Mitochondrial Dysfunction and Apoptosis in Cumulus Cells of Type I Diabetic Mice

Impaired oocyte quality has been demonstrated in diabetic mice; however, the potential pathways by which maternal diabetes exerts its effects on the oocyte are poorly understood. Cumulus cells are in direct contact with the oocyte via gap junctions and provide essential nutrients to support oocyte development. In this study, we investigated the effects of maternal diabetes on the mitochondrial status in cumulus cells. We found an increased frequency of fragmented mitochondria, a decreased transmembrane potential and an aggregated distribution of mitochondria in cumulus cells from diabetic mice. Furthermore, while mitochondrial biogenesis in cumulus cells was induced by maternal diabetes, their metabolic function was disrupted as evidenced by lower ATP and citrate levels. Moreover, we present evidence suggesting that the mitochondrial impairments induced by maternal diabetes, at least in part, lead to cumulus cell apoptosis through the release of cytochrome c. Together the deleterious effects on cumulus cells may disrupt trophic and signaling interactions with the oocyte, contributing to oocyte incompetence and thus poor pregnancy outcomes in diabetic females

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19

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

Women’s Night in Emergency Medicine Mentorship Program: A SWOT Analysis

Introduction: Women in emergency medicine (EM) at all career stages report gender-specific obstacles to satisfaction and advancement. Programs that facilitate longitudinal mentoring, professional development, and networking may ameliorate these barriers.Methods: We designed and implemented a program for female residents, faculty, and alumnae from our EM training program to enhance social support, leadership training and professional mentorship opportunities. An anonymous, online survey was sent to participants at the end of the academic year, using a SWOT (strengths, weaknesses, opportunities, and threats) format. The survey collected free-text responses designed to evaluate the program.Results: Of 43 invited participants, 32 responded (74.4%). Eight themes emerged from the free-text responses and were grouped by SWOT domain. We identified four themes relating to the “strength” domain: 1) creating a dedicated space; 2) networking community; 3) building solidarity; and 4) providing forward guidance. Responses to the “weaknesses” and “threats” questions were combined due to overlapping codes and resulted in three themes: 5) barriers to participation; 6) the threat of poorly structured events lapsing into negativity; and 7) concerns about external optics. A final theme: 8) expansion of program scope was noted in the “opportunity” domain.Conclusion: This program evaluation of the Women’s Night curriculum demonstrates it was a positive addition to the formal curriculum, providing longitudinal professional development opportunities. Sharing the strengths of the program, along with identified weaknesses, threats, and opportunities for advancement allows other departments to learn from this experience and implement similar models that use existing intellectual and social capital

Women’s Night in Emergency Medicine Mentorship Program: A SWOT Analysis

Introduction: Women in emergency medicine (EM) at all career stages report gender-specific obstacles to satisfaction and advancement. Programs that facilitate longitudinal mentoring, professional development, and networking may ameliorate these barriers.Methods: We designed and implemented a program for female residents, faculty, and alumnae from our EM training program to enhance social support, leadership training and professional mentorship opportunities. An anonymous, online survey was sent to participants at the end of the academic year, using a SWOT (strengths, weaknesses, opportunities, and threats) format. The survey collected free-text responses designed to evaluate the program.Results: Of 43 invited participants, 32 responded (74.4%). Eight themes emerged from the free-text responses and were grouped by SWOT domain. We identified four themes relating to the “strength” domain: 1) creating a dedicated space; 2) networking community; 3) building solidarity; and 4) providing forward guidance. Responses to the “weaknesses” and “threats” questions were combined due to overlapping codes and resulted in three themes: 5) barriers to participation; 6) the threat of poorly structured events lapsing into negativity; and 7) concerns about external optics. A final theme: 8) expansion of program scope was noted in the “opportunity” domain.Conclusion: This program evaluation of the Women’s Night curriculum demonstrates it was a positive addition to the formal curriculum, providing longitudinal professional development opportunities. Sharing the strengths of the program, along with identified weaknesses, threats, and opportunities for advancement allows other departments to learn from this experience and implement similar models that use existing intellectual and social capital

The Museum of Renaissance Music: A History in 100 Exhibits

This book collates 100 exhibits with accompanying essays as an imaginary museum dedicated to the musical cultures of Renaissance Europe, at home and in its global horizons. It is a history through artefacts—materials, tools, instruments, art objects, images, texts, and spaces—and their witness to the priorities and activities of people in the past as they addressed their world through music. The result is a history by collage, revealing overlapping musical practices and meanings—not only those of the elite, but reflecting the everyday cacophony of a diverse culture and its musics. Through the lens of its exhibits, this museum surveys music’s central role in culture and lived experience in fifteenth- and sixteenth-century Europe, offering interest and insights well beyond the strictly musicological field

Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2) : results of a randomised, double-blind, placebo-controlled, phase 3 trial

Background Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose. Methods ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing. Findings Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36 center dot 0 (15 center dot 0-62 center dot 0) days. Vaccine efficacy was 75 center dot 2% (adjusted 95% CI 54 center dot 6-87 center dot 3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55 center dot 6%] of 3015 vs 896 [57 center dot 5%] of 1559, respectively; systemic adverse events, 1764 [58 center dot 5%] of 3015 vs 821 [52 center dot 7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity. Interpretation A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed. Funding Janssen Research & Development. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd