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

A need for diet assessment technology for South Asians living in the USA

South Asians are among the fastest growing ethnic group in the USA yet remain understudied in epidemiologic studies. Due to their unique disease profile, identifying risk moderators and mitigators, such as dietary patterns and food intake, will help to determine the diet-disease relationship that is specific to this largely immigrant population group in the USA. The aim of this commentary is to highlight the dietary traditions and acculturated practices experienced by South Asians in the USA with a call for a diet assessment instrument that adequately captures their dietary diversity. Specifically, we call for (i) the inclusion of traditional food items, such as herbs and spices, that individualize diet assessment for participants; and (ii) leveraging technology that will enhance the experience of diet assessment for both researchers and participants, tailoring the collection of habitual dietary intake in this diverse population group

Cardiovascular Health by Life\u27s Essential 8 and Associations With Coronary Artery Calcium in South Asian American Adults in the MASALA Study

South Asian Americans experience high cardiovascular disease risk. We evaluated the distribution and correlates of cardiovascular health (CVH) summarized by the Life\u27s Essential 8 (LE8) score among South Asian adults. In participants of the MASALA (Mediators of Atherosclerosis in South Asians Living in America) study, the association of demographic, social, and cultural factors with LE8 score was evaluated with t tests and analysis of variance. The association of LE8 score with coronary artery calcium (CAC) was evaluated with adjusted logistic regression. There were 556 women (mean age 55.9 years [SD 8.7], mean LE8 score 67.2 (SD 12.6) and 608 men (mean age 57.5 years [SD 9.9], mean LE8 score 61.9 (SD 13.1). Among women and men, the LE8 CVH score was higher in participants with higher annual family income, higher educational attainment, and fewer depressive symptoms. Overall, there was 26% lower odds of any CAC for each 10-point higher LE8 score (odds ratios [OR] 0.74, 95% confidence intervals [CI] 0.66 to 0.83), with similar magnitude of association in women and men. Participants with a high LE8 CVH score had 82% lower odds of CAC (OR 0.18, 95% CI 0.09 to 0.33), and participants with an intermediate LE8 CVH score had 38% lower odds of CAC (OR 0.62, 95% CI 0.41 to 0.94) than did participants with a low LE8 CVH score, with similar findings stratified by gender. In conclusion, in this cohort of South Asian Americans, most adults had suboptimal CVH assessed by the LE8 score. Higher LE8 score correlated with lower odds of any CAC

Concordance between Dash Diet and Hypertension: Results from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study

High blood pressure is an important predictor of atherosclerotic cardiovascular disease (ASCVD), particularly among South Asians, who are at higher risk for ASCVD when compared to other population groups. The Dietary Approaches to Stop Hypertension (DASH) dietary pattern is established as the best proven nonpharmacological approach to preventing hypertension in adults. Using data from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort, we calculated a DASH dietary score to examine the association between adherence to the DASH diet and its components, and prevalent and incident hypertension and systolic and diastolic blood pressure, after five years of follow-up. We found that the relative risk ratio (RRR) of incident hypertension was 67% lower among participants in the highest DASH diet score category (aRRR: 0.33; 95% CI: 0.13, 0.82; p = 0.02) compared with those in the lowest DASH diet score category in fully adjusted models. These findings are consistent with previous clinical trials and large prospective cohort studies, adding to evidence that supports the diet-disease relationship established between DASH diet and hypertension. This study is the first to examine DASH diet adherence and hypertension among South Asian adults in the U.S

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

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

International audienc