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

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The immunogenetics of multiple sclerosis. The frequency of HLA-alleles class 1 and 2 is lower in Southern Brazil than in the European population

ABSTRACT Objective To study the HLA of class 1and 2 in a multiple sclerosis (MS) population to verify the susceptibility for the disease in the Southern Brazil. Methods We analyzed patients with MS and controls, by direct sequencing of the genes related to HLA DRB1, DQB1, DPB1, A, B and C alleles with high resolution techniques. Results We found a lower frequency of all HLA alleles class 1 and 2 in MS and controls comparing to the European population. Several alleles had statistical correlation, but after Bonferroni correction, the only allele with significance was the HLA-DQB1*02:03, which has a positive association with MS. Conclusions Our data have different frequency of HLA-alleles than the previous published papers in the Southeast Brazil and European population, possible due to several ethnic backgrounds

Spinocerebellar ataxias: microsatellite and allele frequency in unaffected and affected individuals Ataxias espinocerebelares: freqüência de alelos e microsatélites em indivíduos normais e afetados

The diagnosis and incidence of spinocerebelar ataxias (SCA) is sometimes difficult to analyze due the overlap of phenotypes subtypes and are disorders of mutations caused by CAG trinucleotide repeat expansion. To investigate the incidence of the SCA in Southern Brazil, we analyzed the trinucleotide repeats (CAG)n at the SCA1, SCA2, SCA3, SCA6 and SCA7 loci to identify allele size ranges and frequencies. We examined blood sample from 154 asymptomatic blood donors and 115 individuals with progressive ataxias. PCR products were submitted to capillary electrophoresis. In the blood donors, the ranges of the five loci were: SCA1, 19 to 36 (CAG)n; SCA2, 6 to 28 (CAG)n; SCA3, 12 to 34 (CAG)n; SCA6, 2 to 13 (CAG)n; and SCA7, 2 to 10 (CAG)n. No deviations from Hardy-Weinberg equilibrium were detected. In the ataxia group, we found (CAG)n above the range of the asymptomatic blood donors in SCA3 (21.74%) followed by SCA2 (5.22%), SCA7 (2.61%), SCA6 (0.87%), and no cases of SCA1. The remaining 80 cases (69.56%) have different diagnoses from the type here studied. These data defined the alleles and their frequencies, as well as demonstrated their stability in the population not affected. The molecular diagnosis test confirmed the clinical diagnosis in 28/45 cases and classified another 7/70 from the clinical unclassified ataxias group.A incidência e o diagnóstico das ataxias espinocerebelares (SCA) é algumas vezes difícil de avaliar devido a sobreposição dos diversos subtipos e por algumas serem devido a mutações das expansões do mesmo trinucleotídeo CAG. Para investigar a incidências das SCA no sul do Brasil, analisamos as repetições do trinucleotídeo (CAG)n nos loci das SCA1, SCA2, SCA3, SCA6 e SCA7, a fim de identificar os seus limites e freqüência. Examinamos o sangue de 154 doadores de sangue assintomáticos e 115 pacientes com ataxias progressivas. O produto do PCR do sangue foi submetido a eletroforese capilar. Nos doadores de sangue, as expansões encontradas nos cinco loci foram: SCA1, 19 a 36 (CAG)n; SCA2, 6 a 28 (CAG)n; SCA3, 12 a 34 (CAG)n; SCA6, 2 a 13 (CAG)n; and SCA7, 2 a 10 (CAG)n. Não foi detectado desequilíbrio na equação de Hardy-Weinberg. No grupo das ataxias encontramos repetições CAG acima das freqüências dos doadores de sangue na SCA3 (21,7%), seguido da SCA2 (5,22%), SCA7 (2,61%), SCA6 (0,8%) e não foi encontrado nenhum caso de SCA1. Os 80 casos restantes (69,56%) devem ter uma forma de ataxia diferente das aqui estudadas. Esses dados definem os alelos e suas freqüências, bem como demonstram a sua estabilidade na população não afetada. O diagnóstico molecular confirmou o diagnóstico clínico em 28/45 dos casos e permitiu classificar outros 7/70 que pertenciam ao grupo de ataxias clinicamente não classificadas

Functional diversity enhances tree growth and reduces herbivory damage in secondary broadleaf forests, but does not influence resilience to drought

Since the mid-20th Century, Europe has experienced an unprecedented forest expansion associated with the abandonment of rural landscapes. Secondary forests may provide relevant ecosystem services such as landscape defragmentation, biodiversity conservation, control of hydrological cycling and carbon sequestration. Secondary forests may benefit from the legacies of the former agricultural land use, and exhibit enhanced growth. Moreover, they may differ from long-established forests in terms of tree species composition and diversity, as community composition has been less modified by succession or management. However, we lack evidence whether the effects of land use legacies on tree species diversity may also result in differences in the response of secondary forests to biotic and abiotic disturbances. We aimed to evaluate the effects of land use legacies on taxonomic and functional diversity and their effects on the response of temperate broadleaf forests to drought and herbivory damage. For this aim, we compared secondary beechFagus sylvaticaforests established after 1950 in abandoned pastures with long-established (pre-1950) forests. We calculated indices of taxonomic and functional diversity and determined mean growth and growth response of beech to two drought events (1991, 2006), and insect herbivory damage. Secondary and long-established beech forests marginally differed in species richness but the former exhibited a significantly higher Shannon diversity index and evenness. Yet, differences in taxonomic diversity did not result in differences in functional diversity between forest types. Mean tree growth was higher in secondary than in long-established forests and it increased with functional diversity in both forest types. However, diversity was unrelated with the growth response to drought. Insect herbivory damage decreased with increasing functional diversity but only in secondary forests. Synthesis and applications. Promoting functional diversity in temperate broadleaf forests is a promising strategy for enhancing productivity (tree growth) while increasing the ability to cope with biotic disturbances (insect herbivory). This principle should be applied both in the management of long-established as well as expanding secondary forests. Yet, functional diversity does not seem to ameliorate tree response to drought, highlighting the need for other silvicultural practices to address this environmental challenge

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research