Search

Background: To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur.Methods and Findings: We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th-95th percentile, to provide an indication of the uncertainty in the estimates. We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th-95th centiles, 83,300-217,700) while causing potentially 253 intussusception deaths (76-689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000-281,500) while potentially causing 547 intussusception deaths (237-1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700-63,700) and cause an additional 294 (161-471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%-25% children, beyond the 63%-73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes.Conclusions: Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths. Please see later in the article for the Editors' Summary. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Estimates of vaccination costs usually provide only point estimates at national level with no information on cost variation. In practice, however, such information is necessary for programme managers. This paper presents information on the variations in costs of delivering routine immunization services in three diverse districts of Peru: Ayacucho (a mountainous area), San Martin (a jungle area) and Lima (a coastal area). METHODS: We consider the impact of variability on predictions of cost and reflect on the likely impact on expected cost-effectiveness ratios, policy decisions and future research practice. All costs are in 2002 prices in US dollars and include the costs of providing vaccination services incurred by 19 government health facilities during the January-December 2002 financial year. Vaccine wastage rates have been estimated using stock records. FINDINGS: The cost per fully vaccinated child ranged from 16.63-24.52 U.S. Dollars in Ayacucho, 21.79-36.69 U.S. Dollars in San Martin and 9.58-20.31 U.S. Dollars in Lima. The volume of vaccines administered and wastage rates are determinants of the variation in costs of delivering routine immunization services. CONCLUSION: This study shows there is considerable variation in the costs of providing vaccines across geographical regions and different types of facilities. Information on how costs vary can be used as a basis from which to generalize to other settings and provide more accurate estimates for decision-makers who do not have disaggregated data on local costs. Future studies should include sufficiently large sample sizes and ensure that regions are carefully selected in order to maximize the interpretation of cost variation. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is the second most common pathogen causing infant mortality. Additionally, RSV is a major cause of morbidity and mortality in older adults (age ≥60 years) similar to influenza. A protein-based maternal vaccine and monoclonal antibody (mAb) are now market-approved to protect infants, while an mRNA and two protein-based vaccines are approved for older adults. First-year experience protecting infants with nirsevimab in high-income countries shows a major public health benefit. It is expected that the RSV vaccine landscape will continue to develop in the coming years to protect all people globally. The vaccine and mAb landscape remain active with 30 candidates in clinical development using four approaches: protein-based, live-attenuated and chimeric vector, mRNA, and mAbs. Candidates in late-phase trials aim to protect young infants using mAbs, older infants and toddlers with live-attenuated vaccines, and children and adults using protein-based and mRNA vaccines. This Review provides an overview of RSV vaccines highlighting different target populations, antigens, and trial results. As RSV vaccines have not yet reached low-income and middle-income countries, we outline urgent next steps to minimise the vaccine delay., Competing Interests: Declaration of interests JT and NIM received support for attending meetings or travel from the ResViNET Foundation. UMC Utrecht (LJB and NIM) received grants from AbbVie, AstraZeneca, The Bill & Melinda Gates Foundation, the Dutch Lung Foundation, The Gates Medical Research Institute, GlaxoSmithKline (GSK), Janssen, MedImmune, MeMed, Merck, Novavax, Pfizer, and Sanofi; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Ablynx, AstraZeneca, Bavaria Nordic, GSK, Janssen, MabXience, MedImmune, MEDtalks, Merck, Moderna, Novavax, Pfizer, Sanofi, and Virology Education. LJB is founding chairman of the ReSViNET Foundation. UJB was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); and is named as an inventor on patents for live-attenuated RSV, with royalties paid to the National Institutes of Health by Sanofi Pasteur. ADC received grants from The Bill & Melinda Gates Foundation and WHO. CC received grants from Sanofi Pasteur, the Centers for Disease Control and Prevention, The Bill & Melinda Gates Foundation, and the Task Force for Global Health. RD received grants from Pfizer, Merck, MedImmune, and AstraZeneca; consulting fees from Pfizer, Merck and GSK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Merck, Sanofi Pasteur, GSK, MedImmune, and AstraZeneca; and participated on a data safety monitoring boards or advisory boards for Pfizer, Merck, and GSK. BSG is named as an inventor on patents for RSV vaccines and mABS; received royalties from the NIH; and consulting fees from GSK, Pfizer, AstraZeneca, Sanofi Pasteur, and Exevir. RAK received grants from the NIH and Sanofi Pasteur. YL received grants from GSK, Merck, and WHO; consulting fees from Pfizer and WHO; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer; and support for attending meetings or travel from Pfizer. AJP received grants from The Bill & Melinda Gates Foundation, Wellcome, Cepi, the Medical Research Council, the NIH and Care Research, AstraZeneca, the European Commission, and the Serum Institute of India; royalties from AstraZeneca for the development of COVID-19 vaccines; consulting fees from Shionogi; is chair of the Joint Committee on Vaccination and Immunization of the Department of Health and Social Care; and has been member of the Strategic Advisory Group of Experts on Immunization for WHO. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Enantiornithines were the most diverse group of birds during the Cretaceous, comprising over half of all known species from this period. The fossil record and subsequently our knowledge of this clade is heavily skewed by the wealth of material from Lower Cretaceous deposits in China. In contrast, specimens from Upper Cretaceous deposits are rare and typically fragmentary, yet critical for understanding the extinction of this clade across the K-Pg boundary. The most complete North American Late Cretaceous enantiornithine is Mirarce eatoni, a member of the diverse clade Avisauridae. Except for Mirarce, avisaurids are known only from isolated hindlimb elements from North and South America. Here we describe three new enantiornithines from the Maastrichtian Hell Creek Formation, two of which represent new avisaurid taxa. These materials represent a substantial increase in the known diversity of Enantiornithes in the latest Cretaceous. Re-examination of material referred to Avisauridae through phylogenetic analysis provides strong support for a more exclusive Avisauridae consisting of six taxa. Exploration of the functional morphology of the avisaurid tarsometatarsus indicates potential strong constriction and raptorial attributes. The lower aspect ratio of the tarsometatarsus facilitates a more biomechanically efficient lever system which in extant birds of prey equates to lifting proportionally heavier prey items. In addition, the proportional size and distal position of the m. tibialis cranialis tubercle of the tarsometatarsus is similar to the morphology seen in extant birds of prey. Together with the deeply-grooved metatarsal trochlea facilitating robust and likely powerful pedal digits, morphologies of the hindlimb suggest avisaurids as Late Cretaceous birds of prey., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Clark et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Alzheimer's disease (AD) is the most common form of dementia and is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology of AD includes the formation of extracellular amyloid-β plaque and intracellular neurofibrillary tangles of phosphorylated tau, along with neuronal loss. While neuronal loss is an AD hallmark, cell-cell communication between neuronal and non-neuronal cell populations maintains neuronal health and brain homeostasis. To study changes in cellcell communication during disease progression, we performed snRNA-sequencing of the hippocampus from female 3xTg-AD and wild-type littermates at 6 and 12 months. We inferred differential cell-cell communication between 3xTg-AD and wild-type mice across time points and between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) of interest. We also assessed the downstream effects of altered glia-neuron communication using pseudobulk differential gene expression, functional enrichment, and gene regulatory analyses. We found that glia-neuron communication is increasingly dysregulated in 12-month 3xTg-AD mice. We also identified 23 AD-associated ligand-receptor pairs that are upregulated in the 12-month-old 3xTg-AD hippocampus. Our results suggest increased AD association of interactions originating from microglia. Signaling mediators were not significantly differentially expressed but showed altered gene regulation and TF activity. Our findings indicate that altered glia-neuron communication is increasingly dysregulated and affects the gene regulatory mechanisms in neurons of 12-month-old 3xTg-AD mice., Competing Interests: Conflict of interest disclosure: The authors declare that they do not have competing interests.

Background: Afghanistan introduced monovalent rotavirus vaccine (Rotarix) into its national immunisation schedule in January, 2018. While post-licensure studies have shown substantial declines in rotavirus gastroenteritis cases and deaths globally, there is little evidence of rotavirus vaccine effectiveness and impact from low-income countries in Asia. We aimed to evaluate the effectiveness of the Rotarix vaccine and the impact of Rotarix vaccine on rotavirus gastroenteritis hospitalisations (ie, hospital admissions) among children younger than 5 years in Afghanistan., Methods: We used a test-negative case-control design embedded in an active sentinel surveillance platform to evaluate vaccine effectiveness. Children born on or after Jan 1, 2018, who had documentation of their rotavirus vaccination status and who were admitted for acute gastroenteritis at one of four sentinel hospitals from May, 2018 to December, 2021 were eligible to be included. We used an unconditional logistic regression model to estimate vaccine effectiveness and 95% CIs for a complete series of doses compared with no rotavirus vaccine doses among patients admitted with acute gastroenteritis. Vaccine effectiveness against hospitalisation was calculated as (1 - [odds of being vaccinated in cases] / [odds of being vaccinated in controls]) × 100%. We compared pre-vaccine (2013-15) and post-vaccine (2019-21) surveillance data from two sites to calculate vaccine impact., Findings: The vaccine effectiveness analysis included 1172 cases and 2173 controls. Approximately 2108 (63·0%) of 3345 cases and controls were male, 1237 (37·0%) were female, and 2171 (65·0%) were aged 6-11 months. Two doses of Rotarix were 45% (95% CI 22-62) effective against rotavirus hospitalisation in children aged 6-59 months, adjusting for age, severity, admission year, and rotavirus season. Rotavirus positivity decreased from 51% pre-vaccine to 39% post-vaccine, resulting in a 39% adjusted reduction in rotavirus positivity among children younger than 5 years admitted with acute gastroenteritis., Interpretation: Rotarix showed moderate effectiveness in preventing rotavirus gastroenteritis hospitalisations, consistent with findings in other low-income countries. These findings support the continued administration of the rotavirus vaccine in Afghanistan., Funding: Gavi, the Vaccine Alliance., Translation: For the Dari translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Alternative splicing (AS) contributes to the biological heterogeneity between species, sexes, tissues, and cell types. Many diseases are either caused by alterations in AS or by alterations to AS. Therefore, measuring AS accurately and efficiently is critical for assessing molecular phenotypes, including those associated with disease. Long-read sequencing enables more accurate quantification of differentially spliced isoform expression than short-read sequencing approaches, and third-generation platforms facilitate high-throughput experiments. To assess differences in AS across the cerebellum, cortex, hippocampus, and striatum by sex, we generated and analyzed Oxford Nanopore Technologies (ONT) long-read RNA sequencing (lrRNA-Seq) C57BL/6J mouse brain cDNA libraries. From > 85 million reads that passed quality control metrics, we calculated differential gene expression (DGE), differential transcript expression (DTE), and differential transcript usage (DTU) across brain regions and by sex. We found significant DGE, DTE, and DTU across brain regions and that the cerebellum had the most differences compared to the other three regions. Additionally, we found region-specific differential splicing between sexes, with the most sex differences in DTU in the cortex and no DTU in the hippocampus. We also report on two distinct patterns of sex DTU we observed, sex-divergent and sex-specific, that could potentially help explain sex differences in the prevalence and prognosis of various neurological and psychiatric disorders in future studies. Finally, we built a Shiny web application for researchers to explore the data further. Our study provides a resource for the community; it underscores the importance of AS in biological heterogeneity and the utility of long-read sequencing to better understand AS in the brain., (© 2024. The Author(s).)

Introduction: Current estimates indicate that up to 50-75% of dementia cases are undiagnosed at an early stage when treatments are most effective. Conducting robust accurate cognitive assessments can be time-consuming for providers and difficult to incorporate into a time-limited Primary Care Provider (PCP) visit. We wanted to compare PCP visits with and without using the self-administered SAGE to determine differences in identification rates of new cognitive disorders., Methods: Three hundred patients aged 65-89 without diagnosed cognitive disorders completing a non-acute office visit were enrolled (ClinicalTrials.gov identifier: NCT04063371). Two PCP offices conducted routine visits for 100 consecutive eligible patients each. One office used the SAGE in an additional 100 subjects and asked available informants about cognitive changes over the previous year. Chart reviews were conducted 60 days later. One-way analysis of variance and Fisher exact tests were used to compare the groups and outcomes., Results: When SAGE was utilized, the PCP documented the detection of new cognitive conditions/concerns six times (9% versus 1.5%) as often ( p  = 0.003). The detection rate was nearly 4-fold for those with cognitively impaired SAGE scores ( p  = 0.034). Patients having impaired SAGE score and informant concerns were 15-fold as likely to have new cognitive conditions/concerns documented ( p  = 0.0007). Among providers using SAGE, 86% would recommend SAGE to colleagues., Discussion: SAGE was easily incorporated into PCP visits and significantly increased identification of new cognitive conditions/concerns leading to new diagnoses, treatment, or management changes. The detection rate increased 15-fold for those with impaired SAGE scores combined with informant reports., Competing Interests: Ohio State University holds the copyright for the SAGE test. SAGE was developed by DWS at Ohio State University and is freely available. This research only evaluated SAGE in its paper form. The digital version of SAGE made for tablet use is commercially available at: BrainTest.com through a license agreement with Ohio State University. DS is a member of the Scientific Advisory Board of BrainTest Inc. SEZC., (Copyright © 2024 Scharre, Vrettos, Nagaraja, Wexler, Clark and Nguyen.)

