Typing myalgic encephalomyelitis by infection at onset: A DecodeME study [version 4; peer review: 2 approved]

Background: People with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) experience core symptoms of post-exertional malaise, unrefreshing sleep, and cognitive impairment. Despite numbering 0.2-0.4% of the population, no laboratory test is available for their diagnosis, no effective therapy exists for their treatment, and no scientific breakthrough regarding pathogenesis has been made. It remains unknown, despite decades of small-scale studies, whether individuals experience different types of ME/CFS separated by onset-type, sex or age. Methods: DecodeME is a large population-based study of ME/CFS that recruited 17,074 participants in the first 3 months following full launch. Detailed questionnaire responses from UK-based participants who all reported being diagnosed with ME/CFS by a health professional provided an unparalleled opportunity to investigate, using logistic regression, whether ME/CFS severity or onset type is significantly associated with sex, age, illness duration, comorbid conditions or symptoms. Results: The well-established sex-bias among ME/CFS patients is evident in the initial DecodeME cohort: 83.5% of participants were females. What was not known previously was that females tend to have more comorbidities than males. Moreover, being female, being older and being over 10 years from ME/CFS onset are significantly associated with greater severity.  Five different ME/CFS onset types were examined in the self-reported data: those with ME/CFS onset (i) after glandular fever (infectious mononucleosis); (ii) after COVID-19 infection; (iii) after other infections; (iv) without an infection at onset; and, (v) where the occurrence of an infection at or preceding onset is not known. Among other findings, ME/CFS onset with unknown infection status was significantly associated with active fibromyalgia. Conclusions: DecodeME participants differ in symptoms, comorbid conditions and/or illness severity when stratified by their sex-at-birth and/or infection around the time of ME/CFS onset

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

The incidence and burden of injuries in elite English youth female soccer players

This study aimed to investigate the incidence, severity and burden of injury in English elite youth female soccer players. Qualified therapists at six English girls’ academies prospectively recorded all injuries that required medical attention or caused time loss for matches and training in 375 elite youth female soccer players (under-10 [U10], U12, U14 and U16) during the 2019/2020 season. One hundred- and eleven time-loss injuries (52 from training, 59 from matches) were sustained, resulting in 1,946 days absent (779 days from training injuries, 1,167 days from match injuries) from soccer activities. The injury incidence for matches (9.3/1000 hours, 95% CIs: 7.2–11.9) was significantly greater than training (1.1/1000 hours, 95% CIs: 0.9–1.5, p &lt; 0.001). Additionally, the injury burden for matches (183 days lost/1000 hours, 95% CIs: 142–237) was significantly greater than training (17 days lost/1000 hours, 95% CIs: 13–22, p &lt; 0.001). Injury incidence and burden were greatest in the U16 age group and were found to increase with age. Whilst injury incidence and burden are greater in matches than training, a large proportion of preventable injuries, soft-tissue and non-contact in nature, were sustained in training. Findings provide comparative data for elite youth female soccer players.</p

DecodeME: Community recruitment for a large genetics study of myalgic encephalomyelitis / chronic fatigue syndrome

BACKGROUND: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, long-term condition characterised by post-exertional malaise, often with fatigue that is not significantly relieved by rest. ME/CFS has no confirmed diagnostic test or effective treatment and we lack knowledge of its causes. Identification of genes and cellular processes whose disruption adds to ME/CFS risk is a necessary first step towards development of effective therapy. METHODS: Here we describe DecodeME, an ongoing study co-produced by people with lived experience of ME/CFS and scientists. Together we designed the study and obtained funding and are now recruiting up to 25,000 people in the UK with a clinical diagnosis of ME/CFS. Those eligible for the study are at least 16 years old, pass international study criteria, and lack any alternative diagnoses that can result in chronic fatigue. These will include 5,000 people whose ME/CFS diagnosis was a consequence of SARS-CoV-2 infection. Questionnaires are completed online or on paper. Participants’ saliva DNA samples are acquired by post, which improves participation by more severely-affected individuals. Digital marketing and social media approaches resulted in 29,000 people with ME/CFS in the UK pre-registering their interest in participating. We will perform a genome-wide association study, comparing participants’ genotypes with those from UK Biobank as controls. This should generate hypotheses regarding the genes, mechanisms and cell types contributing to ME/CFS disease aetiology. DISCUSSION: The DecodeME study has been reviewed and given a favourable opinion by the North West – Liverpool Central Research Ethics Committee (21/NW/0169). Relevant documents will be available online (www.decodeme.org.uk). Genetic data will be disseminated as associated variants and genomic intervals, and as summary statistics. Results will be reported on the DecodeME website and via open access publications

Zoe Wicomb and the Cape Cosmopolitan

This essay places Zoë Wicomb's writing in the context of recent accounts of the ‘new cosmopolitanism’, and argues that the imagined figure of the Cape cosmopolitan produced in her writing puts into question the either-or relation of the terms ‘national’ and ‘cosmopolitan’. Comparing the metaphorics of the ‘tavern of the seas’ (applied to the Cape of Good Hope) with the US national myth of the ‘melting pot’, the essay re-situates the former in order to claim for the Cape cosmopolitan an inclusivity, fluidity and non-hegemonic character practically denied the latter. The essay focuses largely on David's Story, but refers also to You Can't Get Lost in Cape Town, Playing in the Light and The One that Got Away, and foregrounds the ironic mode of Wicomb's writing, in which all claims to truth, including the claims about the ‘new cosmopolitanism’ put forward in recent cosmopolitan studies as well as in this essay, are held in question.Dorothy Drive

U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics

Background: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided. Objectives: We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum. Methods: Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data. Results: Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to-severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels. Conclusion: Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways