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Reactivation of fetal-specific genes and isoforms occurs during heart failure. However, the underlying molecular mechanisms and the extent to which the fetal program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of alternative splicing differences (i.e. isoform switching) in cardiovascular system (CVS) tissues between fetal, healthy adult and heart failure have included both cellular heterogeneity across bulk RNA-seq samples and limited availability of fetal tissue for research. To overcome these limitations, we have deconvoluted the cellular compositions of 996 RNA-seq samples representing heart failure, healthy adult (heart and arteria), and fetal-like (iPSC-derived cardiovascular progenitor cells) CVS tissues. Comparison of the expression profiles revealed that reactivation of fetal-specific RNA-binding proteins (RBPs), and the accompanied re-expression of 1,523 fetal-specific isoforms, contribute to the transcriptome differences between heart failure and healthy adult heart. Of note, isoforms for 20 different RBPs were among those that reverted in heart failure to the fetal-like expression pattern. We determined that, compared with adult-specific isoforms, fetal-specific isoforms encode proteins that tend to have more functions, are more likely to harbor RBP binding sites, have canonical sequences at their splice sites, and contain typical upstream polypyrimidine tracts. Our study suggests that compared with healthy adult, fetal cardiac tissue requires stricter transcriptional regulation, and that during heart failure reversion to this stricter transcriptional regulation occurs. Furthermore, we provide a resource of cardiac developmental stage-specific and heart failure-associated genes and isoforms, which are largely unexplored and can be exploited to investigate novel therapeutics for heart failure.

Patients with neurodevelopmental disabilities generally have less access to necessary medical care compared to those without disabilities. Barriers to adequate care include patient fear and uncooperative behavior during routine medical procedures and inadequate preparation of medical professionals to treat this population. Researchers have identified multiple behavior-analytic procedures for promoting comfort and cooperation during medical treatments. Efficient, cost-effective training programs are needed to widely disseminate behavior-analytic procedures to medical students and professionals. The purpose of this study was to assess the efficacy of a virtual training to prepare medical students to implement behavioral procedures that could be easily incorporated into typical wellness examinations. Seven medical students received behavioral skills training (BST) delivered remotely via the Internet. Results showed that the training successfully increased students' correct implementation of the procedures in roleplay with the experimenter and with patients with neurodevelopmental disabilities. Responding also maintained at high levels 2 weeks after the training. These findings suggest that virtual BST is an efficient, practical approach for training health care professionals to implement general behavior management strategies to increase the comfort and cooperation of patients with NDD.

ABSTRACTCo-formulation of multiple drug products is an efficient and convenient approach to simultaneously deliver multiple biotherapeutics with the potentially added benefit of a synergistic therapeutic effect. However, co-formulation also increases the risk of heteromeric interactions, giving rise to unique impurities with unknown efficacy and immunogenicity. Therefore, it is critical to develop methods to evaluate the risk of heteromers as an impurity that could affect potency, efficacy, and/or immunogenicity. The most direct strategy to evaluate antibody heteromers is via specific enrichment. However, the fact that antibody heterodimers generated from the co-formulated cocktail share highly similar molar mass and size properties as homodimers natively present in each individual antibody drug product poses a unique purification challenge. Here, we report the path to successful enrichment of heterodimers from co-formulated REGEN-COVⓇ and discuss its potential impacts on drug quality.

Abstract Background and Objective Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia results in substantial morbidity and mortality. As current treatments often lead to unsatisfactory outcomes, evidence guiding alternative treatment options is needed. This study evaluated real-world clinical outcomes of ceftaroline fosamil for the treatment of MRSA bacteremia. Methods This retrospective study included adults hospitalized with MRSA bacteremia between 2011 and 2019. Patients were classified according to treatment with ceftaroline fosamil (ceftaroline), vancomycin, or daptomycin: Group 1, ceftaroline; Group 2, vancomycin or daptomycin (without ceftaroline); Group 3, combination therapy with ≥ 2 of these three agents. Clinical outcomes were compared using propensity-score-adjusted odds ratios (ORs) from logistic regression models. Results Overall, 24,479 patients were included (Group 1, n = 532; Group 2, n = 21,555; Group 3, n = 2392). Mean age was 59.6, 60.8, and 57.4 years in Groups 1, 2, and 3, respectively. Mean post-index treatment length of stay was 8.8, 8.8, and 8.0 days, respectively. The most frequent line of therapy was ceftaroline first-line (42.1%), vancomycin or daptomycin first-line (95.4%), and combination therapy third-line or later (67.8%) in Groups 1, 2, and 3, respectively. Compared with Group 2, Groups 1 and 3 had similar favorable clinical responses {odds ratio [OR] = 1.18 [95% confidence interval (CI) 0.98–1.44], p = 0.08; OR = 1.20 [95% CI 0.97–1.47], p = 0.09, respectively} and were less likely to switch treatment (both p

Introduction The COVID-19 pandemic triggered one of the largest global health and economic crises in recent history. COVID-19 vaccination (CV) has been the central tool for global health and macroeconomic recovery, yet estimates of CV’s global health and macroeconomic value remain scarce.Methods We used regression analyses to measure the impact of CV on gross domestic product (GDP), infections and deaths. We combined regression estimates of vaccine-averted infections and deaths with estimates of quality-adjusted life years (QALY) losses, and direct and indirect costs, to estimate three broad value components: (i) QALY gains, (ii) direct and indirect costs averted and (iii) GDP impacts. The global value is the sum of components over 148 countries between January 2020 and December 2021 for CV generally and for Pfizer-BioNTech specifically.Results CV’s global value was US$5.2 (95% CI US$4.1 to US$6.2) trillion, with Pfizer-BioNTech’s vaccines contributing over US$1.9 (95% CI US$1.5 to US$2.3) trillion. Varying key parameters results in values 10%–20% higher or lower than the base-case value. The largest value component was GDP impacts, followed by QALY gains, then direct and indirect costs averted. CV provided US$740 of value per dose, while Pfizer-BioNTech specifically provided >US$1600 per dose. We estimated conservative benefit-cost ratios of 13.9 and 30.8 for CV and Pfizer-BioNTech, respectively.Conclusions We provide the first estimates of the broad value of CV incorporating GDP, QALY and direct and indirect cost impacts. Through December 2021, CV produced significant health and economic value, represented strong value for money and produced significant macroeconomic benefits that should be considered in vaccine evaluation.

Abstract Stem cells exist in vitro in a spectrum of interconvertible pluripotent states. Analyzing hundreds of hiPSCs derived from different individuals, we show the proportions of these pluripotent states vary considerably across lines. We discover 13 gene network modules (GNMs) and 13 regulatory network modules (RNMs), which are highly correlated with each other suggesting that the coordinated co-accessibility of regulatory elements in the RNMs likely underlie the coordinated expression of genes in the GNMs. Epigenetic analyses reveal that regulatory networks underlying self-renewal and pluripotency are more complex than previously realized. Genetic analyses identify thousands of regulatory variants that overlapped predicted transcription factor binding sites and are associated with chromatin accessibility in the hiPSCs. We show that the master regulator of pluripotency, the NANOG-OCT4 Complex, and its associated network are significantly enriched for regulatory variants with large effects, suggesting that they play a role in the varying cellular proportions of pluripotency states between hiPSCs. Our work bins tens of thousands of regulatory elements in hiPSCs into discrete regulatory networks, shows that pluripotency and self-renewal processes have a surprising level of regulatory complexity, and suggests that genetic factors may contribute to cell state transitions in human iPSC lines.

Abstract Background The aim of this study was to estimate the impact of mild-to-moderate COVID-19 on health-related quality of life (HRQoL) over time among individuals in the United Kingdom, adding to the evidence base that had focussed on severe COVID-19. Methods A bespoke online survey was administered to individuals who self-reported a positive COVID-19 test. An amended version of a validated generic HRQoL instrument (EQ-5D-5L) was used to measure HRQoL retrospectively at different timepoints over the course of an infection: pre-COVID-19, acute COVID-19, and long COVID. In addition, HRQoL post-COVID-19 was captured by the original EQ-5D-5L questionnaire. A mixed-effects model was used to estimate changes in HRQoL over time, adjusted for a range of variables correlated with HRQoL. Results The study recruited 406 participants: (i) 300 adults and 53 adolescents with mild-to-moderate COVID-19 who had not been hospitalised for COVID-19 during acute COVID-19, and (ii) 53 adults who had been hospitalised for COVID-19 in the acute phase and who had been recruited for validation purposes. Data were collected between January and April 2022. Among participants included in the base-case analysis, EQ-5D-5L utility scores were lower during both acute COVID-19 (β=-0.080, p = 0.001) and long COVID (β=-0.072, p

We noted three key inconsistencies in the Moderna-funded cost-effectiveness analysis by Fust et al [...]

Background We aimed to estimate the public health impact of booster vaccination against COVID-19 in the UK during an Omicron-predominant period. Research design and methods A dynamic transmission model was developed to compare public health outcomes for actual and alternative UK booster vaccination programs. Input sources were publicly available data and targeted literature reviews. Base case analyses estimated outcomes from the UK’s Autumn–Winter 2021–2022 booster program during January–March 2022, an Omicron-predominant period. Scenario analyses projected outcomes from Spring and in Autumn 2022 booster programs over an extended time horizon from April 2022–April 2023, assuming continued Omicron predominance, and explored hypothetical program alternatives with modified eligibility criteria and/or increased uptake. Results Estimates predicted that the Autumn–Winter 2021–2022 booster program averted approximately 12.8 million cases, 1.1 million hospitalizations, and 290,000 deaths. Scenario analyses suggested that Spring and Autumn 2022 programs would avert approximately 6.2 million cases, 716,000 hospitalizations, and 125,000 deaths; alternatives extending eligibility or targeting risk groups would improve these benefits, and increasing uptake would further strengthen impact. Conclusions Boosters were estimated to provide substantial benefit to UK public health during Omicron predominance. Benefits of booster vaccination could be maximized by extending eligibility and increasing uptake.

Background Limited data are available describing the global impact of COVID-19 vaccines. This study estimated the global public health and economic impact of COVID-19 vaccines before the emergence of the Omicron variant. Methods A static model covering 215 countries/territories compared the direct effects of COVID-19 vaccination to no vaccination during 13 December 2020–30 September 2021. After adjusting for underreporting of cases and deaths, base case analyses estimated total cases and deaths averted, and direct outpatient and productivity costs saved through averted health outcomes. Sensitivity analyses applied alternative model assumptions. Results COVID-19 vaccines prevented an estimated median (IQR) of 151.7 (133.7–226.1) million cases and 620.5 (411.1–698.1) thousand deaths globally through September 2021. In sensitivity analysis applying an alternative underreporting assumption, median deaths averted were 2.1 million. Estimated direct outpatient cost savings were $21.2 ($18.9–30.9) billion and indirect savings of avoided productivity loss were $135.1 ($121.1–206.4) billion, yielding a total cost savings of $155 billion globally through averted infections. Conclusions Using a conservative modeling approach that considered direct effects only, we estimated that COVID-19 vaccines have averted millions of infections and deaths, generating billions of cost savings worldwide, which underscore the continued importance of vaccination in public health response to COVID-19.

Abstract The impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4065 genes and 4016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate eQTLs identified in adult islets and whole pancreas samples, which reveal 1805 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1043 eQTLs that exhibit regulatory plasticity across the fetal-like and adult pancreas tissues. Colocalization with GWAS risk loci for pancreatic diseases and traits show that some putative causal regulatory variants are active only in the fetal-like iPSC-PPCs and likely influence disease by modulating expression of disease-associated genes in early development, while others with regulatory plasticity likely exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages.

Methods Medline, EMBASE and the Cochrane Library were searched and supplemented with conference and grey literature searches. Eligible studies included individuals with (1) PCC or (2) a positive SARS-CoV-2 test or COVID-19 diagnosis who were followed over time. Included studies were published in English between 1 January 2020 and 14 November 2022.Findings Of 291 publications included, 175 (60%) followed individuals with confirmed COVID-19 over time for PCC and 116 (40%) used a prespecified PCC definition. There was substantial heterogeneity in study design, geography, age group, PCC conditions/symptoms assessed and their classification and duration of follow-up. Among studies using a prespecified PCC definition, author-defined criteria (51%) were more common than criteria recommended by major public health organisations (19%). Measurement periods for PCC outcomes from date of acute COVID-19 test were primarily 3 to

Objective To create case definitions for confirmed COVID-19 diagnoses, COVID-19 vaccination status and three separate definitions of high risk of severe COVID-19, as well as to assess whether the implementation of these definitions in a cohort reflected the sociodemographic and clinical characteristics of COVID-19 epidemiology in England.Design Retrospective cohort study.Setting Electronic healthcare records from primary care (Clinical Practice Research Datalink, CPRD) linked to secondary care data (Hospital Episode Statistics) data covering 24% of the population in England.Participants 2 271 072 persons aged 1 year and older diagnosed with COVID-19 in CPRD Aurum between 1 August 2020 and 31 January 2022.Main outcome measures Age, sex and regional distribution of COVID-19 cases and COVID-19 vaccine doses received prior to diagnosis were assessed separately for the cohorts of cases identified in primary care and those hospitalised for COVID-19 (primary diagnosis code of ICD-10 U07.1 ‘COVID-19’). Smoking status, body mass index and Charlson Comorbidity Index were compared for the two cohorts, as well as for three separate definitions of high risk of severe disease used in the UK (National Health Service Highest Risk, PANORAMIC trial eligibility, UK Health Security Agency Clinical Risk prioritisation for vaccination).Results Compared with national estimates, CPRD case estimates under-represented older adults in both the primary care (age 65–84: 6% in CPRD vs 9% nationally) and hospitalised (31% vs 40%) cohorts, and over-represented people living in regions with the highest median wealth areas of England (20% primary care and 20% hospital admitted cases in South East vs 15% nationally). The majority of non-hospitalised cases and all hospitalised cases had not completed primary series vaccination. In primary care, persons meeting high-risk definitions were older, more often smokers, overweight or obese, and had higher Charlson Comorbidity Index score.Conclusions CPRD primary care data are a robust real-world data source and can be used for some COVID-19 research questions, however, limitations of the data availability should be carefully considered. Included in this publication are supplemental files for a total of over 28 000 codes to define each of three definitions of high risk of severe disease.

Objectives To quantify direct costs and healthcare resource utilisation (HCRU) associated with acute COVID-19 in adults in England.Design Population-based retrospective cohort study using Clinical Practice Research Datalink Aurum primary care electronic medical records linked to Hospital Episode Statistics secondary care administrative data.Setting Patients registered to primary care practices in England.Population 1 706 368 adults with a positive SARS-CoV-2 PCR or antigen test from August 2020 to January 2022 were included; 13 105 within the hospitalised cohort indexed between August 2020 and March 2021, and 1 693 263 within the primary care cohort indexed between August 2020 and January 2022. Patients with a COVID-19-related hospitalisation within 84 days of a positive test were included in the hospitalised cohort.Main outcome measures Primary and secondary care HCRU and associated costs ≤4 weeks following positive COVID-19 test, stratified by age group, risk of severe COVID-19 and immunocompromised status.Results Among the hospitalised cohort, average length of stay, including critical care stays, was longer in older adults. Median healthcare cost per hospitalisation was higher in those aged 75–84 (£8942) and ≥85 years (£8835) than in those aged

Abstract Determining whether SARS-CoV-2 exhibits seasonality like other respiratory viruses is critical for public health planning. We evaluated whether COVID-19 rates follow a seasonal pattern using time series models. We used time series decomposition to extract the annual seasonal component of COVID-19 case, hospitalization, and mortality rates from March 2020 through December 2022 for the United States and Europe. Models were adjusted for a country-specific stringency index to account for confounding by various interventions. Despite year-round disease activity, we identified seasonal spikes in COVID-19 from approximately November through April for all outcomes and in all countries. Our results support employing annual preventative measures against SARS-CoV-2, such as administering seasonal booster vaccines in a similar timeframe as those in place for influenza. Whether certain high-risk individuals may need more than one COVID-19 vaccine booster dose each year will depend on factors like vaccine durability against severe illness and levels of year-round disease activity.

Abstract The causal variants and genes underlying thousands of cardiac GWAS signals have yet to be identified. Here, we leverage spatiotemporal information on 966 RNA-seq cardiac samples and perform an expression quantitative trait locus (eQTL) analysis detecting eQTLs considering both eGenes and eIsoforms. We identify 2,578 eQTLs associated with a specific developmental stage-, tissue- and/or cell type. Colocalization between eQTL and GWAS signals of five cardiac traits identified variants with high posterior probabilities for being causal in 210 GWAS loci. Pulse pressure GWAS loci are enriched for colocalization with fetal- and smooth muscle- eQTLs; pulse rate with adult- and cardiac muscle- eQTLs; and atrial fibrillation with cardiac muscle- eQTLs. Fine mapping identifies 79 credible sets with five or fewer SNPs, of which 15 were associated with spatiotemporal eQTLs. Our study shows that many cardiac GWAS variants impact traits and disease in a developmental stage-, tissue- and/or cell type-specific fashion.

BackgroundThe COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has substantially impacted healthcare utilization worldwide. The objective of this retrospective analysis of a large hospital discharge database was to compare all-cause and cause-specific hospitalizations during the first six months of the pandemic in the United States with the same months in the previous four years.MethodsData were collected from all hospitals in the Premier Healthcare Database (PHD) and PHD Special Release reporting hospitalizations from January through July for each year from 2016 through 2020. Hospitalization trends were analyzed stratified by age group, major diagnostic categories (MDCs), and geographic region.ResultsThe analysis included 286 hospitals from all 9 US Census divisions. The number of all-cause hospitalizations per month was relatively stable from 2016 through 2019 and then fell by 21% (57,281 fewer hospitalizations) between March and April 2020, particularly in hospitalizations for non-respiratory illnesses. From April onward there was a rise in the number of monthly hospitalizations per month. Hospitalizations per month, nationally and in each Census division, decreased for 20 of 25 MDCs between March and April 2020. There was also a decrease in hospitalizations per month for all age groups between March and April 2020 with the greatest decreases in hospitalizations observed for patients 50-64 and ≥65 years of age.ConclusionsRates of hospitalization declined substantially during the first months of the COVID-19 pandemic, suggesting delayed routine, elective, and emergency care in the United States. These lapses in care for illnesses not related to COVID-19 may lead to increases in morbidity and mortality for other conditions. Thus, in the current stage of the pandemic, clinicians and public-health officials should work, not only to prevent SARS-CoV-2 transmission, but also to ensure that care for non-COVID-19 conditions is not delayed.

Summary: Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.

Metals have been used in medicine since ancient times for the treatment of different ailments with various elements such as iron, gold and arsenic. Metal complexes have also been reported to show antibiotic and antiparasitic activity. In this context, we tested the antiparasitic potential of 10 organotin (IV) derivatives from 4-(4-methoxyphenylamino)-4 oxobutanoic acid (MS26) against seven eukaryotic pathogens of medical importance: Leishmania donovani, Trypanosoma cruzi, Trypanosoma brucei, Entamoeba histolytica, Giardia lamblia, Naegleria fowleri and Schistosoma mansoni. Among the compounds with and without antiparasitic activity, compound MS26Et3 stood out with a 50% effective concentration (EC50) of 0.21 and 0.19 µM against promastigotes and intracellular amastigotes of L. donovani, respectively, 0.24 µM against intracellular amastigotes of T. cruzi, 0.09 µM against T. brucei, 1.4 µM against N. fowleri and impaired adult S. mansoni viability at 1.25 µM. In terms of host/pathogen selectivity, MS26Et3 demonstrated relatively mild cytotoxicity toward host cells with a 50% viability concentration of 4.87 µM against B10R cells (mouse monocyte cell line), 2.79 µM against C2C12 cells (mouse myoblast cell line) and 1.24 µM against HEK923 cells (human embryonic kidney cell line). The selectivity index supports this molecule as a therapeutic starting point for a broad spectrum antiparasitic alternative. Proteomic analysis of host cells infected with L. donovani after exposure to MS26Et3 showed a reduced expression of Rab7, which may affect the fusion of the endosome with the lysosome, and, consequently, impairing the differentiation of L. donovani to the amastigote form. Future studies to investigate the molecular target(s) and mechanism of action of MS26Et3 will support its chemical optimization.

Summary: Despite the importance of understanding how variability across induced pluripotent stem cell (iPSC) lines due to non-genetic factors (clone and passage) influences their differentiation outcome, large-scale studies capable of addressing this question have not yet been conducted. Here, we differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). We observed cellular heterogeneity across the iPSC-CVPC samples due to varying fractions of two cell types: cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Comparing the transcriptomes of CM-fated and EPDC-fated iPSCs, we discovered that 91 signature genes and X chromosome dosage differences are associated with these two distinct cardiac developmental trajectories. In an independent set of 39 iPSCs differentiated into CMs, we confirmed that sex and transcriptional differences affect cardiac-fate outcome. Our study provides novel insights into how iPSC transcriptional and X chromosome gene dosage differences influence their response to differentiation stimuli and, hence, cardiac cell fate. : In this article, D'Antonio-Chronowska, Donovan and colleagues differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). The iPSC-CVPC samples showed cellular heterogeneity due to varying fractions of cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Donor sex and expression levels of signature genes in iPSCs played a role in the relative proportions of CMs and EPDCs present in the derived CVPCs. Keywords: iPSC, iPSC-derived cardiovascular progenitor cells, iPSC-derived cardiomyocytes, iPSC-derived epicardium, scRNA-seq, single-cell transcriptomics, X chromosome inactivation, X chromosome erosion, iPSC differentiation

The Asian Pacific American Medical Student Association (APAMSA) is a national student organization that advocates for the health of the Asian American Pacific Islanders. In May 2020, our APAMSA chapter at Oakland University William Beaumont (OUWB) School of Medicine located in Michigan, USA hosted a virtual mental health campaign titled, “Socially Distant but Emotionally Connected: 6ft Closer During Quarantine.” We reached out to medical students and faculty within the OUWB community to share their experiences during the initial phases of quarantine. Our goal was to create a space for everyone at OUWB to engage in meaningful conversations about mental health and support each other during the pandemic. The responses we received varied across numerous topics, including xenophobia, loneliness, and lack of motivation. Participants also followed up with words of encouragement for their peers and guidance on how to cope with social isolation. Our virtual campaign was very feasible and successful under the constraints of social distancing, and we urge other medical schools to implement their own mental health awareness initiatives to destigmatize the topic in their communities. General steps on how to start your own campaign include: collaborating with interest groups, deciding on social media platforms, and sharing with your community.

Introduction: This study quantified stroke-related changes in the following: (1) the averaged discharge rate of motor units (individually tracked and untracked) identified from high-density electromyography (HD-EMG) recordings, (2) global muscle EMG properties of the dorsiflexors during a fatiguing contraction, and the relationship between task endurance and measures of leg function.Methods: Ten individuals with chronic stroke performed a sustained sub-maximal, isometric, fatiguing dorsiflexion contraction in paretic and non-paretic legs. Motor-unit firing behavior, task duration, maximal voluntary contraction strength (MVC), and clinical measures of leg function were obtained.Results: Compared to the non-paretic leg, the paretic leg task duration was shorter, and there was a larger exercise-related reduction in motor unit global rates, individually tracked discharge rates, and overall magnitude of EMG. Task duration of the paretic leg was more predictive of walking speed and lower extremity Fugl-Meyer scores compared to the non-paretic leg.Discussion: Paretic leg muscle fatigability is increased post stroke. It is characterized by impaired rate coding and recruitment and relates to measures of motor function.

Pulmonary function is influenced by environmental factors, lifestyle, and genetics. Here, in a multiethnic GWAS meta-analysis for pulmonary function traits, the authors identify over 50 additional genetic loci, a subset of which are specific for European, African, Asian, or Hispanic/Latino ancestry.

Abstract Background We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study. Methods We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hispanic White (n = 2,434), African American (n = 2,470), Hispanic (n = 2,065) and Chinese (n = 702), as well as stratified by race/ethnicity. Results Among 7,671 participants, regions at genome-wide significance were identified for basilar peel-core ratio of HAA in FLJ35282 downstream of ANRIL (rs7852363, P = 2.1x10−9) and within introns of SNAI3-AS1 (rs140142658, P = 9.6x10−9) and D21S2088E (rs3079677, P = 2.3x10−8). Within race/ethnic groups, 18 additional loci were identified at genome-wide significance, including genes related to development (FOXP4), cell adhesion (ALCAM) and glycosylation (GNPDA2, GYPC, GFPT1 and FUT10). Among these loci, SNP rs6844387 near GNPDA2 demonstrated nominal evidence of replication in analysis of n = 1,959 participants from the Framingham Heart Study (P = 0.029). FOXP4 region SNP rs2894439 demonstrated evidence of validation in analysis of n = 228 White ILD cases from the Columbia ILD Study compared to race/ethnicity-matched controls from MESA (one-sided P = 0.007). In lung tissue from 15 adults with idiopathic pulmonary fibrosis compared to 15 adults without lung disease. ANRIL (P = 0.001), ALCAM (P = 0.03) and FOXP4 (P = 0.046) were differentially expressed. Conclusions Our results suggest novel roles for protein glycosylation and cell cycle disinhibition by long non-coding RNA in the pathogenesis of ILD.

The objective of this study was to examine variations in the determinants of joint replacement (JR) across gender and age, with emphasis on the role of social support and family dynamics. We analyzed data from the US Health and Retirement Study (1998-2010) on individuals aged 45 or older with no prior receipt of JR. We used logistic regression to analyze the probability of receiving knee or hip replacement by gender and age (

Human RTEL1 is an essential, multifunctional helicase that maintains telomeres, regulates homologous recombination, and helps prevent bone marrow failure. Here, we show that RTEL1 also blocks trinucleotide repeat expansions, the causal mutation for 17 neurological diseases. Increased expansion frequencies of (CTG⋅CAG) repeats occurred in human cells following knockdown of RTEL1, but not the alternative helicase Fbh1, and purified RTEL1 efficiently unwound triplet repeat hairpins in vitro. The expansion-blocking activity of RTEL1 also required Rad18 and HLTF, homologs of yeast Rad18 and Rad5. These findings are reminiscent of budding yeast Srs2, which inhibits expansions, unwinds hairpins, and prevents triplet-repeat-induced chromosome fragility. Accordingly, we found expansions and fragility were suppressed in yeast srs2 mutants expressing RTEL1, but not Fbh1. We propose that RTEL1 serves as a human analog of Srs2 to inhibit (CTG⋅CAG) repeat expansions and fragility, likely by unwinding problematic hairpins.

Most organisms rely on innate immune receptors to recognize conserved molecular structures from invading microbes. Two essential innate immune receptors, RIG-I and MDA5, detect viral double-stranded RNA in the cytoplasm. The inflammatory response triggered by these RIG-I-like receptors (RLRs) is one of the first and most important lines of defense against infection. RIG-I recognizes short RNA ligands with 5’-triphosphate caps. MDA5 recognizes long kilobase-scale genomic RNA and replication intermediates. Ligand binding induces conformational changes and oligomerization of RLRs that activate the signaling partner MAVS on the mitochondrial and peroxisomal membranes. This signaling process is under tight regulation, dependent on post-translational modifications of RIG-I and MDA5, and on regulatory proteins including unanchored ubiquitin chains and a third RLR, LGP2. Here we review recent advances that have shifted the paradigm of RLR signaling away from the conventional linear signaling cascade. In the emerging RLR signaling model, large multimeric signaling platforms generate a highly cooperative, self-propagating and context-dependent signal, which varies with the subcellular localization of the signaling platform.

Abstract Objective This study examines changes in utilization and costs trends associated with migraine medications. Background Migraine attacks are a burden to many patients. There are many pharmacotherapy options available with newer migraine drug classes entering the market in the past decade. Little is known about the use, associated costs, and the impact of the newer agents. Methods This retrospective, cross-sectional study examined 2017–2020 administrative claims from a large national pharmacy benefits manager. Patients aged ≥ 18 years enrolled in commercial, Medicare, Medicaid, or health insurance exchange insurance plans who filled ≥ 2 prescription claims for triptans, ergotamines, isometheptenes, gepants, ditans, and CGRP mABs were included. A two-sample t-test was conducted to estimate whether differences in mean utilization and costs between 2017 and 2020 were statistically significant for migraine drug classes, except for CGRP mABs, which were estimated between 2018 and 2020. Results The sample ranged from 161,369 (2017) to 240,330 (2020) patients. 84.5% (n = 203,110; 2020) of patients were women. The number of 30-day adjusted prescription fills for prophylaxis remained stable over the four-year period, except for CGRP mABs, which increased from 0.5% (n = 0.007; 2018) to 5.3% (n = 0.075; 2020). Antiepileptics, antidepressants and beta blockers were the most common prophylaxes, while triptans, non-steroidal anti-inflammatory drugs/non-narcotic analgesics and opioids were the most common treatments utilized. CGRP mABs were the most expensive, while utilization of triptans were the highest. CGRP mABs had the largest increase in utilization (177.5%) and costs (166.3%) PPPM in 2020 ($291.17) compared to 2018 ($109.35), the year they were first available (p

Observational studies are needed to demonstrate real-world vaccine effectiveness (VE) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcomes. Our objective was to conduct a review of published SARS-CoV-2 VE articles, supplemented by preprints, during the first 6 months of COVID-19 vaccine availability. This review compares the effectiveness of completing the primary COVID-19 vaccination series against multiple SARS-CoV-2 disease presentations and disease severity outcomes in three population groups (general population, frontline workers, and older adults). Four hundred and seventy-one published articles and 47 preprints were identified. After title and abstract screening and full article review, 50 studies (28 published articles, 22 preprints) were included. VE results were reported for five COVID-19 vaccines and four combinations of COVID-19 vaccines. VE results for BNT162b2 were reported in 70.6% of all studies. Seventeen studies reported variant specific VE estimates; Alpha was the most common. This comprehensive review demonstrates that COVID-19 vaccination is an important tool for preventing COVID-19 morbidity and mortality among fully vaccinated persons aged 16 years and older and serves as an important baseline from which to follow future trends in COVID-19 evolution and effectiveness of new and updated vaccines.