Background: Alzheimer's disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer's disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer's disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons., Methods: Using public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in a second and third independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons., Results: Cell-cell communication between glia and neurons is altered in Alzheimer's disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We identified ligand-receptor pairs in three independent datasets and found involvement of the Alzheimer's disease risk genes APP and APOE across datasets. Most of the signaling mediators of these interactions were not significantly differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely, MYC and TP53, which are associated with WNT and p53 signaling, respectively, had decreased TF activity in Alzheimer's disease, along with decreased WNT and p53 pathway activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and increased TF activity of NFIL3, an NFkB signaling-associated transcription factor., Conclusions: Cell-cell communication between glia and neurons in Alzheimer's disease is altered in a cell-type-specific manner involving Alzheimer's disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons., (© 2024. The Author(s).)

Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient-derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers., (© 2024 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: In January 2018, Afghanistan introduced the monovalent oral rotavirus vaccine (Rotarix) nationwide, administered as a 2-dose series at six and ten weeks of age. We describe characteristics of intussusception cases and assess potential intussusception risk associated with Rotarix vaccination in Afghan infants., Methods: Multi-center prospective active hospital-based surveillance for intussusception was conducted from May 2018 to March 2022 in four sentinel sites in Afghanistan. We applied the Brighton Level 1 criteria for intussusception and verified vaccination status by reviewing vaccine cards. We used the self-controlled case series (SCCS) methodology to compare intussusception incidence in the 1 to 21 days after each dose of Rotarix vaccination against non-risk periods., Results: A total of 468 intussusception cases were identified in infants under 12 months, with 264 cases aged between 28 and 245 days having confirmed vaccination status contributing to the SCCS analysis. Most case-patients (98 %) required surgery for treatment, and over half (59 %) of those who underwent surgery required intestinal resection. Nineteen (7 %) case-patients died. Eighty-six percent of case-patients received the first dose of Rotarix, and 69 % received the second dose before intussusception symptom onset. There was no increased risk of intussusception in the 1-7 days (relative incidence: 0.9, 95 % CI: 0.1, 7.5), 8-21 days (1.3, 95 % CI: 0.4, 4.2), or 1-21 days (1.1, 95 % CI: 0.4, 3.4) following receipt of the first dose or in the 1-7 days (0.2, 95 % CI: 0.3, 1.8), 8-21 days (0.7, 95 % CI: 0.3, 1.5), or 1-21 days (0.6, 95 % CI: 0.3, 1.2) following the second dose., Conclusion: Rotarix vaccination was not associated with an increased intussusception risk, supporting its continued use in Afghanistan's immunization program. However, there was a high level of death and resection due to intussusception among Afghan infants., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Authors are often faced with the decision of whether to maximize traditional impact metrics or minimize costs when choosing where to publish the results of their research. Many subscription-based journals now offer the option of paying an article processing charge (APC) to make their work open. Though such "hybrid" journals make research more accessible to readers, their APCs often come with high price tags and can exclude authors who lack the capacity to pay to make their research accessible. Here, we tested if paying to publish open access in a subscription-based journal benefited authors by conferring more citations relative to closed access articles. We identified 146,415 articles published in 152 hybrid journals in the field of biology from 2013-2018 to compare the number of citations between various types of open access and closed access articles. In a simple generalized linear model analysis of our full dataset, we found that publishing open access in hybrid journals that offer the option confers an average citation advantage to authors of 17.8 citations compared to closed access articles in similar journals. After taking into account the number of authors, Journal Citation Reports 2020 Quartile, year of publication, and Web of Science category, we still found that open access generated significantly more citations than closed access ( p  < 0.0001). However, results were complex, with exact differences in citation rates among access types impacted by these other variables. This citation advantage based on access type was even similar when comparing open and closed access articles published in the same issue of a journal ( p  < 0.0001). However, by examining articles where the authors paid an article processing charge, we found that cost itself was not predictive of citation rates ( p  = 0.14). Based on our findings of access type and other model parameters, we suggest that, in the case of the 152 journals we analyzed, paying for open access does confer a citation advantage. For authors with limited budgets, we recommend pursuing open access alternatives that do not require paying a fee as they still yielded more citations than closed access. For authors who are considering where to submit their next article, we offer additional suggestions on how to balance exposure via citations with publishing costs., Competing Interests: The authors declare there are no competing interests., (©2024 Clark et al.)

The SET binding protein 1 (SETBP1) gene encodes a transcription factor (TF) involved in various cellular processes. Variants in SETBP1 can result in three different diseases determined by the introduction (germline vs. somatic) and location of the variant. Germline variants cause the ultra-rare pediatric Schinzel Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disorder (SETBP1-HD), characterized by severe multisystemic abnormalities with neurodegeneration or a less severe brain phenotype accompanied by hypotonia and strabismus, respectively. Somatic variants in SETBP1 are associated with hematological malignancies and cancer development in other tissues in adults. To better understand the tissue-specific mechanisms involving SETBP1, we analyzed publicly available RNA-sequencing (RNA-seq) data from the Genotype-Tissue Expression (GTEx) project. We found SETBP1 and its known target genes were widely expressed across 31 adult human tissues. K-means clustering identified three distinct expression patterns of SETBP1 targets across tissues. Functional enrichment analysis (FEA) of each cluster revealed gene sets related to transcriptional regulation, DNA binding, and mitochondrial function. TF activity analysis of SETBP1 and its target TFs revealed tissue-specific TF activity, underscoring the role of tissue context-driven regulation and suggesting its impact in SETBP1-associated disease. In addition to uncovering tissue-specific molecular signatures of SETBP1 expression and TF activity, we provide a Shiny web application to facilitate exploring TF activity across human tissues for 758 TFs. This study provides insight into the landscape of SETBP1 expression and TF activity across 31 non-diseased human tissues and reveals tissue-specific expression and activity of SETBP1 and its targets. In conjunction with the web application we constructed, our framework enables researchers to generate hypotheses related to the role tissue backgrounds play with respect to gene expression and TF activity in different disease contexts., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Whitlock et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Previous pharmacovigilance studies and a retroactive review of cancer clinical trial studies identified that women were more likely to experience drug adverse events (i.e., any unintended effects of medication), and men were more likely to experience adverse events that resulted in hospitalization or death. These sex-biased adverse events (SBAEs) are due to many factors not entirely understood, including differences in body mass, hormones, pharmacokinetics, and liver drug metabolism enzymes and transporters., Methods: We first identified drugs associated with SBAEs from the FDA Adverse Event Reporting System (FAERS) database. Next, we evaluated sex-specific gene expression of the known drug targets and metabolism enzymes for those SBAE-associated drugs. We also constructed sex-specific tissue gene-regulatory networks to determine if these known drug targets and metabolism enzymes from the SBAE-associated drugs had sex-specific gene-regulatory network properties and predicted regulatory relationships., Results: We identified liver-specific gene-regulatory differences for drug metabolism genes between males and females, which could explain observed sex differences in pharmacokinetics and pharmacodynamics. In addition, we found that ~ 85% of SBAE-associated drug targets had sex-biased gene expression or were core genes of sex- and tissue-specific network communities, significantly higher than randomly selected drug targets. Lastly, we provide the sex-biased drug-adverse event pairs, drug targets, and drug metabolism enzymes as a resource for the research community., Conclusions: Overall, we provide evidence that many SBAEs are associated with drug targets and drug metabolism genes that are differentially expressed and regulated between males and females. These SBAE-associated drug metabolism enzymes and drug targets may be useful for future studies seeking to explain or predict SBAEs., (© 2023. The Author(s).)

Summary: High-throughput sequencing technologies have enabled cross-species comparative transcriptomic studies; however, there are numerous challenges for these studies due to biological and technical factors. We developed CoSIA (Cross-Species Investigation and Analysis), a Bioconductor R package and Shiny app that provides an alternative framework for cross-species transcriptomic comparison of non-diseased wild-type RNA sequencing gene expression data from Bgee across tissues and species (human, mouse, rat, zebrafish, fly, and nematode) through visualization of variability, diversity, and specificity metrics., Availability and Implementation: https://github.com/lasseignelab/CoSIA., (© The Author(s) 2023. Published by Oxford University Press.)

Traditional biology curricula depict science as an objective field, overlooking the important influence that human values and biases have on what is studied and who can be a scientist. We can work to address this shortcoming by incorporating ideological awareness into the curriculum, which is an understanding of biases, stereotypes, and assumptions that shape contemporary and historical science. We surveyed a national sample of lower-level biology instructors to determine 1) why it is important for students to learn science, 2) the perceived educational value of ideological awareness in the classroom, and 3) hesitancies associated with ideological awareness implementation. We found that most instructors reported "understanding the world" as the main goal of science education. Despite the perceived value of ideological awareness, such as increasing student engagement and dispelling misconceptions, instructors were hesitant to implement ideological awareness modules due to potential personal and professional consequences.

Diurnal and seasonal rhythmicity, entrained by environmental and nutritional cues, is a vital part of all life on Earth operating at every level of organization; from individual cells, to multicellular organisms, whole ecosystems and societies. Redox processes are intrinsic to physiological function and circadian regulation, but how they are integrated with other regulatory processes at the whole-body level is poorly understood. Circadian misalignment triggered by a major stressor (e.g. viral infection with SARS-CoV-2) or recurring stressors of lesser magnitude such as shift work elicit a complex stress response that leads to desynchronization of metabolic processes. This in turn challenges the system's ability to achieve redox balance due to alterations in metabolic fluxes (redox rewiring). We infer that the emerging 'alternative redox states' do not always revert readily to their evolved natural states; 'Long COVID' and other complex disorders of unknown aetiology are the clinical manifestations of such rearrangements. To better support and successfully manage bodily resilience to major stress and other redox challenges needs a clear perspective on the pattern of the hysteretic response for the interaction between the redox system and the circadian clock. Characterization of this system requires repeated (ideally continuous) recording of relevant clinical measures of the stress responses and whole-body redox state (temporal redox phenotyping). The human/animal body is a complex 'system of systems' with multi-level buffering capabilities, and it requires consideration of the wider dynamic context to identify a limited number of stress-markers suitable for routine clinical decision making. Systematically mapping the patterns and dynamics of redox biomarkers along the stressor/disease trajectory will provide an operational model of whole-body redox regulation/balance that can serve as basis for the identification of effective interventions which promote health by enhancing resilience.

Across the evolution of powered flight, the ecological niche of aerial insectivore has been occupied by members of the three volant vertebrate clades-Aves and Chiroptera, and the first known volant vertebrates, pterosaurs. However, morphological and quantitative evidence to support pterosaurs exhibiting this ecology remains scant. Anurognathids are an unusual group of pterosaurs in which the skull exhibits the unique morphology of being mediolaterally expanded, so much so that their skulls may be wider than rostrocaudally long. Here, we conduct quantitative comparative cranial measurements and dental morphology in anurognathids against extant avian and chiropteran taxa, respectively, with ecologies and behaviors that are similar to predicted putative behaviors of anurognathids. Comparative analyses of both skull and dental morphology suggest anurognathid specimens in similar morphospaces as insectivorous crepuscular and nocturnal extant volant taxa. Our results support that this unique group of pterosaurs likely occupied a niche of mid-flight insectivorous capture in low-light conditions., (© 2022 Anatomical Society.)

The Longipterygidae are a unique clade among the enantiornithines in that they exhibit elongate rostra (≥60% total skull length) with dentition restricted to the distal tip of the rostrum, and pedal morphologies suited for an arboreal lifestyle (as in other enantiornithines). This suite of features has made interpretations of this group's diet and ecology difficult to determine due to the lack of analogous taxa that exhibit similar morphologies together. Many extant bird groups exhibit rostral elongation, which is associated with several disparate ecologies and diets ( e.g ., aerial insectivory, piscivory, terrestrial carnivory). Thus, the presence of rostral elongation in the Longipterygidae only somewhat refines trophic predictions of this clade. Anatomical morphologies do not function singularly but as part of a whole and thus, any dietary or ecological hypothesis regarding this clade must also consider other features such as their unique dentition. The only extant group of dentulous volant tetrapods are the chiropterans, in which tooth morphology and enamel thickness vary depending upon food preference. Drawing inferences from both avian bill proportions and variations in the dental morphology of extinct and extant taxa, we provide quantitative data to support the hypothesis that the Longipterygidae were animalivorous, with greater support for insectivory., Competing Interests: The authors declare that they have no competing interests., (© 2023 Clark et al.)

Objectives: Medication for opioid use disorder (MOUD) has gained significant momentum as an evidence-based intervention for treating opioid use disorder (OUD). The purpose of this study was to characterize MOUD initiations for buprenorphine and extended release (ER) naltrexone across all care sites at a major health system in the Midwest and determine whether MOUD initiation was associated with inpatient outcomes., Methods: The study population comprised patients with OUD in the health system between 2018 and 2021. First, we described characteristics of all MOUD initiations for the study population within the health system. Second, we compared inpatient length of stay (LOS) and unplanned readmission rates between patients prescribed MOUD and patients not prescribed MOUD, including a pre-post comparison of patients prescribed MOUD before versus after initiation., Results: The 3,831 patients receiving MOUD were mostly white, non-Hispanic and generally received buprenorphine over ER naltrexone. 65.5% of most recent initiations occurred in an inpatient setting. Compared to those not prescribed MOUD, inpatient encounters where patients received MOUD on or before the admission date were significantly less likely to be unplanned readmissions (13% vs. 20%, p < 0.001) and their LOS was 0.14 days shorter ( p  = 0.278). Among patients prescribed MOUD, there was a significant reduction in the readmission rate after initiation compared to before (13% vs. 22%, p < 0.001)., Conclusions: This study is the first to examine MOUD initiations for thousands of patients across multiple care sites in a health system, finding that receiving MOUD is associated with clinically meaningful reductions in readmission rates., Competing Interests: No conflict declared., (© 2022 The Author(s).)

Tissue-resident memory T cells (Trm), which typically do not enter the blood or lymphatic circulation at steady-state, are considered crucial for controlling pathogen entry at skin and mucosal barriers. Two recent studies (Fonseca et al. and Crowl et al.) shed light on the mechanisms of Trm cell differentiation., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Published by Elsevier Ltd.)

In blood, the majority of endothelial nitric oxide (NO) is scavenged by oxyhemoglobin, forming nitrate while a small part reacts with dissolved oxygen to nitrite; another fraction may bind to deoxyhemoglobin to generate nitrosylhemoglobin (HbNO) and/or react with a free cysteine to form a nitrosothiol. Circulating nitrite concentrations in healthy individuals are 200-700 nM, and can be even lower in patients with endothelial dysfunction. Those levels are similar to HbNO concentrations ([HbNO]) recently reported, whereby EPR-derived erythrocytic [HbNO] was lower in COVID-19 patients compared to uninfected subjects with similar cardiovascular risk load. We caution the values reported may not reflect true (patho)physiological concentrations but rather originate from complex chemical interactions of endogenous nitrite with hemoglobin and ascorbate/N-acetylcysteine. Using an orthogonal detection method, we find baseline [HbNO] to be in the single-digit nanomolar range; moreover, we find that these antioxidants, added to blood collection tubes to prevent degradation, artificially generate HbNO. Since circulating nitrite also varies with lifestyle, dietary habit and oral bacterial flora, [HbNO] may not reflect endothelial activity alone. Thus, its use as early marker of NO-dependent endothelial dysfunction to stratify COVID-19 patient risk may be premature. Moreover, oxidative stress not only impairs NO formation/bioavailability, but also shifts the chemical landscape into which NO is released, affecting its downstream metabolism. This compromises the endothelium's role as gatekeeper of tissue nutrient supply and modulator of blood cell function, challenging the body's ability to maintain redox balance. Further studies are warranted to clarify whether the nature of vascular dysfunction in COVID-19 is solely of endothelial nature or also includes altered erythrocyte function., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Gabapentin has been shown to reduce opioid use in head and neck cancer patients. Here, we examine the efficacy of prophylactic gabapentin at reducing opioid use in these patients at our institution., Methods: A retrospective study of patients receiving radiation was performed, using patients from our previous study as controls. Risk factors for opioid use at 3 and 6 months were determined using univariate and multivariate analyses., Results: In total, 53/185 patients were treated with gabapentin, 39.6% of which took opioids at 3 months vs. 58.3% in the non-gabapentin cohort (p = 0.021). Gabapentin was independently associated with less opioid use on multivariate analysis at 3 months (OR 0.47, 95% CI 0.24-0.9). Gastrostomy tube dependence and pretreatment opioid use were associated with chronic opioid use despite gabapentin., Conclusions: Gabapentin is effective at expediting opioid tapering in head and neck cancer patients who are not gastrostomy tube dependent or taking opioids pretreatment., (© 2022 Wiley Periodicals LLC.)

Introduction: Good preconception and interconception health are fundamental to optimizing women's health and reducing risk factors for adverse maternal-infant outcomes. Although rural women in the United States tend to experience health disparities, no published qualitative studies have focused on their preconception/interconception health. The purpose of this study was to determine what rural, Midwestern women perceive to be their most pressing health needs and effective ways to provide outreach and education regarding preconception/interconception health and care., Methods: Non-pregnant, reproductive-age women in Hardin County, Ohio, regardless of parity, were recruited through convenience sampling. Semi-structured interviews with four domains (beliefs and behaviors; perceived needs; knowledge and information sources; barriers to care) were conducted in May-June 2021 until saturation was reached. Qualitative methods were used to analyze data and determine themes. Binomial tests were used to compare selected demographic characteristics of participants to the county's reproductive-age residential female population., Results: Nineteen women aged 20-44 years were individually interviewed. Comparing race/ethnicity, education, and insurance status, participants appeared to be representative of the county population. Four themes were identified: (1) needs regarding healthcare and other resources; (2) lack of preconception/interconception care and perceived unimportance due to intergenerational knowledge transfer and paucity of healthcare providers; (3) difference in understanding of the term "women's health" and low health literacy; and (4) suggested interventions including education and outreach., Conclusion: Interviews with rural Midwestern women revealed needs regarding preconception/interconception health and care and potential ways to raise awareness. These findings can inform strategies to improve rural women's health and birth outcomes.

To characterize the transport of respiratory pathogens during commercial air travel, Computational Fluid Dynamics simulations were performed to track particles expelled by coughing by a passenger assigned to different seats on a Boeing 737 aircraft. Simulation data were post-processed to calculate the amounts of particles inhaled by nearby passengers. Different airflow rates were used, as well as different initial conditions to account for random fluctuations of the flow field. Overall, 80% of the particles were removed from the cabin in 1.3-2.6 min, depending on conditions, and 95% of the particles were removed in 2.4-4.6 min. Reducing airflow increased particle dispersion throughout the cabin but did not increase the highest exposure of nearby passengers. The highest exposure was 0.3% of the nonvolatile mass expelled by the cough, and the median exposure for seats within 3 feet of the cough discharge was 0.1%, which was in line with recent experimental testing., (© 2021. The Author(s).)

