Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Close-Up Great Cinematic Performances Volume 1: America

Analyses what makes an acting performance excellent, through a range of examples from American filmThis two-volume set presents detailed interpretations of singular performances by several of the most compelling actors in cinema history, asking in many different and complementary ways what makes performance meaningful, how it reflects a director's style, as well as how it contributes to the development of national cinemas and cultures. Whether noting the precise ways actors shape film narrative, achieve emotional effect, or move toward political subversion, the essays in these books innovate new approaches to studying screen performance as an art form and cultural force.This volume focuses on American cinema, including case studies of key performances from actors like Bette Davis, Irene Dunne, Whoopi Goldberg, Cary Grant, Oscar Isaac, Jack Nicholson, Al Pacino, Sidney Poitier, Gena Rowlands, Peter Sellers, Kristen Stewart, and Ethel Waters, amongst many others.Read the introduction (pdf)ContributorsBrenda Austin-Smith, University of ManitobaRebecca Bell-Metereau, Texas State UniversityCharles Ramírez Berg, University of Texas at AustinJanet Bergstrom, UCLAJohn Bruns College of CharlestonAlex Clayton, University of BristolShonni Enelow, Fordham UniversityAnna Everett, University of California, Santa BarbaraLucy Fischer, University of PittsburghLester D. Friedman, Hobart and William Smith CollegesFrances Gateward, California State University NorthridgeDavid Greven, University of South CarolinaJason Jacobs, University of QueenslandElliott Logan, University of Queensland, BrisbaneDouglas McFarland, Flagler College, Saint AugustineAdrienne L. McLean, University of Texas at DallasR. Barton Palmer, Clemson UniversityHomer B. Pettey, University of ArizonaMurray Pomerance, Ryerson University William Rothman, University of MiamiSteven Rybin, Minnesota State University, MankatoKyle Stevens, Appalachian State UniversityGeorge Toles, University of ManitobaDaniel Varndell, University of WinchesterTimotheus Vermeulen, University of OsloRick Warner, University of North Carolina at Chapel Hill

Get with the guidelines: management of chronic obstructive pulmonary disease in emergency departments in Europe and Australasia is sub‐optimal

International audienc

Young Adulthood as a Factor in Social Change in the United States

This essay compares family change during two periods of social and historical upheaval in the United States: the industrial revolution of the late nineteenth century and the more recent family changes of the late twentieth century. Despite the manifest social and demographic changes brought about by the industrial revolution, some aspects of family life remained unchanged. Almost all new families formed in the United States before and during the industrial revolution were same-race heterosexual marriages. In the past half-century, however, family diversity has become the new rule; interracial marriages and extramarital cohabitation have both risen sharply. A key to understanding the lack of family diversity in the past and the recent rise in diversity is the changing nature of young adulthood. Copyright 2006 The Population Council, Inc..

BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial)

IntroductionBCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19.Methods and analysisThis international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections.Ethics and disseminationEthical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system.Trial registrationClinicalTrials.gov NCT0432720

Off-target effects of bacillus Calmette–Guérin vaccination on immune responses to SARS-CoV-2: implications for protection against severe COVID-19

AbstractBackground and objectivesBecause of its beneficial off‐target effects against non‐mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID‐19). Using samples from participants in a placebo‐controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID‐19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS‐CoV‐2.MethodsThis study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID‐19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ‐irradiated SARS‐CoV‐2‐infected or mock‐infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single‐cell immunophenotyping was made by flow cytometry.ResultsBCG vaccination, but not placebo vaccination, reduced SARS‐CoV‐2‐induced secretion of cytokines known to be associated with severe COVID‐19, including IL‐6, TNF‐α and IL‐10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS‐CoV‐2.ConclusionsThe immunomodulatory signature of BCG’s off‐target effects on SARS‐CoV‐2 is consistent with a protective immune response against severe COVID‐19

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc