In December of 2019, a novel coronavirus, SARS-CoV-2, emerged in the city of Wuhan, China, causing severe morbidity and mortality. Since then, the virus has swept across the globe, causing millions ...of confirmed infections and hundreds of thousands of deaths. To better understand the nature of the pandemic and the introduction and spread of the virus in Arizona, we sequenced viral genomes from clinical samples tested at the TGen North Clinical Laboratory, the Arizona Department of Health Services, and those collected as part of community surveillance projects at Arizona State University and the University of Arizona. Phylogenetic analysis of 84 genomes from across Arizona revealed a minimum of 11 distinct introductions inferred to have occurred during February and March. We show that >80% of our sequences descend from strains that were initially circulating widely in Europe but have since dominated the outbreak in the United States. In addition, we show that the first reported case of community transmission in Arizona descended from the Washington state outbreak that was discovered in late February. Notably, none of the observed transmission clusters are epidemiologically linked to the original travel-related case in the state, suggesting successful early isolation and quarantine. Finally, we use molecular clock analyses to demonstrate a lack of identifiable, widespread cryptic transmission in Arizona prior to the middle of February 2020.
As the COVID-19 pandemic swept across the United States, there was great differential impact on local and regional communities. One of the earliest and hardest hit regions was in New York, while at the same time Arizona (for example) had low incidence. That situation has changed dramatically, with Arizona now having the highest rate of disease increase in the country. Understanding the roots of the pandemic during the initial months is essential as the pandemic continues and reaches new heights. Genomic analysis and phylogenetic modeling of SARS-COV-2 in Arizona can help to reconstruct population composition and predict the earliest undetected introductions. This foundational work represents the basis for future analysis and understanding as the pandemic continues.
Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variations in human disease has not been ...explored at scale. Exome-sequencing studies of population biobanks provide an opportunity to systematically evaluate the impact of rare coding variations across a wide range of phenotypes to discover genes and allelic series relevant to human health and disease. Here, we present results from systematic association analyses of 4,529 phenotypes using single-variant and gene tests of 394,841 individuals in the UK Biobank with exome-sequence data. We find that the discovery of genetic associations is tightly linked to frequency and is correlated with metrics of deleteriousness and natural selection. We highlight biological findings elucidated by these data and release the dataset as a public resource alongside the Genebass browser for rapidly exploring rare-variant association results.
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•Public release of gene-based association statistics for 4,529 diseases and traits•Genebass, a browser framework to display rare-variant associations•Tight coupling between frequency, natural selection, and power for genetic discovery•Biological signal between SCRIB and white-matter integrity (from MRI)
Karczewski et al. generated a massive-scale association dataset between rare genetic mutations and thousands of diseases and traits and released these data in the Genebass browser. They quantify the influence of natural selection and gene function on association discovery and highlight an association between SCRIB and a brain-imaging trait.
Health professionals who care for patients and their families at the end of life (EOL) may experience gratitude, and enhanced spirituality and meaning in life, yet they are also at increased risk of ...psychological distress, compassion fatigue, and occupational burnout given the stressors they encounter in their work.
This research evaluated the feasibility and acceptability of a novel six-week mindfulness-based compassion training intervention, which was tailored to health professionals involved in EOL care ("MBCT4HP"), and explored its impact on levels of psychological distress, compassion fatigue, compassion satisfaction, occupational burnout, self-compassion, and mindfulness.
We adopted an observational, repeated measures pilot study.
Thirty-one health professionals participated. The intervention comprised six, weekly sessions (totaling seven hours) designed to foster compassion for self and others, including formal and informal compassion and mindfulness practices, daily home practice, and a reflective experiential pedagogy.
Validated outcome measures for anxiety, depression, and stress; compassion satisfaction, compassion fatigue (burnout, secondary traumatic stress); occupational burnout (emotional exhaustion, personal accomplishment, and depersonalization), self-compassion, and mindfulness were administered at baseline, end of intervention, and eight weeks postintervention. The feasibility and acceptability of the intervention was assessed using attendance records, home practice logs, and self-report satisfaction items. Descriptive statistics and Generalized Linear Mixed Models were used to analyze the data.
Participants reported that the sessions were useful, relevant, easy to understand, and that they gave them sufficient knowledge to implement the strategies learned. Levels of anxiety, compassion fatigue (burnout only), and emotional exhaustion decreased over time with some decay in effects at follow up, and levels of compassion satisfaction and self-compassion increased with time.
The intervention was feasible and acceptable to health professionals involved in EOL care and had a positive impact on levels of anxiety, compassion fatigue (burnout), emotional exhaustion, compassion satisfaction, and self-compassion.
CD4+ T cell differentiation into multiple T helper (Th) cell lineages is critical for optimal adaptive immune responses. This report identifies an intrinsic mechanism by which programmed death-1 ...receptor (PD-1) signaling imparted regulatory phenotype to Foxp3+ Th1 cells (denoted as Tbet+iTregPDL1 cells) and inducible regulatory T (iTreg) cells. Tbet+iTregPDL1 cells prevented inflammation in murine models of experimental colitis and experimental graft versus host disease (GvHD). Programmed death ligand-1 (PDL-1) binding to PD-1 imparted regulatory function to Tbet+iTregPDL1 cells and iTreg cells by specifically downregulating endo-lysosomal protease asparaginyl endopeptidase (AEP). AEP regulated Foxp3 stability and blocking AEP imparted regulatory function in Tbet+iTreg cells. Also, Aep−/− iTreg cells significantly inhibited GvHD and maintained Foxp3 expression. PD-1-mediated Foxp3 maintenance in Tbet+ Th1 cells occurred both in tumor infiltrating lymphocytes (TILs) and during chronic viral infection. Collectively, this report has identified an intrinsic function for PD-1 in maintaining Foxp3 through proteolytic pathway.
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•Asparaginyl endopeptidase (AEP) is expressed in induced regulatory T cells•AEP cleaves Foxp3 and Aep−/− mice have elevated numbers of peripheral Treg cells•AEP deficiency increases Treg cell frequency and numbers in GvHD and melanoma•PD-1 signaling maintains Foxp3 protein expression by inhibiting AEP
Th1 cells are known for their enhanced stability, so mechanisms that mediate their flexibility are poorly studied. Here, Stathopoulou et al. demonstrate that plasticity of Th1 cells to Tbet+iTreg cells is mediated by PD-1 signaling via asparaginyl endopeptidase (AEP). AEP inhibition enhanced iTreg cells in GvHD and tumor models.
Abstract
During infection, bacteriophages produce diverse gene products to overcome bacterial antiphage defenses, to outcompete other phages, and to take over cellular processes. Even in the ...best-studied model phages, the roles of most phage-encoded gene products are unknown, and the phage population represents a largely untapped reservoir of novel gene functions. Considering the sheer size of this population, experimental screening methods are needed to sort through the enormous collection of available sequences and identify gene products that can modulate bacterial behavior for downstream functional characterization. Here, we describe the construction of a plasmid-based overexpression library of 94 genes encoded by Hammy, a Cluster K mycobacteriophage closely related to those infecting clinically important mycobacteria. The arrayed library was systematically screened in a plate-based cytotoxicity assay, identifying a diverse set of 24 gene products (representing ∼25% of the Hammy genome) capable of inhibiting growth of the host bacterium Mycobacterium smegmatis. Half of these are related to growth inhibitors previously identified in related phage Waterfoul, supporting their functional conservation; the other genes represent novel additions to the list of known antimycobacterial growth inhibitors. This work, conducted as part of the HHMI-supported Science Education Alliance Gene-function Exploration by a Network of Emerging Scientists (SEA-GENES) project, highlights the value of parallel, comprehensive overexpression screens in exploring genome-wide patterns of phage gene function and novel interactions between phages and their hosts.
Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and ...methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.
Objectives‘Healthier Wealthier Families’ (HWF) seeks to reduce financial hardship in the early years by embedding a referral pathway between Australia’s universal child and family health (CFH) ...services and financial counselling. This pilot study investigated the feasibility and short-term impacts of HWF, adapted from a successful Scottish initiative.MethodsSetting: CFH services in five sites across two states, coinciding with the COVID-19 pandemic. Participants: Caregivers of children aged 0–5 years experiencing financial hardship (study-designed screen). Design: Mixed methods. With limited progress using a randomised trial (RCT) design in sites 1–3 (March 2020–November 2021), qualitative interviews with service providers identified implementation barriers including stigma, lack of knowledge of financial counselling, low financial literacy, research burden and pandemic disruption. This informed a simplified RCT protocol (site 4) and direct referral model (no randomisation, pre–post evaluation, site 5) (June 2021–May 2022). Intervention: financial counselling; comparator: usual care (sites 1–4). Feasibility measures: proportions of caregivers screened, enrolled, followed up and who accessed financial counselling. Impact measures: finances (quantitative) and other (qualitative) to 6 months post-enrolment.Results355/434 caregivers completed the screen (60%–100% across sites). In RCT sites (1–4), 79/365 (19%–41%) reported hardship but less than one-quarter enrolled. In site 5, n=66/69 (96%) caregivers reported hardship and 44/66 (67%) engaged with financial counselling; common issues were utility debts (73%), and obtaining entitlements (43%) or material aid/emergency relief (27%). Per family, financial counselling increased income from government entitlements by an average $A6504 annually plus $A784 from concessions, grants, brokerage and debt waivers. Caregivers described benefits (qualitative) including reduced stress, practical help, increased knowledge and empowerment.ConclusionsFinancial hardship screening via CFH was acceptable to caregivers, direct referral was feasible, but individual randomisation was infeasible. Larger-scale implementation will require careful, staged adaptations where CFH populations and the intervention are well matched and low burden evaluation.Trial registration numberACTRN12620000154909.
This literature review of 46 articles uses the ecological model as a framework for organizing concepts and themes related to health care transition among youth with disabilities or special health ...care needs (SHCN). Transition involves interactions in immediate and distal environmental systems. Important interactions in immediate environments include those with family members, health care providers, and peers. Activities in distal systems include policies at the governmental and health system levels. The ecological model can help researchers and practitioners to design experimental interventions in multiple settings that ensure smooth transitions and support the well-being of youth with disabilities or SHCN.
IntroductionViolence against women is a global public health concern; around a quarter of women will experience intimate partner physical or sexual violence during their lifetime. We assessed the ...impact of a gender transformative intervention for women designed to prevent intimate partner violence (IPV).MethodsWe conducted a cluster randomised controlled trial in Mwanza city, Tanzania, among women in newly formed neighbourhood groups to evaluate a 10-session participatory intervention that aims to empower women, prevent IPV and promote healthy relationships. Following a baseline interview, groups were randomly assigned (1:1 ratio) to the intervention or control arm. An intention-to-treat analysis was conducted to assess the impact of the intervention on the main outcomes, assessed 24 months postintervention. These included past-year physical IPV and sexual IPV (primary); past-year emotional abuse; and acceptability and tolerance of IPV.ResultsBetween September 2015 and February 2017, 1265 women were recruited in 66 neighbourhoods and randomly allocated to intervention (n=627 women in 33 neighbourhoods) or control (n=638 women in 33 neighbourhoods). Assessment of outcomes was completed for 551 (88%) intervention and 575 (90%) control women. Among intervention women, 113 (21%) reported physical IPV compared with 117 (20%) control women (adjusted OR (aOR) 0.98, 95% CI 0.72 to 1.33, p=0.892), and 109 (20%) intervention women reported sexual IPV compared with 121 (21%) control women (aOR 0.98, 95% CI 0.72 to 1.32, p=0.881). Intervention women reported less emotional abuse (aOR 0.74, 95% CI 0.56 to 0.98, p=0.035), and were less likely to express attitudes accepting of IPV (aOR 0.49, 95% CI 0.36 to 0.66, p<0.001), and beliefs that IPV is a private matter (aOR 0.54, 95% CI 0.38 to 0.78, p=0.001), or should be tolerated (aOR 0.48, 95% CI 0.34 to 0.66, p<0.001).ConclusionThese results indicate that the intervention was effective in reducing emotional abuse and positively impacting attitudes and beliefs condoning IPV, but was not sufficient to reduce physical or sexual IPV.Trial registration numberNCT02592252.
Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15–44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: ...safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.
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