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

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Systematic reanalysis of copy number losses of uncertain clinical significance

Background Re-analysis of whole exome/genome data improves diagnostic yield. However, the value of re-analysis of clinical array comparative genomic hybridisation (aCGH) data has never been investigated. Case-by-case re-analysis is impractical in busy diagnostic laboratories. Methods and Results We harmonised historical post-natal clinical aCGH results from ∼16,000 patients tested via our diagnostic laboratory over ∼7 years with current clinical guidance. This led to identification of 33,857 benign, 2,173 class 3, and 979 pathogenic copy number losses (CNLs). We found benign CNLs to be significantly less likely to encompass haploinsufficient genes compared to the pathogenic or class 3 CNLs in our database. Using this observation, we developed a re-analysis pipeline (using up-to-date disease association data and haploinsufficiency scores) and shortlisted 207 class 3 CNLs encompassing at least one autosomal dominant disease-gene associated with haploinsufficiency or loss-of-function mechanism. Clinical scientist review led to reclassification of 7.2% shortlisted class 3 CNLs as pathogenic or likely pathogenic. This included first cases of CNV-mediated disease for some genes where all previously described cases involved only point variants. Interestingly, some CNLs could not be re-classified because the phenotypes of patients with CNLs seemed distinct from the known clinical features resulting from point variants, thus raising questions about accepted underlying disease mechanisms. Several potential novel disease-genes were identified that would need further validation. Conclusions Re-analysis of clinical aCGH data increases diagnostic yield and demonstrates their research value. In future, the aCGH reanalysis program should be expanded to include other copy number variant types. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The University of Manchester ethics and GDPR committee confirmed that no ethics approval was required for this study as it was data reanalysis I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the author

Biallelic loss of function variants in STAG3 result in primary ovarian insufficiency.

From PubMed via Jisc Publications RouterHistory: received 2021-04-23, revised 2021-06-24, accepted 2021-07-06Publication status: aheadofprintDoes a genetic condition underlie the diagnosis of primary ovarian insufficiency (POI) in a 21-year-old woman with primary amenorrhoea? A karyotype and genetic testing for Fragile X syndrome was undertaken. A next-generation sequencing panel of 24 genes associated with syndromal and non-syndromal POI was conducted. A nonsense variant c.1336G>T, p.(Glu446Ter) and whole gene deletion in STAG3 were identified. Biallelic loss of function variants in STAG3 are associated with primary ovarian failure type 8 and are a rare cause of POI. [Abstract copyright: Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.