Significance: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19), affects every aspect of human life by challenging bodily, socioeconomic, and political systems at unprecedented levels. As vaccines become available, their distribution, safety, and efficacy against emerging variants remain uncertain, and specific treatments are lacking. Recent Advances: Initially affecting the lungs, COVID-19 is a complex multisystems disease that disturbs the whole-body redox balance and can be long-lasting (Long-COVID). Numerous risk factors have been identified, but the reasons for variations in susceptibility to infection, disease severity, and outcome are poorly understood. The reactive species interactome (RSI) was recently introduced as a framework to conceptualize how cells and whole organisms sense, integrate, and accommodate stress. Critical Issues: We here consider COVID-19 as a redox disease, offering a holistic perspective of its effects on the human body, considering the vulnerability of complex interconnected systems with multiorgan/multilevel interdependencies. Host/viral glycan interactions underpin SARS-CoV-2's extraordinary efficiency in gaining cellular access, crossing the epithelial/endothelial barrier to spread along the vascular/lymphatic endothelium, and evading antiviral/antioxidant defences. An inflammation-driven "oxidative storm" alters the redox landscape, eliciting epithelial, endothelial, mitochondrial, metabolic, and immune dysfunction, and coagulopathy. Concomitantly reduced nitric oxide availability renders the sulfur-based redox circuitry vulnerable to oxidation, with eventual catastrophic failure in redox communication/regulation. Host nutrient limitations are crucial determinants of resilience at the individual and population level. Future Directions: While inflicting considerable damage to health and well-being, COVID-19 may provide the ultimate testing ground to improve the diagnosis and treatment of redox-related stress diseases. "Redox phenotyping" of patients to characterize whole-body RSI status as the disease progresses may inform new therapeutic approaches to regain redox balance, reduce mortality in COVID-19 and other redox diseases, and provide opportunities to tackle Long-COVID. Antioxid. Redox Signal . 35, 1226-1268.

Daphnia species are well-suited for studying local adaptation and evolutionary responses to stress(ors) including those caused by algal blooms. Algal blooms, characterized by an overgrowth (bloom) of cyanobacteria, are detrimental to the health of aquatic and terrestrial members of freshwater ecosystems. Some strains of Daphnia pulicaria have demonstrated resistance to toxic algae and the ability to mitigate toxic algal blooms. Understanding the genetic mechanism associated with this toxin resistance requires adequate genomic resources. Using whole-genome sequence data mapped to the Daphnia pulex reference genome (PA42), we present reference-guided draft assemblies from one tolerant and one sensitive strain of D. pulicaria, Wintergreen-6 (WI-6), and Bassett-411 (BA-411), respectively. Assessment of the draft assemblies reveal low contamination levels, and high levels (95%) of genic content. Reference scaffolds had coverage breadths of 98.9-99.4%, and average depths of 33X and 29X for BA-411 and WI-6, respectively. Within, we discuss caveats and suggestions for improving these draft assemblies. These genomic resources are presented with a goal of contributing to the resources necessary to understand the genetic mechanisms and associations of toxic prey resistance observed in this species., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Abstract: Opioid use, particularly via injection, is associated with an increased risk of infection, injury, and death. Safer consumption sites (SCSs), where people may consume previously obtained drugs under observation, have been shown to reduce these risks among people who use drugs. Most SCSs employ nurses, but there is limited research into their roles. The objective of this article is to describe and synthesize the roles of nurses at SCSs to better understand their importance in a rapidly proliferating public health intervention. We extracted data from 48 qualitative, quantitative, peer-reviewed, and gray literature, as well as primary source narrative articles on SCSs, whether they were explicitly about nursing or not. We coded each mention of nurses or nursing in each article and identified 11 descriptive themes or roles that SCS nurses carry out. From these, we identified the following three analytical themes or hypotheses about the character of these roles: (a) The primary aim of SCS nursing care is to reduce morbidity and mortality; (b) SCS nurses create a therapeutic community; and (c) SCS nurses engage in research, professional activities, and activism to better understand and promote SCSs. More research into the roles of SCS nurses is needed to better serve a vulnerable population., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article., (Copyright © 2021 International Nurses Society on Addictions.)

Background: High-quality genomic resources facilitate investigations into behavioral ecology, morphological and physiological adaptations, and the evolution of genomic architecture. Lizards in the genus Sceloporus have a long history as important ecological, evolutionary, and physiological models, making them a valuable target for the development of genomic resources., Findings: We present a high-quality chromosome-level reference genome assembly, SceUnd1.0 (using 10X Genomics Chromium, HiC, and Pacific Biosciences data), and tissue/developmental stage transcriptomes for the eastern fence lizard, Sceloporus undulatus. We performed synteny analysis with other snake and lizard assemblies to identify broad patterns of chromosome evolution including the fusion of micro- and macrochromosomes. We also used this new assembly to provide improved reference-based genome assemblies for 34 additional Sceloporus species. Finally, we used RNAseq and whole-genome resequencing data to compare 3 assemblies, each representing an increased level of cost and effort: Supernova Assembly with data from 10X Genomics Chromium, HiRise Assembly that added data from HiC, and PBJelly Assembly that added data from Pacific Biosciences sequencing. We found that the Supernova Assembly contained the full genome and was a suitable reference for RNAseq and single-nucleotide polymorphism calling, but the chromosome-level scaffolds provided by the addition of HiC data allowed synteny and whole-genome association mapping analyses. The subsequent addition of PacBio data doubled the contig N50 but provided negligible gains in scaffold length., Conclusions: These new genomic resources provide valuable tools for advanced molecular analysis of an organism that has become a model in physiology and evolutionary ecology., (© The Author(s) 2021. Published by Oxford University Press GigaScience.)

Bayesian networks can be used to identify possible causal relationships between variables based on their conditional dependencies and independencies, which can be particularly useful in complex biological scenarios with many measured variables. Here we propose two improvements to an existing method for Bayesian network analysis, designed to increase the power to detect potential causal relationships between variables (including potentially a mixture of both discrete and continuous variables). Our first improvement relates to the treatment of missing data. When there is missing data, the standard approach is to remove every individual with any missing data before performing analysis. This can be wasteful and undesirable when there are many individuals with missing data, perhaps with only one or a few variables missing. This motivates the use of imputation. We present a new imputation method that uses a version of nearest neighbour imputation, whereby missing data from one individual is replaced with data from another individual, their nearest neighbour. For each individual with missing data, the subsets of variables to be used to select the nearest neighbour are chosen by sampling without replacement the complete data and estimating a best fit Bayesian network. We show that this approach leads to marked improvements in the recall and precision of directed edges in the final network identified, and we illustrate the approach through application to data from a recent study investigating the causal relationship between methylation and gene expression in early inflammatory arthritis patients. We also describe a second improvement in the form of a pseudo-Bayesian approach for upweighting certain network edges, which can be useful when there is prior evidence concerning their directions., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the relationship between treatment modality and chronic opioid use in a large cohort of patients with head and neck cancer., Study Design: Retrospective cohort study., Setting: Single academic center., Methods: There were 388 patients with head and neck cancer treated between January 2011 and December 2017 who met inclusion criteria. Clinical risk factors for opioid use at 3 and 6 months were determined with univariate and multivariate analyses., Results: The prevalence of opioid use was 43.0% at 3 months and 33.2% at 6 months. On multivariate analysis, primary chemoradiation (odds ratio [OR], 4.04; 95% CI, 1.91-8.55) and surgery with adjuvant chemoradiation (OR, 2.39; 95% CI, 1.09-5.26) were associated with opioid use at 3 months. Additional risk factors at that time point included pretreatment opioid use (OR, 7.63; 95% CI, 4.09-14.21) and decreasing age (OR, 1.03; 95% CI, 1.01-1.06). At 6 months, primary chemoradiation (OR, 2.40; 95% CI, 1.34-4.28), pretreatment opioid use (OR, 5.86; 95% CI, 3.30-10.38), current tobacco use (OR, 2.00; 95% CI, 1.18-3.40), and psychiatric disorder (OR, 1.79; 95% CI, 1.02-3.14) were associated with opioid use., Conclusion: Of the patients who receive different treatment modalities, those receiving primary chemoradiation are independently at highest risk for chronic opioid use. Other risk factors include pretreatment opioid use, tobacco use, and a psychiatric disorder. In an effort to reduce their risk of chronic opioid use, preventative strategies should be especially directed to these patients.

Online extraction of fission products, such as the medical isotope Mo-99, is a key advantage of the proposed molten salt nuclear reactor design. The chemical and structural behavior of Mo solvated in fluoride salt has been relatively unknown. Ab initio molecular dynamics simulations were employed to examine the behavior of molybdenum in the molten salt FLiNaK (LiF-NaF-KF) for oxidation states between 0 and 6+. Mo complexation was found to vary with the Mo oxidation state, with lower oxidation states tending to result in complexes with more molybdenum ions. Complexes containing multiple Mo ions were observed for all Mo oxidation states studied except 5+ and 6+. A relationship between the solubility of a complex and electronic isolation of a complex in a molten salt is explored using the Bader atoms in molecule electron density partitioning scheme, with more volatile complexes exhibiting greater electronic isolation. The impacts of UF 4 and H 2 O on the predominant molybdenum species are also considered. While no impacts on Mo behavior by UF 4 were observed, Mo-O interactions may inhibit the formation of complexes containing multiple Mo ions.

The COVID-19 pandemic poses unique challenges within the austere clinical setting, and the time between patient presentation and deterioration is a critical opportunity for intervention. In some cases, this may be a life-saving transfer to a higher level of care. US Central Command (CENTCOM) has provided valuable guidance for COVID-19 management in the operational environment,1 and has proposed the National Early Warning System 2 (NEWS2) scoring tool as a useful adjunct to gauging illness severity. NEWS2, however, does not consider co-morbidities, such as diabetes or chronic cardiac disease, which could worsen the clinical course of SARS-CoV-2 patients. Thus, NEWS2 fails to address such factors during the risk stratification of patients to a higher level of care. To address this concern, June 2020, 3rd Medical Brigade, Operation Spartan Shield (OSS) developed the COVID-19 Army Rapid Assessment Tool (CARAT) with inputs from clinicians and researchers (The Team). The CARAT is a clinical scoring system, modified from the NEWS2, which combines the effects of co-morbid disease with the current physiological condition of a COVID-19 patient. The Team obtained clinical data for 105 patients from the CENTCOM area of responsibility (AOR), who presented to a military treatment facility (MTF) symptomatic for, and testing positive for SARS-CoV-2, during the time period of June to mid-August 2020. Each patient was retrospectively assigned a CARAT score based on his or her initial presentation. Preliminary review of data suggested a CARAT value of 4 or greater was an indicator for risk of further deterioration. Patients were then grouped into two categories: patients who received transfer to a higher level of care, versus "stay-in-place" supportive care. Results showed that 100% of patients with a score ≥4 had been transferred to a higher echelon of care, compared to 2% of patients with scores less than 4. A Fisher's exact test demonstrated a statistically significant difference between these two groups (p is less than 0.001). Interestingly, when compared with the NEWS2 score, the CARAT identified 9 individuals for transfer to a higher level of care, of whom only one patient was identified by the NEWS2, clearly underscoring the significance of CARAT despite small sample size. We therefore recommend that CARAT be further validated in predicting disease severity and need for emergent evacuation in larger patient settings.

The duration of the developmental period represents a fundamental axis of life-history variation, yet broad insights regarding the drivers of this diversity are currently lacking. Here, we test mechanistic and ecological explanations for the evolution of developmental duration using embryological data and information on incubation and fledging for 3096 avian species. Developmental phases associated primarily with growth are the longest and most variable, consistent with a role for allometric constraint in determining the duration of development. In addition, developmental durations retain a strong imprint of deep evolutionary history and body size differences among species explain less variation than previously thought. Finally, we reveal ecological correlates of developmental durations, including variables associated with the relative safety of the developmental environment and pressures of breeding phenology. Overall, our results provide broad-scale insight into the relative importance of mechanistic, ecological and evolutionary constraints in shaping the diversification of this key life-history trait.

Background: Defining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era., Objectives: With a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies., Methods: Whole-genome methylation and transcriptional data from isolated CD4 + T cells and B cells of more than 100 genotyped and phenotyped patients with inflammatory arthritis, all of whom were naive to immunomodulatory treatments, were obtained. Analysis integrated these comprehensive data with genome-wide association study findings across IMDs and other publicly available resources., Results: We provide strong evidence that disease-associated DNA variants regulate cis-CpG methylation in CD4 + T and/or B cells at 37% RA loci. Using paired, cell-specific transcriptomic data and causal inference testing, we identify examples where site-specific DNA methylation in turn mediates gene expression, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4 + T cells. A number of genes regulated in this way highlight mechanisms common to RA and other IMDs including multiple sclerosis and asthma, in turn distinguishing them from osteoarthritis, a primarily degenerative disease. Finally, we corroborate the observed effects experimentally., Conclusions: Our observations highlight important mechanisms of genetic risk in RA and the wider context of immune dysregulation. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritization and, potentially, therapeutic targeting in complex IMD., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Consideration of the properties of the sources of selection potentially helps biologists account for variation in selection. Here we explore how the variability of natural selection is affected by organisms that regulate the experienced environment through their activities (whether by constructing components of their local environments, such as nests, burrows, or pupal cases, or by choosing suitable resources). Specifically, we test the predictions that organism-constructed sources of selection that buffer environmental variation will result in (i) reduced variation in selection gradients, including reduced variation between ( a ) years (temporal variation) and ( b ) locations (spatial variation), and (ii) weaker directional selection relative to nonconstructed sources. Using compiled data sets of 1,045 temporally replicated selection gradients, 257 spatially replicated selection gradients, and a pooled data set of 1,230 selection gradients, we find compelling evidence for reduced temporal variation and weaker selection in response to constructed compared to nonconstructed sources of selection and some evidence for reduced spatial variation in selection. These findings, which remained robust to alternative data sets, taxa, analytical methods, definitions of constructed/nonconstructed, and other tests of reliability, suggest that organism-manufactured or chosen components of environments may have qualitatively different properties from other environmental features.

We evaluated the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in transplant-naïve patients with relapsed/refractory Hodgkin lymphoma (HL) who failed to attain metabolic complete response (mCR) to 1 to 2 lines of salvage chemotherapyThose with residual but nonprogressive disease assessed by positron emission tomography/computed tomography scanning were eligible. An additional 1 to 2 cycles of salvage therapy were permissible in those with progressive disease or when required to bridge to allo-HSCT, with additional imaging at baseline before transplantation. Conditioning consisted of carmustine, etoposide, cytarabine, melphalan, and alemtuzumab. Donor lymphocyte infusions (DLI) were administered for mixed chimerism or residual or relapsed disease. Eleven patients had sibling donors, 13 had HLA-matched unrelated donors, and 7 had HLA-mismatched unrelated donors. There were no graft failures, and no episodes of grade 4 acute graft-versus-host disease (GVHD); only 19.4% of patients had grade 2 to 3 GVHD, and 22.2% had extensive chronic GVHD. The non-relapse mortality rate was 16.1% (95% confidence interval [CI], 7.1%-34.5%). Relapse incidence was 18.7% (95% CI, 8.2%-39.2%). The study met its primary objective, with a 3-year progression-free survival of 67.7% (95% CI, 48.4%-81.2%). Survival outcomes were equivalent in those with residual metabolically active disease immediately before transplantation (n = 24 [70.8%; 95% CI, 17.2%-83.7%]). Two of the 5 patients who relapsed received DLI and remained in mCR at latest follow-up, with a 3-year overall survival of 80.7% (95% CI, 61.9%-90.8%). We demonstrate encouraging results that establish a potential role for allo-HSCT in selected high-risk patients with HL. This trial was registered at www.clinicaltrials.gov as #NCT00908180., (© 2019 by The American Society of Hematology.)

Purpose: The purpose of this research is to evaluate a collaborative workflow aimed at decreasing prescription abandonment., Setting: A federally qualified health center and a 340B contracted grocery store-based community pharmacy., Practice Workflow: An ambulatory care clinic with an established partnership with a community pharmacy chain identified a need to decrease prescription abandonment rates. A process was developed whereby an ambulatory care pharmacy technician received a report from the pharmacy of prescriptions filled for at least 7 days since the initial fill date and at risk for abandonment at the community pharmacy. The pharmacy technician identified health-system barriers, attempted to remedy any identified barriers, and conducted patient reminder phone calls. Health-system barriers were classified by the following categories: incorrect contact information at the community pharmacy, incorrect 340B copayment, incorrect insurance information at the community pharmacy, and need for prior authorization., Evaluation: A prospective cohort study was conducted from February 2016 to April 2016 in order to evaluate the effectiveness of this workflow., Results: 551 prescriptions and 350 patients were included in this cohort. Of the 551 prescriptions, 362 had at least one identified barrier that may have led to prescription abandonment. There were 111 health-system identified barriers, and 96 of these barriers were acted upon. Additionally, there were 459 patient identified barriers, and 179 of these barriers were acted upon. When a pharmacy technician was able to identify and act upon at least one barrier, 106 prescriptions (46.9%) were picked-up from the pharmacy., Conclusion: From the information gathered in this quality improvement project, operational changes have been implemented at the ambulatory care clinic and community pharmacy as a means to further decrease modifiable health-system barriers that may lead to prescription abandonment., (© Individual authors.)

Background: In some countries that have introduced oral rotavirus vaccines, a small but elevated risk of intussusception-a rare bowel disorder-has been reported. Updated estimates on the global epidemiology of intussusception are needed to help predict the potential number of intussusception cases that could be caused by the vaccine in different settings., Methods: We estimated incidence rates, age distributions and case-fatality ratios (CFRs) for intussusception hospital admissions among children aged <5 years, before the introduction of rotavirus vaccines. We included all articles identified in a systematic review between January 2002 and January 2018, and contacted authors for more granular unpublished data on age distributions., Results: We identified 128 articles containing 227 country datasets (61 age distributions, 71 incidence rates and 95 CFRs). The median age of intussusception ranged from 29 weeks in Africa (83% of cases in the first year of life) to 70 weeks in the Western Pacific region (35% of cases in the first year of life). The median (range) annual incidence of intussusception hospital admissions per 100 000 aged <1 year ranged from 34 (13-56) in Africa to 90 (9-380) in the Western Pacific region. We found extreme differences between the CFRs in Africa (1 death in every 10 hospital admissions) and the rest of the world (fewer than 1 death in every 100-2000 hospital admissions)., Conclusion: Intussusception epidemiology varies by country and region. Understanding and recognizing these differences will be important when assessing the potential number of intussusception cases associated with rotavirus vaccines., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Dietary inorganic nitrate prevents aspects of cardiac mitochondrial dysfunction induced by hypoxia, although the mechanism is not completely understood. In both heart and skeletal muscle, nitrate increases fatty acid oxidation capacity, and in the latter case, this involves up-regulation of peroxisome proliferator-activated receptor (PPAR)α expression. Here, we investigated whether dietary nitrate modifies mitochondrial function in the hypoxic heart in a PPARα-dependent manner. Wild-type (WT) mice and mice without PPARα ( Ppara -/- ) were given water containing 0.7 mM NaCl (control) or 0.7 mM NaNO 3 for 35 d. After 7 d, mice were exposed to normoxia or hypoxia (10% O 2 ) for the remainder of the study. Mitochondrial respiratory function and metabolism were assessed in saponin-permeabilized cardiac muscle fibers. Environmental hypoxia suppressed mass-specific mitochondrial respiration and additionally lowered the proportion of respiration supported by fatty acid oxidation by 18% ( P < 0.001). This switch away from fatty acid oxidation was reversed by nitrate treatment in hypoxic WT but not Ppara mice. Our findings indicate that PPARα plays a key role in mediating cardiac metabolic remodeling in response to both hypoxia and dietary nitrate supplementation.-Horscroft, J. A., O'Brien, K. A., Clark, A. D., Lindsay, R. T., Steel, A. S., Procter, N. E. K., Devaux, J., Frenneaux, M., Harridge, S. D. R., Murray, A. J. Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration-probing the role of PPARα.-/- mice, indicating a PPARα-dependent effect. Hypoxia increased hexokinase activity by 33% in all mice, whereas lactate dehydrogenase activity increased by 71% in hypoxic WT but not Ppara -/- mice. Our findings indicate that PPARα plays a key role in mediating cardiac metabolic remodeling in response to both hypoxia and dietary nitrate supplementation.-Horscroft, J. A., O'Brien, K. A., Clark, A. D., Lindsay, R. T., Steel, A. S., Procter, N. E. K., Devaux, J., Frenneaux, M., Harridge, S. D. R., Murray, A. J. Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration-probing the role of PPARα.