognosis could inform clinical decision-making for management at diagnosis, and inform development of chemotherapeutic agents targeting aggressive disease. Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in cancer susceptibility. Presently there are limited published studies using GWAS data to identify single nucleotide polymorphisms (SNPs) associated with tumour prognostic indicators, such as grade. We used case data from an endometrial cancer case-control GWAS to assess association of SNPs with endometrial cancer grade. Genome-wide genotyping of 1285 Australian and British women with endometrioid endometrial cancer and reporting Caucasian ethnicity was performed using the Illumina 610K BeadChip. After applying quality control measures, data on 583,366 SNPs for 1220 cases with grade information were used in the analysis. PLINK software was used to assess SNP association with grade , adjusting for study group . Fifty-seven SNPs were found to be significant at <10"}
{"text": "Reduced muscle strength- commonly characterized by decreased handgrip strength compared to population norms- is associated with numerous untoward outcomes. Preoperative handgrip strength is a potentially attractive real-time, non-invasive, cheap and easy-to-perform \"bedside\" assessment tool. Using systematic review procedure, we investigated whether preoperative handgrip strength was associated with postoperative outcomes in adults undergoing surgery.PRISMA and MOOSE consensus guidelines for reporting systematic reviews were followed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials (1980-2010) were systematically searched by two independent reviewers. The selection criteria were limited to include studies of preoperative handgrip strength in human adults undergoing non-emergency, cardiac and non-cardiac surgery. Study procedural quality was analysed using the Newcastle-Ottawa Quality Assessment score. The outcomes assessed were postoperative morbidity, mortality and hospital stay.Nineteen clinical studies comprising 2194 patients were identified between1980-2010. Impaired handgrip strength and postoperative morbidity were defined inconsistently between studies. Only 2 studies explicitly ensured investigators collecting postoperative outcomes data were blinded to preoperative handgrip strength test results. The heterogeneity of study design used and the diversity of surgical procedures precluded formal meta-analysis. Despite the moderate quality of these observational studies, lower handgrip strength was associated with increased morbidity (n = 10 studies), mortality (n = 2/5 studies) and length of hospital stay (n = 3/7 studies).Impaired preoperative handgrip strength may be associated with poorer postoperative outcomes, but further work exploring its predictive power is warranted using prospectively acquired, objectively defined measures of postoperative morbidity. A substantial minority of patients sustain an excess of postoperative complications and acceThe systematic review was undertaken in accordance with the PRISMA Preferr.Two of the authors (P.S. and M.A.H.) searched the electronic databases MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials independently using the following population search terms: 'postoperative complications' OR 'perioperative complications' OR 'surgical complications' OR 'surgical outcome'. These search results were combined with 'handgrip dynamometry' OR 'hand grip dynamometry' OR 'hand grip strength' OR 'handgrip strength' OR 'maximal voluntary contraction' in the title or abstract text using the Boolean search operator 'AND'. . The references of retrieved articles were hand searched for any relevant articles not identified in the original search. The study selection criteria were limited to include only studies reported in the English language and those involving human adults undergoing surgery (including cardiac and transplant surgery). Each abstract was screened to identify studies that had assessed handgrip strength prior to surgery. Studies were excluded if postoperative outcomes focussed on upper limb neuromuscular functional outcomes alone.The data were extracted on to a standardized data entry form by each reviewer. Differences between the reviewers were resolved by re-examination of the original manuscript until consensus was obtained. Data extracted for comparison included year of publication, primary author, total number of subjects, mean patient age, proportion of male subjects and co-morbidity (where reported). The method of quantifying or qualifying handgrip strength was recorded.The specific outcomes sought in each article were: (i) mortality, (ii) postoperative morbidity, categorized according to the Post Operative Morbidity Survey, (iii) length of hospital stay . PrimaryThe procedural quality of each trial was assessed using several criteria, although no studies were excluded on the basis of these assessments. The quality of studies was scored according to the Newcastle-Ottawa Quality Assessment Scale Additio, on a scNineteen studies were identified that compared postoperative outcomes in relation to handgrip strength Table , comprisThe majority of studies measured handgrip strength pre-operatively Table . Eleven Variable definitions for impaired handgrip strength have been used across studies Table . StudiesTable Tables Table Contrary to large population studies, our systematic review of the relationship between preoperative handgrip strength and postoperative outcome did not find compelling data to support the hypothesis that the results of studies in the general population translate to perioperative medicine. The majority of studies were considered to be of reasonable quality. Despite these quality scores, many studies contained important potential confounding factors which varied markedly between studies. A range of different instruments have been employed to measure grip strength, with other corroborative assessments of strength being frequently absent. Due to the substantial variation in the way in which each specified outcome had been defined between studies, plus the lack of analyses testing any one particular association, it was not possible to perform meta-analyses of results or formally test the heterogeneity (consistency) between studies. This marked heterogeneity between studies limits any definitive conclusions for the perioperative environment and renders this preoperative assessment largely unexplored. Nevertheless, several of these studies - albeit with the limitations as discussed above - suggest the role for preoperative handgrip strength assessment should be explored further.Large epidemiological studies have shown that perioperative morbidity is associated with dramatic differences in post-discharge life expectancy across different operations and health systems . The cosThere are also compelling basic biological reasons for establishing the role of handgrip strength in preoperative assessment. Cardiopulmonary reserve is a long-established predictor of cardiovascular and all-cause mortality, in both asymptomatic individuals and patients with cardiovascular disease . CardiacOne limitation of this systematic review is that no original study data were retrieved, although given the heterogeneity of both study design and the surgical populations in question this would have been unlikely to alter the main conclusions. Because only published reports were examined , a formal assessment of publication bias was not undertaken. It remains possible that not all relevant studies may have been identified since unpublished studies were not sought. There is very little perioperative demographic data provided in these studies, including cardiovascular risk and the identification of higher risk patients. Standards of postoperative care were not reported or apparently standardized. Since no interventions were conducted based on preoperative handgrip strength assessment, the studies only provide associative conclusions.This systematic review has generated two significant clinical implications. Firstly, given the compelling general population data that predicts longevity, there is clearly a need for the further prospective assessment of whether preoperative handgrip strength can help stratify risk of adverse postoperative outcomes. Second, these studies demonstrate that handgrip strength is a feasible, pragmatic, real-time bedside tool that may enhance preoperative risk stratification.Impaired preoperative handgrip strength may be associated with increased postoperative morbidity, mortality and prolonged hospital stay following surgery. Given the robust predictive power of this inexpensive, objective bedside test beyond the perioperative population, further studies of its' role in predicting postoperative outcomes appear to be warranted provided prospective, objectively defined measures of morbidity are employed.The authors declare that they have no competing interests.All authors contributed to Study design, Conduct of study, Data analysis and Manuscript preparation.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2253/12/1/prepubChecklist of items demonstrating adherence to PRIMSA systematic review guidelines.Click here for fileNewcastle Ottowa Scale.Click here for file"}
{"text": "Petromyzon marinus). This dataset allows the exploration of early vertebrate evolution because the lamprey lineage split from that of other vertebrates before the emergence of hinged jaws, the defining feature of jawed vertebrates . Additionally, lamprey axons are not ensheathed by myelin is particularly relevant because MBP is an abundant structural myelin constituent essential for myelination in the central nervous system (CNS). The fact that MBP had not been traced in species more ancient than gnathostomata Figure . The fun) Figure . MBP andOther presumed myelin proteins traced in the lamprey genome are not functionally related to myelin at all, despite an equivalent gene ontology (GO) term. For example, MYT1L (myelin transcription factor-1-like), a neuronal transcription factor , PMP22 , MAL (myelin and lymphocyte protein), and PLP (proteolipid protein) were previously noted to be evolutionarily older than vertebrates (Mazumder et al., Taken together, the lamprey genome does not provide reason to consider that myelin may have evolved in non-jawed vertebrates. More generally, conclusions from genomic datasets on cellular structures come with the danger of misinterpretations if not carefully considered in conjunction with morphological analyses (Bullock et al.,"}
{"text": "Transplantation therapy for diabetes is limited by unavailability of donor organs and outcomes complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation (embryonic day 28 (E28)) engraft long-term in non-immune, suppressed diabetic rats or rhesus macaques. Morphologically, similar cells originating from adult porcine islets of Langerhans (islets) engraft in non-immune-suppressed rats or rhesus macaques previously transplanted with E28 pig pancreatic primordia. Our data are consistent with induction of tolerance to an endocrine cell component of porcine islets induced by previous transplantation of embryonic pig pancreas, a novel finding we designate organogenetic tolerance. The potential exists for its use to enable the use of pigs as islet cell donors for humans with no immune suppression requirement. J. Transplantation, why transplantation of embryonic pancreatic primordia to replace endocrine pancreas function is advantageous relative to transplantation of either pluripotent embryonic stem (ES) cells, or of terminally differentiated (adult) organs [We have reviewed previously, for ) organs : (1) unlTransplantation of human embryonic pancreas in human hosts has been contemplated . HoweverCells originating from E28 pig pancreatic primordia transplanted in mesentery engraft similarly in non-immune-suppressed STZ-diabetic rhesus macaques , 8. GlucIn lieu of increasing the numbers of transplanted primordia or transplant surgeries in diabetic rhesus macaques, we embarked on a series of experiments to determine whether porcine islets, a more easily obtainable and possibly more robust source of insulin-producing cells, could be substituted for animals in which embryonic pig pancreas already had been engrafted. To this end, we implanted adult porcine islets beneath the capsule of one kidney of rats or macaques, that several weeks earlier had been transplanted with E28 pig pancreatic primordia in mesentery. We employed the renal subcapsular site for islet implantation so that we could differentiate engrafted porcine tissue originating from the islets from tissue originating from prior mesenteric E28 pig pancreatic transplants, that never engraft in host kidney , 8. In t Figures Neither cells that stain for insulin nor cells to which the probe for porcine proinsulin mRNA binds are present in contralateral (nonimplanted) kidneys of STZ diabetic rats or macaqTo provide additional evidence that cells in the kidneys of islet-implanted rats or macaques previously transplanted with E28 pig pancreatic primordia in mesentery are of porcine origin, we demonstrated using fluorescent in situ hybridization, that the cells contain pig X chromosomes , 8. ShowMultiple organs were excised from a STZ-diabetic macaque transplanted with E28 pig pancreatic primordia in mesentery and subsequently with porcine islets in the renal subcapsular space of one kidney. Tissues were homogenized individually and total RNA was purified. RT-PCR was performed using primers specific for pig or monkey proinsulin mRNA. Products were separated by electrophoresis on 3% agarose gels and their identities confirmed by sequencing in the Washington University Core Protein and Nucleic Acid Chemistry Laboratory [To ascertain whether cells originating from kidney-implanted porcine islets function in rats or rhesus macaques, we determined whether the glucose tolerance of STZ-diabetic animals normalized partially by prior transplantation of E28 pig pancreatic primordia in mesentery was rendered normal by subsequent islet implantation, and measured glucose-stimulated insulin release from islet-implanted kidneys in vitro. Rats were rendered fully glucose tolerant by subsequent implantation of porcine islets in one kidney . The gluAs illustrated in a representative of 3 experiments using weight-matched tissue, no insulin could be detected at time 0 in supernatants from the implanted macaque kidney . HoweverCells containing endocrine granules in an expanded renal subcapsular space were identified in electron micrographs of kidneys from rats implanted with porcine islets following transplantation of E28 pig pancreatic primordia in mesentery . FigureThe shortage of human pancreas donor organs imposes severe restrictions on the use of allotransplantation to treat diabetes mellitus \u201322. WhenThe severity of humoral rejection effectively precludes the use of pigs as whole pancreas organ donors for humans. However, because they are vascularized by the host posttransplantation, islets like other cell transplants are not subject to humoral rejection. Porcine islets are rejected within two weeks of transplantation in non-immune suppressed non-human primates , 16\u201318. Xenotransplantation of embryonic pig pancreatic primordia in lieu of mature pig organs or porcine islets couples the wide availability of pig organs with the immunological advantages inherent in transplanting cellular embryonic tissue, circumventing humoral rejection and obviating the need for host immune suppression . HoweverCells from porcine islets do not survive afterimplantation in rat or macaque kidneys without prior transplantation of E28 pig pancreatic primordia transplantation in mesentery , 8. WholSchroeder et al. define tEngraftment of pancreatic progenitors transplanted across a xenogeneic barrier to non-immune-suppressed immune-sufficient hosts has been reported twice previously. Eloy et al. described normalization of glucose posttransplantation of E15, but not E18 embryonic chick pancreas into liver of non-immune-suppressed STZ-diabetic rats . AbrahamHost immune suppression is required for successful engraftment of embryonic pig pancreas in rodents or non-hInterestingly, GALT may have served similarly to prevent an immune response to insulin-producing cells scattered originally in the gut epithelium of primitive vertebrates , 32 and Harada et al. have proposed a similar coopting of oral tolerance to explain the muted immune response in vivo and by cells from mesenteric lymph nodes in vitro to a colon carcinoma of BALB/c origin or a human CD80-transfected DBA/2 mastocytoma injected into the subserosal space of cecum in BALB/c mice relative to tumors injected subcutaneously . One way to confirm a causative link between gut immunity and our ability to transplant E28 pig pancreatic primordia and porcine islets in non-immune-suppressed hosts would be to \u201cbreak\u201d the established oral tolerance , using gIn any case, we have demonstrated in two species , 8, a no"}
{"text": "Natural Killer (NK) cells contribute to the control of cancer through immunosurveillance and may influence phenotypic sculpting of cancer through immunoediting. NK cells may also contribute to the control of hematological malignancies such as acute myeloid leukemia (AML) following allogeneic stem cell transplantation. However, no studies have shown direct clinical evidence that supports immunoediting by NK cells in AML at presentation, or whether activating ligand expression at diagnosis serves as a prognostic indicator of survival. We now show that at diagnosis, expression of NK cell ligands on AML blast populations is heterogeneous. Furthermore, expression of multiple activating ligands is associated with favorable cytogenetics and improved leukemia-free survival. In analyses of paired diagnostic and relapse samples, AML blasts exhibiting lower expression of activating ligands were selectively increased at relapse, indicating that NK cell-mediated blast immunoediting occurred prior to AML escape. Therapeutically, NK cell activating ligands could be upregulated on AML by in vitro treatment with bortezomib that enhanced NK cell-mediated cytotoxicity. Thus, diagnostic analyses of the expression of NK cell activating ligands in AML could be used to design therapeutic approaches for specific patients, and agents that stimulate NK cell function by restoring NK cell ligand expression may be appropriate to eliminate minimal residual disease and reduce risk of relapse."}
{"text": "Disseminated metastatic breast cancer needs aggressive treatment due to its reduced response to anticancer treatment and hence low survival and quality of life. Although in theory a combination drug therapy has advantages over single-agent therapy, no appreciable survival enhancement is generally reported whereas increased toxicity is frequently seen in combination treatment especially in chemotherapy. Currently used combination treatments in metastatic breast cancer will be discussed with their challenges leading to the introduction of novel combination anticancer drug delivery systems that aim to overcome these challenges. Widely studied drug delivery systems such as liposomes, dendrimers, polymeric nanoparticles, and water-soluble polymers can concurrently carry multiple anticancer drugs in one platform. These carriers can provide improved target specificity achieved by passive and/or active targeting mechanisms. Breast cancer is the most common cancer in females and the second most common cause of death in women in the United States . MetastaFor better therapeutic effectiveness combination anticancer treatment has long been adopted in clinics. The general rationale for employing combination therapy is twofold. First, when multiple drugs with different molecular targets are applied, the cancer adaptation process such as cancer cell mutations can be delayed. Second, when multiple drugs target the same cellular pathway they could function synergistically for higher therapeutic efficacy and higher target selectivity. Currently available combination regimens for metastatic breast cancer in clinics are limited to administrating a physical mixture of two or more anticancer agents. The clinically used combination regimens in the US can be broadly classified based on their mechanisms of action Figures includinSmall molecule chemotherapeutic agents can be given singly or in combination . ToxicitStreptomyces bacteria, are a class of drugs widely used and studied in cancer chemotherapy. Mechanisms of action of anthracyclines are (1) to inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells, (2) to inhibit topoisomerase II, preventing the relaxing of supercoiled DNA, and thus blocking DNA transcription and replication, and (3) to create iron-mediated free oxygen radicals that damage the DNA and cell membranes. Anthracyclines-based combination chemotherapy has shown improved anticancer activity than anthracyclines alone. For example, doxorubicin has achieved response rate of 40\u201350% as single agent while 60\u201370% in combination [With response rates of up to 60% in previously untreated patients with metastatic breast cancer anthracycline-based regimens are one of the most widely used first-line chemotherapies. Because of this advantage patients relapsing more than 12 months after anthracycline-based treatment may be reinduced with anthracycline-based combination chemotherapy . Anthracbination . These rbination . The combination . These rbination , 24. JoeTaxanes are another class of chemotherapy agents originally derived from natural sources then synthetically derivatized including paclitaxel (Taxol) and docetaxel (Taxotere). The mechanism of action of taxanes is to disrupt microtubule function. Microtubules are essential to cell division, and taxanes stabilize GDP-bound tubulin in the microtubule, thereby inhibiting the process of cell division. Therefore taxanes also can be classified as mitotic inhibitors. However due to their poor water-solubility, taxanes encounter difficulties in pharmaceutical formulation and this often results in reduced bioavailability.Different mechanisms of action of anthracyclines and taxanes provide the rationale of combination therapy of these two classes of drugs. Taxanes and anthracyclines typically do not produce overlapping toxicities with existing therapies. Bria et al. reported improved time to progression and overall survival from doxorubicin with paclitaxel (or docetaxel) therapy compared to anthracycline-based combination therapy (FAC or AC). Although greater hematologic toxicity (such as neutropenia) occurs from taxane containing regimen (74%) than the anthracycline regimen (63%) the overTaxane with nonanthracycline combinations is another highly effective regimen and is particularly useful in patients with rapidly progressive visceral metastases, who were previously treated with an anthracycline. In this regimen, capecitabine and gemcitabine are drugs of choices as nonanthracycline drugs for combination with taxanes (docetaxel or paclitaxel). Albain et al. reported the combination of gemcitabine and paclitaxel regimen to be superior to paclitaxel alone with longer time to progression (6 versus 4 months) and better response rate (41% versus 26%). However toxicity of this combination was higher with increased neutropenia (61% versus 22%), fatigue (19% versus 13%), and neuropathy (24% versus 22%) .Increased use of anthracyclines and taxanes in adjuvant (given in addition to main treatment) and neoadjuvant (given before the main treatment) settings limits the treatment options for patients upon relapse. Multidrug resistance (MDR) is a major limitation of conventional chemotherapy . This isAs discussed above most combination therapies with small molecule chemotherapeutic agents present improved clinical benefits including enhanced response rate and prolonged overall survival, progression-free survival, relapse-free survival, and/or time to progression. However, with additive efficacy the adverse effects from each agent are compounded resulting in patients' suffering from more treatment-related toxicity. The nonspecific nature of small molecule chemotherapeutics accounts for much of the toxicity due to nonselective biodistribution in healthy tissues concurrently with tumor accumulation. Additionally exposure to multiple conventional chemotherapeutic agents reduces response rate due to increased efflux of these drugs out of the cells mediated by the overexpression of MDR related efflux pumps or transporters . TherefoSmall molecule chemotherapeutic agents lack cancer cell-specific targeting ability and also affect the fast-dividing normal cells of the body . Therefore, the major adverse effects from these chemotherapeutic agents are nonspecific toxicities including anemia, nausea, vomiting, and hair loss. Biologic agents are advantageous to chemotherapy in their ability to actively target-specific receptors. Conventional chemotherapy does not discriminate effectively between tumor cells and rapidly dividing normal cells thus leading to nonspecific adverse effects. In contrast, target-specific anticancer therapies interfere with molecular targets that have an important role in tumor growth or progression distinct from normal cells. Also some of these agents act as inhibitors to MDR-related proteins thereby increasing the response rate . OverallMonoclonal antibodies are monospecific antibodies made by identical immune cells as clones of a unique parent cell. Due to their nature monoclonal antibodies can be designed to bind to specific substances hence they are widely used for target specific detection or purification . ApproxiBevacizumab, a monoclonal antibody against VEGFR, acts as an inhibitor of angiogenesis. VEGF is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from preexisting vasculature). Since angiogenesis is the essential way of providing nutrition to tumors and a fundamental step in the transition of tumors from a dormant state to a malignant one, it serves as important target for anticancer therapy. As monotherapy in metastatic breast cancer, it has only modest activity (response rate of 9%) . HoweverCetuximab is a monoclonal antibody that targets overexpressed EGFR in various cancers . EGFR isMonoclonal antibodies as biologic anticancer agents have shown reduced toxicity while having modest activities. The low response rates due to drug resistance can explain such modest activities. TRZ resistance is developed in about 70% of TRZ-treated breast cancer patients in early treatment period and onlyLapatinib is a small molecule dual tyrosine kinase receptor inhibitor of EGFR and HER2 that, like TRZ, has demonstrated a significant improvement in overall survival when added to the treatment of HER2-positive metastatic breast cancer . The benAnother strategy for targeting VEGF and tumor angiogenesis is the use of small molecule tyrosine kinase receptor inhibitors that target the VEGF receptor (VEGFR), including sunitinib, sorafenib, axitinib, and pazopanib. Gianni et al. reported improved response rate of 72% with the docetaxel plus sunitinib combination compared to 11% with sunitinib monotherapy. Most common side effects of sunitinib are anorexia, fatigue, mucositis, diarrhea, and nausea. However, the combination was well tolerated and did not significantly worsen the toxicity associated with the chemotherapy alone . Although these agents, alone or in combination with chemotherapy and/or other biologics, hold great promise, to date they have failed to demonstrate significant activity in metastatic breast cancer , 55. MosP = 0.02) of patients receiving olaparib, gemcitabine, and carboplatin compared to that of placebo and chemotherapy groups [Poly(adenosine diphosphate-ribose) polymerase (PARP) is a DNA-binding protein involved in detection and repair of DNA strand breaks . PARP iny groups .Although not many of the regimens are clinically approved, the concept of combination of two or more target-specific biologic agents is promising . The ratCmax\u2061 were not significantly different in comparing the combination with lapatinib alone. AUC24 and Cmax of TRZ were not significantly different when comparing the combination to trastuzumab alone [Beneficial therapeutic effectiveness from combination treatment is promising when considering theoretically nonoverlapping mechanisms of action of each anticancer agent. However, current combination treatments in metastatic breast cancer are far from perfect with moderate enhanced efficacy but additive toxicity as described above. Commonly these anticancer agents are administered together as a physical mixture of each agent without pharmacokinetic modification. These agents (free drugs) therefore distribute are eliminated independently of each other. As a result the additive effects are seen not only in anticancer activity but concurrently in adverse effects. Combining molecularly targeted agents is an improved strategy, but brings added complications including patient compliance issue. For example, in HER2 targeted combination therapy with TRZ and lapatinib, these two agents have two different routes of administration. TRZ is given intravenously weekly while lapatinib is administered daily as an oral formulation. Due to two different ways of administration with different schedules it is challenging to manage proper pharmacokinetic and pharmacodynamic profiles and virtually impossible to achieve uniform temporal and spatial codelivery. Storniolo et al. reported the results of a pharmacokinetic study of coadministration of TRZ and lapatinib to 27 patients. Serial blood samples were collected over a 24-hour period after ingestion of the lapatinib dose and/or the initiation of the 0.5-hour TRZ infusion. They reported that lapatinib area under the plasma drug concentration versus time curve within a 24-hour period after dosing and ab alone . HoweverThe challenges discussed above have driven researchers to investigate novel approaches by incorporating nanotechnology with combination anticancer treatment. The promising hypothesis is that by delivering two of more drugs simultaneously using a carrier-mediated drug delivery system the combination system can generate synergistic anticancer effects and reduce individual drug related toxicity. However this area of delivering multiple drugs with a single vehicle remains largely unexplored while most research efforts focus on single agent delivery systems. Therefore, here we will review carrier-mediated drug delivery systems containing multiple anticancer agents for cancer treatment in general not limited to metastatic breast cancer. Carrier-mediated drug delivery systems can offer many advantages over delivery of physical mixture of multiple drugs. The advantages include (1) prolonged drug circulation half-life mediated by the carrier, (2) reduced nonspecific uptake, (3) increased accumulation at the tumor site through passive enhanced permeation and retention (EPR) effect and/or active targeting by incorporation of targeting ligands , (4) preLiposomes are spherical vesicles composed of one or more lipid bilayers with a drug containing aqueous core . LiposomAnother unique liposomal system is a polymer-caged nanobin PCN, developeAttaching targeting ligands such as antibodies and peptides to a drug carrier is a widely applied strategy drastically increasing carrier accumulation in the desired cells, tissues, and organs. Several such targeted liposomes have been developed for combination drug delivery applications . Wu et aAs with any carrier-mediated codelivery system, determination of the optimal dose as the relative ratio of multiple drugs is a complex aspect in liposome-based combination drug delivery system. Mayer et al. reported precise control over combinatorial drug dosing in liposomes . The comDendrimers are well-established three-dimensional, branched polymers that have been thoroughly investigated as controlled and targeted drug delivery systems. The structure of dendrimers can be defined by an initiator core and layers of branched repeating units with functional end groups on the outmost layer . DendrimPolymeric nanoparticles are submicron-sized aggregate structures (3\u2013200\u2009nm) that are prepared using random or block copolymers. Polymeric nanoparticles are widely used as drug delivery carriers where the active drug may be physically encapsulated or covalently bound to the polymer matrix depending upon the method of preparation. Several polymeric nanoparticle systems have been explored specifically for combination drug delivery in cancer using both passive and active targeting strategies . For exaIn general it has been shown that polymeric nanoparticles, compared to liposomes, have greater stability, controlled size distribution, more tunable physicochemical properties, sustained and more controllable drug-release profiles, and higher loading capacity for poorly water-soluble drugs. While majority of the nanoparticle systems described above have demonstrated synergistic therapeutic efficacy in both in vitro and in vivo models some of these studies specifically illustrate that synergistic therapeutic effect is primarily due to the ability to administer two drugs in a tunable mass ratio with predictable spatial and temporal drug release profiles. For example Sengupta et al. developed a hybrid polymeric micelle comprisiPolymer-drug conjugates are drug delivery systems in which a drug is covalently bound to a water-soluble polymeric carrier, normally via a biodegradable linker. Such nanoconstructs were first proposed in the 1970s , develop N-(2-hydroxypropyl)methacrylamide (HPMA) is one example of biocompatible, non-immunogenic, non-toxic water-soluble copolymers that can be tailor-made for specific combination drug delivery needs . The uniOthers have explored modifications of the PEG backbone to conjugate a combination of chemotherapeutic agents. While unmodified PEG can only conjugate two drug molecules per chain (one on each end), Pasut et al. developed a PEG with a dendritic structure on one end that allowed coupling of upto 8 nitric oxide (NO) and one epirubicin (EPI) molecule per chain , 100. InOur research group has recently proposed a novel carrier-mediated combination drug delivery system for HER2 overexpressing metastatic breast cancer . We synthttp://www.celator.ca/) has developed a methodical approach to assess different drug ratios within their liposomal technology resulting in the development of different liposomal formulations that are now being assessed in phase II clinical trials, namely, CPX-1 (irinotecan: floxuridine) and CPX-351 (cytarabine: daunorubicin). Such an approach needs to be extended to other combination delivery systems such as dendrimers or polymer-drug conjugates. Determination of the kinetics of release of each drug in a multidrug combination system will be also necessary to determine the optimum ratio as one drug may affect the release profile of the other drug and thereby affect activity. Finally clinical development of these combination products is extremely challenging, due to developmental costs of designing such complex systems. However, these combination drug delivery system-based therapeutics are likely to be perceived by pharmaceutical companies as novel opportunities to extend the patent lives compared to current blockbuster drugs.The presence of two or more therapeutic agents on a single carrier platform offers new therapeutic possibilities but at the same time poses many new challenges. In order to identify an appropriate drug combination, it is necessary to perform thorough biological evaluation which must be supported by a profound understanding of the molecular mechanisms involved. Another critical aspect is the determination of the optimal mass ratio of each component within a combination drug delivery system. This requires systematic research investigating the impact of different drug ratios on the biological activity of the combination delivery systems. Recently a Canadian pharmaceutical company Celator ("}
{"text": "Tension-type headache (TTH) is the most prevalent headache among adults and is associated with impaired functional and psychosocial quality of life. Further analysis of eventual pathophysiology and comorbidities is needed. Temporomandibular Disorders (TMD) and TTH are frequently coexisting disorders and both characterized by increased pericranial tenderness. In a specialised tertiary headache centre more than half of the patients were also diagnosed with TMD but their eventual causality is yet unknown. Likewise is the relationship between tenderness, sleep quality and oral health in TTH patients also unknown. Our aim was to characterize the relationship between pericranial tenderness, sleep quality and oral health in TTH patients in comparison with healthy controls.The survey included 58 consecutive patients with frequent, episodic TTH or chronic TTH from a tertiary Headache Center and 58 healthy controls. Questionnaires regarding The Research Diagnostic Criteria for Temporomandibular Disorders (RDC), Oral Health Impact profile and Sleep/tiredness/snoring were completed.TTH-patients were significantly more affected in the RDC-Screening by increased characteristic pain intensity (CPI) regarding self reported temporomandibular pain (TMP) (p<0.001), decreased quality of life , and the total sleep score (p<0.001) compared to healthy controls).TTH patients are severely affected by TMP; demonstrate impaired sleep quality and oral health function and may reflect common underlying pathophysiological mechanisms."}
{"text": "Complex patients present with numerous risk factors and disease states. Clinical uses of biomarkers include diagnosis , risk stratification (assessing future risk of adverse outcomes or monitoring risk of adverse events), screening, and guiding therapy. Plasma natriuretic peptide are released from the heart in response to volume overload, as well as serving as markers of elevated filling pressures, a finding that in many cases would otherwise only be detectable with invasive testing. Therefore, the use of natriuretic peptides is an important adjunct to echocardiography in many circumstances. Just as BNP levels can be considered the arbitrator of CHF, cardiac troponins (TnI/TnT) are decisive for myocardial necrosis. The introduction of novel assays with even higher clinical sensitivity, detecting troponin levels at nanogram quantities, suggest even earlier diagnosis of acute myocardial infarction and identification of patients at substantial risk post-infarction. NGAL is one of the earliest and most robustly induced genes and proteins in the kidney after ischemic or nephrotoxic injury. Elevations are detectable within hours of acute kidney injury (AKI); whereas corresponding creatinine elevations lag 1 to 3 days behind."}
{"text": "This manuscript describes the NIH Human Microbiome Project, including a brief review of human microbiome research, a history of the project, and a comprehensive overview of the consortium's recent collection of publications analyzing the human microbiome. The Human Microbiome Project (HMP) Pioneering medical microbiologists applied these approaches, finding far more microbial diversity than expected even in well-studied body site habitats http://commonfund.nih.gov/hmp/) To coordinate these efforts relating the microbiome to human health, the NIH Common Fund launched the HMP as a community resource program unique to the study of the microbiome Any study of human populations must put both subject protection and study design first, and the HMP was no exception. Power calculations for microbiome studies in human cohorts are particularly challenging, as they must simultaneously address assay types , depth of sequencing, taxon detection, and fold abundance changes in clades, genes, or pathways of interest http://hmpdacc.org) hosts all available HMP data and many tools, focusing the tremendous quantity of raw data through lenses such as SitePainter Finally, quality data generation from appropriately designed microbiome studies enables a variety of subsequent computational analyses . While wThe HMP was designed in part to address a key question about our microbial selves: do all humans have an identifiable \u201ccore\" microbiome of shared components comparable to our shared genome A potentially more universal \u201ccore\" human microbiome emerged during the consideration of microbial genes and pathways carried throughout communities' metagenomes. While microbial organisms varied among subjects as described above, metabolic pathways necessary for human-associated microbial life were consistently present, forming a functional \u201ccore\" to the microbiome at all body sites Data from individuals without overt signs of disease serve as an excellent reference for disease-associated microbiome studies, while also providing a comprehensive baseline for comparison of Western populations with disparate geographic, ethnic, and genetic cohorts The HMP has thus greatly advanced our knowledge of the microbes in a healthy adult reference population, and provided much-needed infrastructure in terms of reference genomes, laboratory protocols, computational methods, and ELSI considerations"}
{"text": "Although very late stent thrombosis (VLST) after drug-eluting stent (DES) implantation remains a major concern, the precise mechanisms have not been clarified. An association between late acquired incomplete stent apposition (ISA) and VLST of DES has been suggested by several intravascular ultrasound studies demonstrating very high prevalence of ISA in the setting of VLST. To clarify the pathological mechanisms of VLST, we investigated vascular responses of coronary arteries of VLST cases after DES implantation. Drug-eluting stents (DESs) have dramatically reduced angiographic restenosis and clinical need for repeat revascularization procedures , 2. Howe The pathological findings from patients who died of late DES thrombosis have demonstrated that delayed arterial healing characterized by incomplete reendothelialization is an important underlying factor . The patAlthough a correlation has been observed between uncovered DES struts and LST, in our pathological studies of Japanese patients, considerable number of cases showed neointimal coverage with reendothelialization of a great deal of the DES struts, especially in simple lesions beyond 1 year . Thus, e Late ISA has been observed on follow-up intravascular ultrasound (IVUS) in patients who received sirolimus-eluting stents (SESs) . Althoug Thus, late ISA by focal positive vessel remodeling caused by medial necrosis may be responsible for LST and/or VLST after DES implantation. Peri-stent contrast staining (PSS) was defined as contrast staining outside the stent contour extending to \u226520% of stent diameter measured by quantitative coronary angiography. PSS found within 12 months after SES implantation appeared to be associated with subsequent VLST . PSS couRecent studies have identified immune cells and mediators at work in atheroma, implicating inflammatory mechanisms in disease development . As prevThus, DES can induce atherosclerotic and thrombogenic lesions with a significantly higher incidence and earlier than with BMS. LST may be more frequently related to incomplete healing and/or inadequate neointimal coverage with poor re-endothelialization. However, in the cases of VLST, several pathological studies have suggested a causal relationship between the inflammatory responses to the durable polymer and VLST, provoking late ISA and accelerated atherosclerosis followed by neointimal disruption. Histopathologic differences among DES platforms have been observed; this may reflect unique responses to the specific polymer/drug. Thus, until novel DES using superbly biocompatible and/or biodegradable polymers becomes available, we still need to be cautious and carefully keep surveying these devices."}
{"text": "Isolated granulomatous noncaseating pancreatitis is a rare condition exceptionally described in human population. We demonstrate a case of the a 71-years-old female patient suffering from recent diabetes mellitus, generalized atherosclerosis and hypertension who died due to pulmonary embolism and terminal bronchopneumonia. Lipomatosis of pancreatic tissue was observed during the postmortem examination. Histological examination of pancreatic tissue discovered multiple small noncaseating epithelioid cell and giant cell granulomas, partly replacing the islets of Langerhans. To our knowledge, our case represents the first description of noninfectious granulomatous pancreatitis associated with acute manifested insulin-dependent diabetes mellitus. Noncaseating granulomatous inflammation confined to the pancreas has been only exceptionally described in human patients. Infections like tuberculosis and syphilis, exogenous noxes, autoimmunity, and systemic granulomatous diseases are the most frequent causes of granuloma formation within the pancreatic tissue . AbdominA 71-year-old obese woman was admitted with the recent onset of diabetes mellitus manifested as hyperglycaemic ketoacidotic precoma. The past medical history was unremarkable. Recently, arterial hypertension was discovered. Her body weight was 110\u2009kg, BMI 38. The plasma glucose level ranged from 3.1 to 15.1\u2009mmol/L. The patient was treated with intensified insulin regime. The status of the patient was complicated by intermittent fever and several antibiotics were repeatedly administered. Terminally, clinical signs of septic shock and multiorgan failure appeared and the patient died. Postmortem examination performed 11 hours after death discovered signs of septic shock with activation of spleen pulp and terminal bronchopneumonia. Thromboemboli were found in several peripheral branches of the pulmonary artery. Hypertrophy of the heart (545\u2009g), predominantly of the left ventricle, was also observed. The pancreas showed a macroscopically lobular arrangement and lipomatosis; other macroscopic changes were not visible. Lungs, thoracic lymph nodes, and other organs did not show any changes corresponding with tuberculous process or sarcoidosis.\u03bcm-thick sections were stained with haematoxylin and eosin and by immunohistochemical methods using N-Histofine Immunohistochemical staining reagent and 3-3\u2032diaminobenzidine as a chromogen to visualize the reaction. The list of antibodies, including manufacturers and the dilutions used, is introduced in Five representative tissue samples of pancreatic tissue taken from head, body, and tail were fixed with 10% formalin and routinely embedded in paraffin. Five-Microscopic examination of pancreatic tissue discovered an increased amount of lipomatous tissue within the pancreatic lobules. Irregular inflammatory infiltrates of a variable density composed predominantly of small lymphocytes and sparse neutrophilic and eosinophilic granulocytes were also observed (\u03bcm) noncaseating epithelioid granulomas with giant cells, without Schaumann bodies, were present within the pancreatic lobules and pancreatic hormones verified the original microscopic finding of absence of islets of Langerhans . The majority of patients were presented by the obstructive jaundice, weight loss, and abdominal pain. Other autoimmune disorders, like sclerosing cholangitis or interstitial pneumonia, can appear in patients with AP. Histologically, AP is characterized by dense lymphoplasmacytic infiltrates and secondary fibrosis within the pancreatic tissue. Inflammation frequently displays a patchy collar arrangement around both small and large interlobular ducts and periphlebitis and obliterative phlebitis is invariably observed . It seemDiabetes mellitus in adults is predominantly of type 2. Much less frequently, type 1 diabetes and latent autoimmune diabetes (LADA) can appear in adult patients . DiabeteOur recent finding suggests that granulomatous pancreatitis is a possible underlying cause of diabetes mellitus and urges the microscopic examination of pancreatic tissue obtained during the post mortem examination of patients who died with signs and symptoms of recently manifested diabetes mellitus."}
