With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms ...from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.
Ebola virus (EBOV), a major global health concern, causes severe, often fatal EBOV disease (EVD) in humans. Host genetic variation plays a critical role, yet the identity of host susceptibility loci ...in mammals remains unknown. Using genetic reference populations, we generate an F2 mapping cohort to identify host susceptibility loci that regulate EVD. While disease-resistant mice display minimal pathogenesis, susceptible mice display severe liver pathology consistent with EVD-like disease and transcriptional signatures associated with inflammatory and liver metabolic processes. A significant quantitative trait locus (QTL) for virus RNA load in blood is identified in chromosome (chr)8, and a severe clinical disease and mortality QTL is mapped to chr7, which includes the Trim5 locus. Using knockout mice, we validate the Trim5 locus as one potential driver of liver failure and mortality after infection. The identification of susceptibility loci provides insight into molecular genetic mechanisms regulating EVD progression and severity, potentially informing therapeutics and vaccination strategies.
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•CC genetic reference population identifies genetic loci regulating EBOV pathogenesis in mice•An F2 population from two CC lines is either highly resistant or vulnerable to EBOV infection•A major locus on chromosome 7, encoding Trim5, drives severe EVD-like disease in mice•Gene expression signatures of liver damage mirror severe EVD in humans
Schäfer et al. use a genetic screening platform based on the collaborative cross (CC) to identify and elucidate the role of the Trim5 locus during Ebola virus (EBOV) infection and the development of EBOV disease (EVD) in mice.
The heterogeneity of the immunocompromised population means some individuals may exhibit variable, weak or reduced vaccine-induced immune responses, leaving them poorly protected from COVID-19 ...disease despite receiving multiple SARS-CoV-2 vaccinations. There is conflicting data on the immunogenicity elicited by multiple vaccinations in immunocompromised groups. The aim of this study was to measure both humoral and cellular vaccine-induced immunity in several immunocompromised cohorts and to compare them to immunocompetent controls.
Cytokine release in peptide-stimulated whole blood, and neutralising antibody and baseline SARS-CoV-2 spike-specific IgG levels in plasma were measured in rheumatology patients (n=29), renal transplant recipients (n=46), people living with HIV (PLWH) (n=27) and immunocompetent participants (n=64) post third or fourth vaccination from just one blood sample. Cytokines were measured by ELISA and multiplex array. Neutralising antibody levels in plasma were determined by a 50% neutralising antibody titre assay and SARS-CoV-2 spike specific IgG levels were quantified by ELISA.
In infection negative donors, IFN-γ, IL-2 and neutralising antibody levels were significantly reduced in rheumatology patients (p=0.0014, p=0.0415, p=0.0319, respectively) and renal transplant recipients (p<0.0001, p=0.0005, p<0.0001, respectively) compared to immunocompetent controls, with IgG antibody responses similarly affected. Conversely, cellular and humoral immune responses were not impaired in PLWH, or between individuals from all groups with previous SARS-CoV-2 infections.
These results suggest that specific subgroups within immunocompromised cohorts could benefit from distinct, personalised immunisation or treatment strategies. Identification of vaccine non-responders could be critical to protect those most at risk.
Genomes for medicine Bentley, David R
Nature,
05/2004, Letnik:
429, Številka:
6990
Journal Article
Recenzirano
We have the human genome sequence. It is freely available, accurate and nearly complete. But is the genome ready for medicine? The new resource is already changing genetic research strategies to find ...information of medical value. Now we need high-quality annotation of all the functionally important sequences and the variations within them that contribute to health and disease. To achieve this, we need more genome sequences, systematic experimental analyses, and extensive information on human phenotypes. Flexible and user-friendly access to well-annotated genomes will create an environment for innovation, and the potential for unlimited use of sequencing in biomedical research and practice.
Abstract
Context
Survival rates after severe injury are improving, but complication rates and outcomes are variable.
Objective
This cohort study addressed the lack of longitudinal data on the steroid ...response to major trauma and during recovery.
Design
We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15).
Main outcome measures
We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models.
Findings
We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 interquartile range 24–31 years; median NISS 34 29–44). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis.
Conclusion
The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation.
Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even ...greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (
= 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (
= 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (
= 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.
The Mepolizumab in Relapsing or Refractory EGPA (MIRRA) trial (GSK ID: 115921/NCT02020889) demonstrated that mepolizumab increased remission time and reduced oral corticosteroid (OCS) use compared ...with placebo in patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA). The present analysis investigated the impact of baseline characteristics on clinical outcomes and characterised the OCS-sparing effect of mepolizumab.
In a phase 3, randomised controlled trial for patients with EGPA (MIRRA), patients received standard of care plus mepolizumab 300 mg or placebo every 4 weeks for 52 weeks. The accrued duration of remission, the proportion of patients in remission at weeks 36 and 48, and the proportion of patients with clinical benefit (remission, OCS or relapse-related) were assessed according to baseline EGPA characteristic subgroups (
). Mepolizumab-related OCS-sparing benefits were also quantified.
Accrued duration of remission and the proportion of patients in remission at weeks 36 and 48 were greater with mepolizumab than placebo across the baseline subgroups of refractory disease, immunosuppressant use, EGPA duration, relapse number and OCS use ≤20 mg·day
. The proportion of patients with clinical benefit was greater with mepolizumab
placebo (range 76-81%
25-39%), irrespective of immunosuppressant use or EGPA duration. Patients treated with mepolizumab
placebo accrued significantly more weeks on OCS ≤4 mg·day
(OR 5.06, 95% CI 2.47-10.38) and had a mean of 1423.1 mg less per-patient OCS exposure over 52 weeks.
Mepolizumab treatment provided benefits to patients with EGPA across varying baseline clinical characteristics and can be considered an OCS-sparing treatment in EGPA.
Low-income subsidy/dual eligibility (LIS/DE) status and disability status may be associated with high-risk medication (HRM) use but are not usually accounted for in medication-use quality measures.
...To examine the association of: 1) LIS/DE status and HRM use; and 2) disability status and HRM use, while controlling for both health plan level effects and patient characteristics for Medicare beneficiaries enrolled in Medicare Advantage Prescription Drug Plans (MA-PD) and stand-alone Prescription Drug Plans (PDP).
This retrospective cross-sectional study used 2013 Medicare data to determine if LIS/DE status and disability status were independently associated with HRM use (using the Pharmacy Quality Alliance HRM measure) in MA-PDs and PDPs. Multivariable generalized linear mixed models assessed the association of LIS/DE and HRM use, and disability and HRM use, after adjusting for health plan effect and patient-level confounders for MA-PD and PDP beneficiaries.
Of 520,019 MA-PD beneficiaries, 88,693 (17.1%) were LIS/DE and 48,997 (9.4%) were disabled. Of 881,264 PDP beneficiaries, 213,096 (24.2%) were LIS/DE, and 83,593 (9.5%) were disabled. LIS/DE beneficiaries had a higher percent of HRM users compared to non-LIS/DE MA-PD (13.3% vs. 9.7%, p < 0.001) and PDP (17.1% vs. 13.2%, p < 0.001) beneficiaries. Disabled beneficiaries had a higher percent of HRM users compared to non-disabled MA-PD (17.0% vs. 9.6%, p < 0.001) and PDP (22.9% vs. 13.2%, p < 0.001) beneficiaries. Multivariable analyses showed LIS/DE (adjusted odds ratio AOR = 1.07; 95% CI = 1.04, 1.10) and disability (AOR = 1.38; 95% CI = 1.34, 1.42) were associated with HRM use among MA-PD and PDP beneficiaries (LIS/DE AOR = 1.14; 95% CI = 1.12, 1.16; disability AOR = 1.37; 95% CI = 1.34, 1.40).
The association of LIS/DE and disability with higher HRM use in both MA-PD and PDP beneficiaries, when controlling for health plan effects and patient characteristics, suggests these factors should be considered when comparing health plan performance on HRM measures.
Current standards in clinical genetics recognize the need to establish the validity of gene-disease relationships as a first step in the interpretation of sequence variants. We describe our ...experience incorporating the ClinGen Gene-Disease Clinical Validity framework in our interpretation and reporting workflow for a clinical genome sequencing (cGS) test for individuals with rare and undiagnosed genetic diseases. This “reactive” gene curation is completed upon identification of candidate variants during active case analysis and within the test turn-around time by focusing on the most impactful evidence and taking advantage of the broad applicability of the framework to cover a wide range of disease areas. We demonstrate that reactive gene curation can be successfully implemented in support of cGS in a clinical laboratory environment, enabling robust clinical decision making and allowing all variants to be fully and appropriately considered and their clinical significance confidently interpreted.
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•Evaluation of gene-disease relationships is essential for variant interpretation•Experience using reactive gene curation to support a clinical genome test•Rigorous reactive gene curation enables robust clinical decision making
Clause et al. describe a clinical laboratory’s experience implementing reactive evaluation of gene-disease relationships within the interpretation and reporting workflow of a clinical genome sequencing test for rare genetic diseases. This work demonstrates that rigorous, reactive gene curation aids in variant interpretation and meets a critical need for clinical reporting.
Despite the widespread implementation of public health measures, coronavirus disease 2019 (COVID-19) continues to spread in the United States. To facilitate an agile response to the pandemic, we ...developed How We Feel, a web and mobile application that collects longitudinal self-reported survey responses on health, behaviour and demographics. Here, we report results from over 500,000 users in the United States from 2 April 2020 to 12 May 2020. We show that self-reported surveys can be used to build predictive models to identify likely COVID-19-positive individuals. We find evidence among our users for asymptomatic or presymptomatic presentation; show a variety of exposure, occupational and demographic risk factors for COVID-19 beyond symptoms; reveal factors for which users have been SARS-CoV-2 PCR tested; and highlight the temporal dynamics of symptoms and self-isolation behaviour. These results highlight the utility of collecting a diverse set of symptomatic, demographic, exposure and behavioural self-reported data to fight the COVID-19 pandemic.
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