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

Pre-pandemic trends and Black:White inequities in life expectancy across the 30 most populous U.S. cities: a population-based study

Abstract Background Racial inequities in life expectancy, driven by structural racism, have been documented at the state and county levels; however, less information is available at the city level where local policy change generally happens. Furthermore, an assessment of life expectancy during the decade preceding COVID-19 provides a point of comparison for life expectancy estimates and trends post COVID-19 as cities recover. Methods Using National Vital Statistics System mortality data and American Community Survey population estimates, we calculated the average annual city-level life expectancies for the non-Hispanic Black (Black), non-Hispanic White (White), and total populations. We then calculated the absolute difference between the Black and White life expectancies for each of the 30 cities and the U.S. We analyzed trends over four time periods (2008-2010, 2011-2013, 2014-2016, and 2017-2019). Results In 2017-2019, life expectancies ranged from 72.75 years in Detroit to 83.15 years in San Francisco (compared to 78.29 years for the U.S.). Black life expectancy ranged from 69.94 years in Houston to 79.04 years in New York, while White life expectancy ranged from 75.18 years in Jacksonville to 86.42 years in Washington, DC. Between 2008-2010 and 2017-2019, 17 of the biggest cities experienced a statistically significant improvement in life expectancy, while 9 cities experienced a significant decrease. Black life expectancy increased significantly in 14 cities and the U.S. but decreased significantly in 4 cities. White life expectancy increased significantly in 17 cities and the U.S. but decreased in 8 cities. In 2017-2019, the U.S. and all but one of the big cities had a significantly longer life expectancy for the White population compared to the Black population. There was more than a 13-year difference between Black and White life expectancies in Washington, DC (compared to 4.18 years at the national level). From 2008-2010 to 2017-2019, the racial gap decreased significantly for the U.S. and eight cities, while it increased in seven cities. Conclusion Urban stakeholders and equity advocates need data on mortality inequities that are aligned with city jurisdictions to help guide the allocation of resources and implementation of interventions

An updated mutation spectrum of the γ-secretase complex: Novel NCSTN gene mutation in an Indian family with hidradenitis suppurativa and acne conglobata

Background: Hidradenitis suppurativa (HS) is a complex, chronic inflammatory skin disorder whose pathophysiology is poorly understood. Genetic studies have shown that HS is predisposed by mutations in the γ-secretase gene, but only a proportion of familial and partial sporadic cases have been shown to possess such mutations. HS has high genetic heterogeneity and is thought to be triggered by a combination of genetics and environmental factors. Aims: The study aimed to investigate the genetic causes of HS in a large cohort of patients and to update the mutation spectrum of γ-secretase complex genes. Methods: We conducted mutational screening of 95 sporadic HS cases and one large family with both HS and acne conglobata (AC) to identify mutations in the coding and splice junction region of γ-secretase complex genes (nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN), and aph-1 homolog B, gamma-secretase subunit (APH1B)). Results: Our study identified a nucleotide substitution of 1876C>T in the NCSTN gene, which caused a stop codon (p.Arg626X) in the affected members of a large family with HS and AC. No pathogenic variants were detected in 95 sporadic cases of HS, indicating there is possible genetic heterogeneity. Conclusion: We report a new family with a nonsense mutation in the NCSTN gene that supports the role of the γ-secretase complex genes in HS with AC. The updated γ-secretase mutation spectrum for HS now includes 78 mutations

Newborn blood DNA epigenetic variations and signaling pathway genes associated with Tetralogy of Fallot (TOF).

Tetralogy of Fallot (TOF) is the most common Critical Congenital Heart Defect (CCHD). The etiology of TOF is unknown in most cases. Preliminary data from our group and others suggest that epigenetic changes may play an important role in CHD. Epidemiologically, a significant percentage of CHD including TOF fail to be diagnosed in the prenatal and early newborn period which can negatively affect health outcomes. We performed genome-wide methylation assay in newborn blood in 24 non-syndromic TOF cases and 24 unaffected matched controls using Illumina Infinium HumanMethylation450 BeadChips. We identified 64 significantly differentially methylated CpG sites in TOF cases, of which 25 CpG sites had high predictive accuracy for TOF, based on the area under the receiver operating characteristics curve (AUC ROC) ≥ 0.90). The CpG methylation difference between TOF and controls was ≥10% in 51 CpG targets suggesting biological significance. Gene ontology analysis identified significant biological processes and functions related to these differentially methylated genes, including: CHD development, cardiomyopathy, diabetes, immunological, inflammation and other plausible pathways in CHD development. Multiple genes known or plausibly linked to heart development and post-natal heart disease were found to be differentially methylated in the blood DNA of newborns with TOF including: ABCB1, PPP2R5C, TLR1, SELL, SCN3A, CREM, RUNX and LHX9. We generated novel and highly accurate putative molecular markers for TOF detection using leucocyte DNA and thus provided information on pathogenesis of TOF

Placental epigenetics for evaluation of fetal congenital heart defects: Ventricular Septal Defect (VSD).

Ventricular Septal Defect (VSD), the most common congenital heart defect, is characterized by a hole in the septum between the right and left ventricles. The pathogenesis of VSD is unknown in most clinical cases. There is a paucity of data relevant to epigenetic changes in VSD. The placenta is a fetal tissue crucial in cardiac development and a potentially useful surrogate for evaluating the development of heart tissue. To understand epigenetic mechanisms that may play a role in the development of VSD, genome-wide DNA methylation assay on placentas of 8 term subjects with isolated VSD and no known or suspected genetic syndromes and 10 unaffected controls was performed using the Illumina HumanMethylation450 BeadChip assay. We identified a total of 80 highly accurate potential CpGs in 80 genes for detection of VSD; area under the receiver operating characteristic curve (AUC ROC) 1.0 with significant 95% CI (FDR) p-values < 0.05 for each individual locus. The biological processes and functions for many of these differentially methylated genes are previously known to be associated with heart development or disease, including cardiac ventricle development (HEY2, ISL1), heart looping (SRF), cardiac muscle cell differentiation (ACTC1, HEY2), cardiac septum development (ISL1), heart morphogenesis (SRF, HEY2, ISL1, HEYL), Notch signaling pathway (HEY2, HEYL), cardiac chamber development (ISL1), and cardiac muscle tissue development (ACTC1, ISL1). In addition, we identified 8 microRNAs that have the potential to be biomarkers for the detection of VSD including: miR-191, miR-548F1, miR-148A, miR-423, miR-92B, miR-611, miR-2110, and miR-548H4. To our knowledge this is the first report in which placental analysis has been used for determining the pathogenesis of and predicting VSD

Integrative Analysis Unveils the Correlation of Aminoacyl-tRNA Biosynthesis Metabolites with the Methylation of the SEPSECS Gene in Huntington’s Disease Brain Tissue

The impact of environmental factors on epigenetic changes is well established, and cellular function is determined not only by the genome but also by interacting partners such as metabolites. Given the significant impact of metabolism on disease progression, exploring the interaction between the metabolome and epigenome may offer new insights into Huntington’s disease (HD) diagnosis and treatment. Using fourteen post-mortem HD cases and fourteen control subjects, we performed metabolomic profiling of human postmortem brain tissue (striatum and frontal lobe), and we performed DNA methylome profiling using the same frontal lobe tissue. Along with finding several perturbed metabolites and differentially methylated loci, Aminoacyl-tRNA biosynthesis (adj p-value = 0.0098) was the most significantly perturbed metabolic pathway with which two CpGs of the SEPSECS gene were correlated. This study improves our understanding of molecular biomarker connections and, importantly, increases our knowledge of metabolic alterations driving HD progression