{"text": "Burden of obesity has increased significantly in the United States over last few decades. Association of obesity with insulin resistance and related cardiometabolic problems is well established. Traditionally, adipose tissue in visceral fat depot has been considered a major culprit in development of insulin resistance. However, growing body of the literature has suggested that adipose tissue in subcutaneous fat depot, not only due to larger volume but also due to inherent functional characteristics, can have significant impact on development of insulin resistance. There are significant differences in functional characteristics of subcutaneous abdominal/truncal versus gluteofemoral depots. Decreased capacity for adipocyte differentiation and angiogenesis along with adipocyte hypertrophy can trigger vicious cycle of inflammation in subcutaneous adipose tissue and subsequent ectopic fat deposition. It is important to shift focus from fat content to functional heterogeneity in adipose tissue depots to better understand the relative role of subcutaneous adipose tissue in metabolic complications of obesity. Therapeutic lifestyle change continues to be the most important intervention in clinical practice at any level of increased adiposity. Future pharmaceutical interventions aimed at improving adipose tissue function in various subcutaneous depots have potential to help maintain adequate insulin sensitivity and reduce risk for development of insulin resistance complications. Prevalence of obesity has been increasing in the US. In 1960s, prevalence of obesity was approximately 13% , 3. ObesHowever, we have to consider clinical paradoxes along the spectrum of obesity, insulin resistance and metabolic complications. Metabolically healthy but obese (MHO) phenotype exhibits higher insulin sensitivity, absence of hypertension, and favorable lipid, inflammation, hormonal and liver enzyme profile. On the basis of epidemiological and clinical studies, prevalence of MHO phenotype varies from 10%\u201340% . The extExcessive insulin resistance and related metabolic abnormalities can be due to differential distribution of adipose tissue and/or adipose tissue dysfunction. Anatomically adipose tissues can be divided into truncal region or peripheral region. Truncal adipose tissue includes subcutaneous fat in thoracic and abdominal region and also intrathoracic and intraabdominal fat depots . PeripheVague in 1947 described two patterns of adipose tissue distribution\u2014android (upper body) and gynoid (lower body)\u2014and suggested that android obesity was associated with diabetes, coronary artery disease, gout, and uric acid renal stones . Later oVisceral fat has increased metabolic activity, both lipogenesis and lipolysis, compared to other fat depots. Free fatty acids, product of lipolysis, can directly enter liver via portal circulation and lead to increased lipid synthesis, gluconeogenesis, and insulin resistance resulting in hyperlipidemia, glucose intolerance, hypertension, and ultimately atherosclerosis . Excess We have examined the relationships between generalized and regional adiposity and insulin sensitivity in a group of nondiabetic men with varying degree of obesity . We concSimple explanation for stronger relationship between subcutaneous adipose tissue and insulin sensitivity comes from larger volume of subcutaneous adipose tissue mass. The subcutaneous abdominal fat mass is approximately twice more than intraperitoneal fat mass and total subcutaneous truncal fat mass can be 4-5 times larger than intraperitoneal fat mass , 23, 26.\u03baB stress pathway were upregulated suggesting stimulation of inflammatory mediators. Lundgren et al. [Inflammation in adipose tissue has been identified as a mediator of systemic insulin resistance. This has been suggested by presence of macrophage in the form of crown-like structures (CLSs) in adipose tissue. Apovian et al. examinedn et al. examinedn et al. . This isn et al. reportedn et al. , 35. Recent work on angiogenesis in adipose tissue has provided important insights into potential mechanisms of heterogeneity in the systemic metabolic impact of specific adipose tissue compartments. Gealekman et al. reportedIn contrast to abdominal subcutaneous adipose tissue, larger subcutaneous thigh fat mass has a protective effect. The Health, Aging, and Body Composition Study reported\u03baB pathway. The resultant effects are downregulation of cellular insulin signaling, recruitment of additional macrophages through monocyte chemoattractant protein 1, propagation of inflammation by interleukins and tumor necrosis factor alpha, and tissue matrix remodeling through matrix metalloproteinase-9 [Finally, it is worth putting truncal/abdominal subcutaneous adipose tissue characteristics all together to explain their emerging role in insulin resistance . Increaseinase-9 . These iConclusion. There is enough evidence in the literature for association between obesity and insulin resistance. Many investigators have proposed that visceral adipose tissue is a major contributor to insulin resistance. Our previous studies, in concordance with those of other investigators, suggest that subcutaneous truncal adipose tissue has significant impact on development of insulin resistance. Thus, adipose tissue distribution and function in different body compartments can be heterogeneous and can differentially contribute to insulin resistance. Changing focus from visceral adipose tissue mass as a sole contributor to insulin resistance to functional heterogeneity in adipose tissue depots can help better understand relationship of adiposity and insulin resistance. Therapeutic lifestyle change, including physical activity and weight loss, continues to be the most important intervention at any level of adiposity. One can envision that better understanding of adipose tissue function in various depots will help identify much needed additional and more effective therapeutic modalities to improve adipose tissue function and maintain adequate systemic glucose and lipid metabolism to reduce risk for morbidity and mortality associated with insulin resistance."}
{"text": "Since the introduction of recombinant human growth hormone (GH) in in the mid-1980s, supplies are almost limitless and predictably GH usage has escalated dramatically. There have been more than 150,000 children treated with GH worldwide with a wide variety of growth disorders.Adverse events (AE) with all forms of drug therapy are markedly under-reported, considerably underestimating the incidence of the AE. This under-reporting occurs even when the AE is serious and has a possible or probable association with GH therapy. Careful audit of the frequency of reporting of severe AE to other drugs with a possible or probable association with treatment is only 14%. Furthermore missing data is very common and adds to the difficulty in interpreting AE.Important conditions (adverse events) possibly linked to GH treatment are fortunately rare. There are several major limitations to accurately assessing the prevalence and risk of rare adverse events. Firstly, extremely large datasets are required found in large databases such KIGS and NCGS each with >50,000 enrolled patients. Secondly, accurate risk assessment of the possible adverse event in an untreated population that matches the GH treated population has rarely been determined.Important potential adverse events that have received considerable attention will be addressed. These include; tumour recurrence, new malignancies including leukaemia, diabetes mellitus, benign intracranial hypertension and slipped upper femoral epiphyses. The physiological rationale and the risk of these conditions during GH treatment will be addressed.Serum IGF-I monitoring to prevent elevated levels that may further increase the risk of adverse events is recommended. The potential adverse consequences of sustained elevated serum IGF-I levels will be discussed. In addition, monitoring IGF-I helps to monitor compliance of GH therapy in children with GH deficiency."}
{"text": "Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory pathological left ventricle (LV) hypertrophy due to sarcomere dysfunction. In an important proportion of patients with HCM, the site and extent of cardiac hypertrophy results in severe obstruction to LV outflow tract (LVOT), contributing to disabling symptoms and increasing the risk of sudden cardiac death (SCD). In patients with progressive and/or refractory symptoms despite optimal pharmacological treatment, invasive therapies that diminish or abolish LVOT obstruction relieve heart failure-related symptoms, improve quality of life and could be associated with long-term survival similar to that observed in the general population. The gold standard in this respect is surgical septal myectomy, which might be supplementary associated with a reduction in SCD. Percutaneous techniques, particularly alcohol septal ablation (ASA) and more recently radiofrequency (RF) septal ablation, can achieve LVOT gradient reduction and symptomatic benefit in a large proportion of HOCM patients at the cost of a supposedly limited septal myocardial necrosis and a 10-20% risk of chronic atrioventricular block. After an initial period of enthusiasm, standard DDD pacing failed to show in randomized trials significant LVOT gradient reductions and objective improvement in exercise capacity. However, case reports and recent small pilot studies suggested that atrial synchronous LV or biventricular (biV) pacing significantly reduce LVOT obstruction and improve symptoms (acutely as well as long-term) in a large proportion of severely symptomatic HOCM patients not suitable to other gradient reduction therapies. Moreover, biV/LV pacing in HOCM seems to be associated with significant LV reverse remodelling. Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory LV hypertrophy mainly due to sarcomere dysfunction. Prevalence of the disorder in the general population is estimated to be 0.2% . A subseMedical therapy is at least partially effective in the majority of HOCM patients and consIn severely symptomatic HOCM patients despite optimal medical treatment and with significant resting or provocable LVOT obstruction (with gradient \u226530 mm Hg at rest or \u226550 mm Hg during exercise) non-pharmacologic treatment is indicated even in less symptomatic HOCM patients , with a even in In the overwhelming majority of HOCM patients LV/biV pacing is acutely more effective for gradient reduction than standard RVA pacing: eight out of nine in one study and all In contrast to studies with DDD RVA pacing, LV/biV pacing showed that the reduction in LVOT gradient induced a progressive and significant reduction in LV mass (reverse remodelling) . The thiDuring long term LV/biV pacing in HOCM there was no SCD/syncope in patients with CRT-P ,38. In tThe small number of patients included in studies with LV/biV pacing in HOCM as well as the fact that all of them are observational and uncontrolled requires caution in interpreting the results. However, the differences observed in comparison with standard DDD RVA pacing warrants further research. Considering the relatively large number of HOCM patients submitted to cardioverter-defibrillator implantation for primary or secondary prevention, data for such analysis should be readily available.In selected patients with HOCM, LV/biV pacing is feasible and usually the best configuration for gradient reduction. Overall, LV/biV pacing in patients with HOCM significantly and progressively improves functional capacity and quality of life. It may also induce LV reverse remodelling."}
{"text": "Microbial cells are highly complex and heterogeneous systems. In general, cell populations contain subgroups of cells which exhibit differences in growth rate as well as resistance to stress and drug treatment In the past 20 years a new form of microscopy, atomic force microscopy (AFM), has revolutionized the way researchers probe the microbial cell surface. Instead of using an incident beam, AFM measures the minute forces acting between a sharp tip and the sample AFM is much more than a surface-imaging tool in that it also measures the localization and mechanical properties of the individual cell surface molecules. In this modality, known as single-molecule force spectroscopy, the cantilever deflection is recorded as a function of the vertical displacement of the scanner (as the sample is pushed towards the tip and it retracts) Lactobacillus rhamnosus GG, Lactococcus lactis, and Lactobacillus plantarumL. rhamnosus GG had a rough surface morphology decorated with 15 nanometer\u2013high wave-like structures, attributed to the production of extracellular polysaccharides involved in host adhesion L. lactis showed 25 nanometer\u2013wide striations documenting peptidoglycan cables running parallel to the short cell axis, thus supporting the classical model for peptidoglycan organization Bacillus subtilisL. plantarum documented a highly polarized surface morphology that was correlated with a heterogeneous distribution of teichoic acids There has been rapid progress in recent years using AFM for imaging microbial surfaces under physiological conditions. In structural biology, AFM has provided fascinating insights into the supramolecular architecture of membrane proteins, thereby complementing data obtained by electron and X-ray crystallography Bacillus thuringiensis flagella involved in cell motility Aspergillus fumigatusCorynebacterium glutamicumStaphylococcus aureus was observed during growth, revealing ring-like and honeycomb structures at 20 nanometers resolution Bacillus atrophaeus spores revealed germination-induced alterations in spore coat architecture and disassembly of rodlet structures Candida albicans and macrophages Remarkably, high-resolution imaging has allowed researchers to observe cell surface structures to a resolution of a few nanometers. Observed structures include Escherichia coli cells AFM imaging thus opens up unprecedented possibilities for studying the structural details of the surface of microbial pathogens without drying, staining, or fixation. As conventional AFM imaging is limited by a rather poor temporal resolution, an important challenge is to increase the speed of AFM to study fast dynamic biological processes Shewanella oneidensis bacteria C. albicans with AFM tips terminated with specific antibodies triggered the formation and propagation of adhesion nanodomains on the cell surface While AFM imaging lacks biochemical specificity, single-molecule force spectroscopy with functionalized AFM tips makes it possible to map the distribution of specific molecules on living cells. The method involves scanning the cell surface with a tip bearing cognate ligands while measuring specific receptor-ligand forces E. coli fimbrial adhesive protein FimH which strengthen under external mechanical force C. albicans revealed sawtooth patterns with multiple force peaks, corresponding to the force-induced unfolding of hydrophobic tandem repeats engaged in cell adhesion and respond to force . Knowing these molecular properties is critical to our understanding of cell surface functions.Many challenges remain to be addressed. As we have already discussed, further developments in high-speed AFMs"}
{"text": "There is no consensus on optimal use of radiotherapy following radical prostatectomy. The purpose of this study was to describe opinions of urologists and radiation oncologists regarding adjuvant and salvage radiotherapy following radical prostatectomy.Urologists and genitourinary radiation oncologists were solicited to participate in an online survey. Respondent characteristics included demographics, training, practice setting, patient volume/experience, and access to radiotherapy. Participant practice patterns and attitudes towards use of adjuvant and salvage radiotherapy in standardized clinical scenarios were assessed.One hundred and forty-six staff physicians participated in the survey (104 urologists and 42 genitourinary radiation oncologists). Overall, high Gleason score , positive surgical margin , and extraprostatic tumour extension conferred an increased probability of recommending adjuvant radiotherapy. Radiation oncologists were more likely to recommend adjuvant radiotherapy across all clinical scenarios . Major differences were found for patients with Gleason 6 and isolated positive surgical margin (radiotherapy selected by 21% of urologists vs. 70% of radiation oncologists), and patients with extraprostatic extension and negative surgical margins (radiotherapy selected by 18% of urologist vs. 57% of radiation oncologists).Urologists and radiation oncologists frequently disagree about recommendation for post-prostatectomy adjuvant radiotherapy. Since clinical equipoise exists between adjuvant versus early salvage post-operative radiotherapy, support of clinical trials comparing these approaches is strongly encouraged. Approximately 40% of patients diagnosed with prostate cancer will be treated with radical prostatectomy and approximately 15-35% will develop a detectible serum prostate-specific antigen (PSA) following surgery . A positTraditionally, clinicians may have been more likely to treat patients with androgen deprivation if clinicopathologic features were associated with high risk of systemic disease and more likely to treat patients with adjuvant or salvage radiotherapy if features were associated with high risk of isolated localized disease . HoweverWhile indications for pelvic radiotherapy may have changed, questions remain about the timing of treatment. Adjuvant radiotherapy is offered to patients prior to PSA recurrence while salvage radiotherapy reserves treatment, and its associated side effects, for men with proven biochemical recurrence. Randomized trials of adjuvant radiotherapy versus observation reveal a reduction in biochemical recurrence and prolonged survival (SWOG 8794) while observational studies suggest salvage radiotherapy versus observation reduces progression and prolongs survival ,20. The th, 2011. Institutional ethics approval was obtained for this survey from the Ottawa Hospital Research Ethics Board prior to study commencement.In October 2011, Canadian Urological Association (CUA) members and genitourinary radiation oncologists from the Canadian Association of Radiation Oncology (CARO) were invited to participate in an online survey. CUA members were contacted through the CUA listserv and radiation oncologist emails were available through the CARO member directory. A second request was made one month following the original invitation. E-mail recipients were provided with a hyperlink to an online survey that populated a secure database. The survey was closed on November 7Participants were asked to provide demographic information including age, geographic location of practice, specialty (urology or radiation oncology), practice type (academic or community), years in practice, sub-specialty training, number of prostate cancer patients assessed per year, and access to radiotherapy.Respondents were asked to rate how various clinical and pathologic variables independently influenced their recommendation for adjuvant and salvage radiotherapy via Likert items. Clinical variables included patient age, urinary continence, and erectile function. Pathologic variables included extraprostatic tumour extension, seminal vesicle tumour invasion, lymph node metastases, pre- and post-operative PSA concentrations, Gleason score, pathologic stage, and surgical margin status. Respondents were provided with a standardized case scenario of a healthy 60 year old male 3-months post radical prostatectomy with an undetectable PSA. They were asked to recommend for or against adjuvant radiotherapy for this patient given varied Gleason score, pathologic stage, and surgical margin status.adjuvant radiotherapy after radical prostatectomy in the provided clinical scenario. A-priori independent variables for the clinical scenario model were Gleason grade, tumour stage, surgical margin status, and medical specialty. P-values < 0.05 were considered statistically significant.Survey responses were summarized with frequencies and percentages. Associations between clinician/patient characteristics and choice of adjuvant radiotherapy were calculated using logistic regression. Log binomial regression was used to calculate relative risks (RR) using the proc genmod procedure in SAS. RR are presented with 95% confidence intervals (CI). Candidate predictor variables included clinician characteristics and pathologic factors . Each predictor variable was assessed as a categorical variable. The primary outcome was the respondent\u2019s decision to recommend From 586 listed emails, 146 (25%) staff physicians participated in the survey and were included in the analysis. 104 (22%) of solicited urologists and 42 (40%) of solicited genitourinary radiation oncologists completed the survey. The majority of radiation oncologists and approximately half of urologists indicated they practiced in an academic institution. Sub-specialty training in genitourinary oncology was reported in 51 (35%) respondents. The mean number of years in practice was 14 years (SD 10.3). Full demographic characteristics are presented in A majority of urologists and radiation oncologists reported that recent randomized trials have changed the way they manage patients after radical prostatectomy. When asked their opinion regarding the value of adding androgen deprivation therapy (ADT) to adjuvant or salvage radiotherapy, 29 (35%) urologists and 13 (32%) radiation oncologists reported believing it is likely beneficial and 44 (52%) urologists and 22 (55%) radiation oncologist would recommend it to high risk patients. A large proportion of urologists and radiation oncologists believed more research is required to evaluate the benefit and harm of ADT when used in conjunction with radiotherapy following prostatectomy. The influence of clinical and pathologic factors on the recommendation for adjuvant or salvage radiotherapy is presented in Large differences were identified in the opinions of radiation oncologists and urologists regarding recommendations for adjuvant radiotherapy when pathologic variables were placed in the context of a standardized clinical scenario . SeventyOverall, radiation oncologists were 48% more likely to recommend adjuvant radiotherapy compared to urologists . Of the remaining clinical factors evaluated, only physician age had a significant impact on the recommendation for adjuvant radiotherapy with older physicians being less likely to recommend radiotherapy . Practice setting, access to radiotherapy, and genitourinary oncology fellowship training did not strongly influence the probability of recommending radiotherapy .Pathologic variables were associated with the recommendation for adjuvant radiotherapy . A GleasTo adjust for potential confounders, multivariable analysis was performed to determine the independent associations between each predictor variable and the recommendation for adjuvant radiotherapy . PatholoThis survey explored the practice patterns and opinions of two different specialty groups involved in the management of patients with prostate cancer, urologists and radiation oncologists, and identified factors that influence recommendations for post-operative radiotherapy. For every pathological variable examined, radiation oncologists were more likely to recommend adjuvant radiotherapy than were urologists with a mean absolute difference of 27% and relative difference of 48%. There were clinical scenarios where urologists and radiation oncologists agreed; specifically, both commonly recommended adjuvant radiotherapy in patients with extraprostatic tumour extension and a positive surgical margin, high Gleason score and a positive surgical margin, or seminal vesicle invasion. Conversely, there was lack of consensus for patients with low Gleason score and an isolated positive surgical margin, and for patients with extraprostatic extension and negative surgical margin. The influence of medical specialty on treatment recommendations was striking and is a trend that has been previously observed amongst urologists and radiation oncologists when selecting primary treatment of prostate cancer .Standardized scenarios in the survey represented patients that would have met inclusion criteria for entry into SWOG 8794 . The SWOExamining each variable independently, a large proportion of physicians surveyed were more likely to recommend adjuvant post-operative radiotherapy in patients with extraprostatic disease, high Gleason score, seminal vesicle invasion, and positive surgical margins. It is interesting to note that surgical margin status appeared to influence urologists much more than radiation oncologists (RR 1.6 vs. 1.08). Taken as a whole, these results indicate a departure from the dogmatic approach of avoiding radiotherapy in patients with high risk of metastases . FactorsAmong post-operative patients who develop a detectable serum PSA, the survey identified several factors that influence the likelihood of physicians recommending salvage radiotherapy. In addition to the pathological and clinical characteristics identified for adjuvant radiotherapy, post-operative PSA kinetics strongly influenced physician opinion. Physicians were more likely to recommend radiotherapy when there was a prolonged duration between prostatectomy and detection of post-operative PSA and when the PSA doubling time was long. This finding is somewhat surprising and illustrates a misconception amongst physicians surveyed regarding the value of salvage radiotherapy for long and short PSA doubling times (PSADT). Although observational studies have reported a better prognosis for men with PSADT > 10 months, the absolute benefit of salvage radiotherapy is in fact greater in men with rapid PSADT ,20. TherA limitation of the current literature is a lack of randomized comparison of adjuvant and salvage radiotherapy. Adjuvant radiotherapy (prior to PSA recurrence) may be better than salvage radiotherapy (when PSA becomes detectible) for several reasons. Firstly, recurrences are predominantly local in the absence of seminal vesicle invasion or lymph node metastases, therefore early local treatment may prevent metastases . FurtherIdentification of patients likely to benefit from post-operative radiotherapy is important since this intervention is associated with harm . ComplicThis survey has limitations. We are unable to determine the true response rate since email lists were used and the activity of the email accounts could not be determined. While a wide distribution of clinician age, practice setting, and sub-specialty training was observed in the respondents, information about non-respondents was not available to assess potential biases. This survey included primarily Canadian physicians, and practice patterns may be different in other health care settings. Finally, this survey draws data from responses to realistic but fictional patient scenarios and thus cannot control for variations in respondent interpretation.The results of this survey reveal some consensus and some salient differences in the opinions of physicians regarding post-radical prostatectomy radiotherapy. Most notably, there was a large difference in the proportion of urologists and radiation oncologists who recommended radiotherapy for patients with low Gleason scores and isolated positive margins or extraprostatic extension. Since clinical equipoise exists between adjuvant and early salvage post-operative radiotherapy, support of clinical trials comparing these two approaches is strongly encouraged."}
{"text": "Cuculus canorus) is a generalist brood parasite that lays its eggs in the nest of many different passerine birds, but each female tends to specialize on one particular host species giving rise to highly specialized host races. The different host species show large variation in their ability to invest in the parasitic offspring, presenting an opportunity for female cuckoos to bias offspring sex ratio in relation to host species quality. Here, we investigate host-race specific sex allocation controlling for maternal identity in the common cuckoo. We found no evidence of any significant relationship between host race and sex ratio in one sympatric population harbouring three different host races, or in a total of five geographically separated populations. There was also no significant association between host quality, as determined by species-specific female host body mass, and cuckoo sex ratio. Finally, we found no significant relationship between individual cuckoo maternal quality, as determined by her egg volume, and sex ratio within each host race. We conclude that the generalist brood-parasitic common cuckoo show no significant sex-ratio bias in relation to host race and discuss this finding in light of gene flow and host adaptations.Sex allocation theory and empirical evidence both suggest that natural selection should favour maternal control of offspring sex ratio in relation to their ability to invest in the offspring. Generalist parasites constitute a particularly interesting group to test this theory as different females commonly utilize different host species showing large variation in provisioning ability. The common cuckoo ( Fisher In birds, females are the heterogametic sex and the sex determining division in avian meiosis occurs prior to ovulation and fertilization, providing the females with an unusual direct opportunity to modify offspring sex ratio Cuculus canorus) therefore constitutes a particular interesting species for investigating sex allocation. The common cuckoo is highly polygynous with ca. half of all males siring offspring with more than one female and is sexually size dimorphic The avian brood-parasitic common cuckoo (Molothrus ater) A few previous studies have not revealed any significant relationship between host species and sex ratio in the common cuckoo or the brood-parasitic brown-headed cowbird was drawn by puncturing either the brachical or femoral vein. Permits for working with cuckoos and their hosts and collect DNA samples was received in each country; permits were issued by the Ministry of Environment and Water in Bulgaria; the Municipal Office in Hodonin (3C2KA/2003) in the Czech Republic; the Southeast Finland Regional Environment Centre in Finland; the Middle-Danube-Valley Inspectorate for Environmental Protection (31873), Nature Conservation and Water in Hungary; and the Regional Ethical Committee in Wroc\u0142aw and the Faculty of Biology (KWB.0118.1-2003), University of Wroc\u0142aw in Poland.Milaria calandra), great reed warblers and marsh warblers was collected in the surroundings of Zlatia, north-western Bulgaria A. scirpaceus) in Luzice, Czech Republic where also great reed warblers, marsh warblers and sedge warblers (A. schoenobaenus) are parsitized Phoenicurus phoenicurus) Data on three sympatrically breeding cuckoo host races parasitizing corn buntings . All loci were amplified by polymerase chain reaction (PCR) on a GeneAmp PCR System 9700 and run on a 3130XL Genetic Analyser . The sex marker and microsatellites were scored in Genemapper v. 3.7 , and the mitochondrial sequence data were assembled and manually checked in Geneious v. 4.7.6 We used the CHD1-M5 primer in combination with P8 for molecular sex determination Many cuckoo nestlings were collected within the same geographic area and could be either full- or halfsiblings, and hence potentially represent a problem of pseudoreplication. We therefore analysed a genetic dataset on 13 microsatellite markers . Furthermore, there were no significant differences in sex ratio between any pair of the five host races pooled across the different geographic localities , or between sympatric and allopatric populations, including host species as a random effect to control for host race identity .In order to analyze the effect of host species quality we included species-specific host female body mass In this study, we investigated host-specific sex ratio in the generalist brood-parasitic common cuckoo. We hypothesized that sex ratio of cuckoo offspring should vary in relation to host species quality in accordance with predictions from sex allocation theory. However, we found no evidence of any significant relationship between host race and sex ratio in one sympatric population harbouring three different host races, or in a total of five different geographically separated populations. Hence, our results corroborate the few previous studies on avian brood parasites According to theory, female cuckoos have both the ability and opportunity to increase their own fitness by selectively producing the rarer sex. Firstly, avian females have an unusual direct opportunity to modify offspring sex ratio because the sex determining division in avian meiosis occurs prior to ovulation and fertilization The traditional Trivers-Willard hypothesis rests on three assumptions. Firstly, parental condition must be associated with offspring condition; secondly, any difference in offspring condition must persist into adulthood; and thirdly, condition must differentially affect the mating success of one sex more than the other sensu Trivers and Willard The occurrence of genetic differentiation and assortative mating may explain why females show no evidence of sex ratio bias in relation to host quality. If males commonly mate within their own host race, males from large host races will not compete directly with males from smaller host races, and therefore not achieve a higher reproductive success than their sisters. Hence, natural selection will not select for a male-biased sex ratio sensu Trivers-Willard may be counteracted by the selection for smaller females in cuckoos. This could also explain the lack of any relationship between sex ratio and female quality, as determined by cuckoo egg volume, within each host race. It is also possible that egg volume does not capture maternal quality in the way we expect, and that other measures like investment in hormones and anti-oxidants in the oocyte would be more suitable A comparative study on the family Cuculidae suggests that sexual size dimorphism has more likely evolved via coevolution than sexual selection in this taxa We conclude that the generalist brood-parasitic common cuckoo show no evidence of sex-ratio bias in relation to host race, host race quality or individual maternal quality."}
{"text": "Aging is accompanied by substantial changes in brain function, including functional reorganization of large-scale brain networks. Such differences in network architecture have been reported both at rest and during cognitive task performance, but an open question is whether these age-related differences show task-dependent effects or represent only task-independent changes attributable to a common factor . To address this question, we used graph theoretic analysis to construct weighted cortical functional networks from hemodynamic responses in 12 younger and 12 older adults during a speech perception task performed in both quiet and noisy listening conditions. Functional networks were constructed for each subject and listening condition based on inter-regional correlations of the fMRI signal among 66 cortical regions, and network measures of global and local efficiency were computed. Across listening conditions, older adult networks showed significantly decreased global efficiency relative to younger adults after normalizing measures to surrogate random networks. Although listening condition produced no main effects on whole-cortex network organization, a significant age group x listening condition interaction was observed. Additionally, an exploratory analysis of regional effects uncovered age-related declines in both global and local efficiency concentrated exclusively in auditory areas , further suggestive of specificity to the speech perception tasks. Global efficiency also correlated positively with mean cortical thickness across all subjects, establishing gross cortical atrophy as a task-independent contributor to age-related differences in functional organization. Together, our findings provide evidence of age-related disruptions in cortical functional network organization during speech perception tasks, and suggest that although task-independent effects such as cortical atrophy clearly underlie age-related changes in cortical functional organization, age-related differences also demonstrate sensitivity to task domains. Aging is characterized by marked declines in sensory and cognitive functions In recent years, graph theoretic analysis has offered a powerful data-driven framework to explore the topological organization of brain networks These functional differences are underlain by neuroanatomical changes across the lifespan. Such changes include widespread atrophy of both subcortical and cortical grey matter structures Given these pervasive, co-occurring functional and neuroanatomial changes, the question also arises whether age-related effects on brain functional organization are independent of cognitive domains , or show task specificity. Recently, Wang et al. examined changes in functional networks of younger and older adults obtained via fMRI during memory encoding and retrieval tasks involving visually presented words and pictures To address these questions, we employed functional MRI to investigate age-related differences in large-scale cortical networks associated with speech perception tasks. In the scanner experiment, we tested 12 younger and 12 older adults' abilities to recognize spoken word stimuli and match them to objects on a screen in both a quiet listening condition and in loud multi-talker background noise regional measures) and also averaged across all nodes in each network to describe the overall network topology. We compared both regional and whole-cortex measures across age groups and task conditions, after normalizing the graph measures to values in surrogate random networks. Additionally, to test for a relationship between age-related changes in functional network properties and neuroanatomical characteristics, we examined the relationship between whole-cortex network measures and mean cortical thickness.In the present analysis, we applied graph theoretic analysis to construct weighted cortical functional networks for each subject and listening condition based upon interregional correlations of the fMRI signal among 66 cortical regions. Graph measures describing the efficiency of global and local information transfer were computed within each individual network node of older adults coupled with age-related increases in cognitive areas in prefrontal and posterior parietal cortex, changes believed to underlie a compensatory mechanism for reduced sensory abilities in aging To foreshadow the results, we found significant age-related decreases in global network efficiency, agreeing with previous studies of age effects on large-scale brain networks globE) and local (locE) efficiency were computed and averaged across all cortical regions to quantify the efficiency of global and local information transfer within the networks. by assigning connections based on the inter-regional correlation of fMRI responses between 66 cortical regions specified in the Desikan-Killiany atlas . Both younger and older adults possessed small-world network topologies characterized by es e.g., . RelativTo test these differences statistically, summary measures of osts see . HencefoConceivably, observed differences in brain functional connectivity could be related to head motion in the scanner Next, we tested for effects of subject group and listening condition on network measures within individual cortical regions. We applied a single p-value cutoff of 0.05 (uncorrected for multiple comparisons) to establish significance for regional effects; thus, our results at the regional level must be regarded as exploratory. Additionally, we found several areas that showed main effects of listening condition on the network measures see . The noiWe also observed regions showing an interaction effect between subject group and task condition see . For , ssubjects .As anticipated, older adults had significantly reduced mean cortical thickness relative to younger adults despite normal peripheral hearing abilities Interestingly, we observed a different pattern of results in these residual data relative to the original results see , S2. ForThe performance effect analysis also revealed a different pattern of results for the regional network measures . As in tyrus see . ListeniIn this study, we applied a weighted graph theoretic analysis to assess cortical functional organization in younger and older adults during performance of a speech perception task in both quiet and noisy listening conditions. We found that older adult cortical networks possessed significantly reduced global efficiency relative to younger adults after normalizing graph measures to values in randomized networks. Most importantly, a significant group x listening condition interaction effect for This report adds to a body of research linking cognitive aging to disrupted organization of communication pathways encompassing the entire cerebral cortex Importantly, the age-related disruptions observed for whole-cortex network properties were underlain by regional changes concentrated in auditory areas of the lateral temporal cortex. Older adults possessed decreased global and local efficiency within bilateral superior and middle temporal cortex. The superior temporal cortices constitute key auditory regions responsible for low-level acoustic analysis; thus, declines in efficient information transfer involving these regions could affect mapping of inputs from the peripheral auditory system onto acoustical representations Additionally, we observed regions that exhibited main effects of listening condition (quiet vs. noisy) on either global or local efficiency. Several of these regions overlapped the default-mode network, including bilateral posterior parietal and right parahippocampal cortex We also found several cortical areas showing significant group x listening condition interaction effects on the regional network measures. Group x condition interaction effects were observed in left primary auditory cortex, right middle temporal cortex, and in default-mode areas within posterior parietal cortex. Thus, in addition to task-dependent age-related differences on whole-cortex network structure, the two listening conditions evoked differential effects on network organization between younger and older adults at the regional level.In addition, group x condition interaction effects on Based on findings of consistent age-related differences in activation patterns and functional network topology across memory encoding and recognition tasks, Grady et al. and Wang et al. argued that age-related changes in brain network organization derive from a common, domain-general factor Declining cognitive performance is a central aspect of aging. Even though the older participants in our study possessed normal peripheral hearing abilities, their speech perception performance was significantly worse than that of younger adults under the increased sensory/cognitive demands of the noisy listening environment Ultimately, the effects of reduced cognitive performance on cortical functional organization in aging remains an area for further investigation. However, the significant age-related effects at both the whole-cortex and regional levels in this residual analysis suggest that task performance is not the only important factor driving the results observed in this study. These types of complementary analyses may prove useful in future studies to help disentangle the various behavioral, anatomical, and physiological factors influencing functional organization of the cortex in both aging research and comparative neuroimaging studies in general.Looking across all subjects, we found a significant positive correlation between mean cortical thickness and It is also worth noting some important limitations of our study. First, similar to previous studies This study provides evidence of age-related disruptions in large-scale cortical functional organization during performance of a speech perception task. Although the observed age-related differences in whole-cortex network topology partly corroborated previous studies of resting-state connectivity All subjects in this experiment gave informed written consent prior to inclusion in the study and were compensated monetarily for their participation. All research was conducted under the approval of the Northwestern University Institutional Review Board, and thus adhered to the ethical standards outlined in the 1964 Declaration of Helsinki.In this study, we employed functional magnetic resonance imaging (fMRI) to examine characteristics of cortical functional networks related to speech perception in noise (SPIN) performance in younger (19\u201327 years) and older (63\u201375 years) adults We recruited twelve younger ; 8 females) and twelve older ; 6 females) adults with no reported neurological deficits for participation in the study.Speech stimuli consisted of a set of twenty target words obtained from In the scanner experiment, subjects were presented with one-word speech stimuli via headphones . During each stimulus presentation, subjects were shown three images on a screen, including an image matching the target word and two distracters, and used a response box to select the image corresponding to the target word. For instance, in one trial, subjects heard the word \u201cwitch\u201d in the presence of background noise, and had to select between images of a witch and two other objects from the list of stimuli. Stimuli were presented in 12-second blocks consisting of three individual stimuli (each corresponding to the same listening condition), limiting response times to four seconds per stimulus. In total, the fMRI experiment consisted of 60 stimulus blocks per condition as well as 30 null blocks during which no stimuli were presented, with all blocks presented in pseudorandomized order.*-weighted functional images were acquired using a susceptibility-weighted EPI pulse sequence , with 24 slices acquired per scan in an interleaved measurement . Functional image acquisition occurred directly after each 12-second stimulus block and lasted two seconds in duration, resulting in a 14-second repetition time (TR). The sparse functional image acquisition (long TR) ensured there was no scanner noise during stimulus presentation MR imaging data were acquired on a Siemens 3T Trio machine at the Center for Advanced MRI at Northwestern University. T1-weighted, high-resolution anatomical images were acquired axially . During the speech perception experiment, T2We pre-processed MRI data using AFNI V) were extracted containing the functional data from the stimulus blocks corresponding to the listening condition of interest, and pair-wise, zero time-lag Pearson's correlations were calculated between nodes such thati and j, where R) containing the pair-wise correlations of the fMRI responses between each pair of cortical regions for each listening condition.Next, using FreeSurfer's automated cortical parcellation G by assigning undirected, weighted connections (edges) between nodes whose absolute pair-wise correlation exceeded a pre-specified cost threshold, cr. This resulted in a weighted adjacency matrix (W), such that ij\u200a=\u200aW|ijR| if ij|\u2265rc|R or ij\u200a=\u200a0W if ij|