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

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Differential gene expression identifies novel markers of CD4+ and CD8+ T cell activation following stimulation by Mycobacterium tuberculosis.

T cell activation in response to antigenic stimulation is a complex process, involving changes in the expression level of a large number of genes. We have used cDNA array technology to characterize the differences in gene expression between human CD4+ and CD8+ T cells. PBMC from six healthy donors were stimulated with live Mycobacterium tuberculosis, and the gene expression profiles of each donor's CD4+ and CD8+ T cells were analyzed separately. ANOVA revealed 518 genes that were consistently differentially expressed between CD4+ and CD8+ T cells. These differentially expressed genes include a combination of well-known, previously characterized genes with a range of biological functions and unknown in silico predicted hypothetical genes. Where possible, the novel genes have been characterized using bioinformatics, and putative transcription factors, signaling molecules, transmembrane, and secreted factors have been identified. A subset of these differentially expressed genes could be exploited as markers of CD4+ and CD8+ T cell activation for use in vaccine trials. These observed differences in the gene expression profile of CD4+ and CD8+ T cells following activation by a human pathogen contribute to an increased understanding of T cell activation and differentiation and the roles these T cell subsets may play in immunity to infection

Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis.

BACKGROUND: The majority of patients with tuberculosis who comply with appropriate treatment are cured. However, approximately 5% subsequently have a repeat disease episode, usually within 2 years of successful combination therapy. Presently, there is no way of predicting which patients will experience a relapse. METHODS: We identified 10 subjects who had previously experienced recurrent tuberculosis and carefully matched them to cured subjects who had had only 1 episode of tuberculosis, to patients with active tuberculosis, and to latently infected healthy subjects. We compared their ex vivo whole-blood gene-expression profiles by use of DNA array technology and confirmed the results by use of quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). RESULTS: The 4 clinical tuberculosis groups exhibited distinct patterns of gene expression. The gene-transcript profiles of the patients with recurrent tuberculosis were more similar to those of the patients with active tuberculosis than to those of the cured or latently infected subjects. Discriminant analysis of a training data set showed that 9 genes were sufficient to classify the subjects. We confirmed that measurement of the expression of these genes by qRT-PCR can accurately discriminate between subjects in a test set of samples. CONCLUSIONS: A simple test based on gene-expression patterns may be used as a biomarker of cure while identifying patients who are at risk for relapse. This would facilitate the introduction of new tuberculosis drugs

RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention

A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCCexp RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy

Prediction of Suicide Attempts and Suicide-Related Events Among Adolescents Seen in Emergency Departments

IMPORTANCE: Screening adolescents in emergency departments (EDs) for suicidal risk is a recommended strategy for suicide prevention. Comparing screening measures on predictive validity could guide ED clinicians in choosing a screening tool. OBJECTIVE: To compare the Ask Suicide-Screening Questions (ASQ) instrument with the Computerized Adaptive Screen for Suicidal Youth (CASSY) instrument for the prediction of suicidal behavior among adolescents seen in EDs, across demographic and clinical strata. DESIGN, SETTING, AND PARTICIPANTS: The Emergency Department Study for Teens at Risk for Suicide is a prospective, random-series, multicenter cohort study that recruited adolescents, oversampled for those with psychiatric symptoms, who presented to the ED from July 24, 2017, through October 29, 2018, with a 3-month follow-up to assess the occurrence of suicidal behavior. The study included 14 pediatric ED members of the Pediatric Emergency Care Applied Research Network and 1 Indian Health Service ED. Statistical analysis was performed from May 2021 through January 2023. MAIN OUTCOMES AND MEASURES: This study used a prediction model to assess outcomes. The primary outcome was suicide attempt (SA), and the secondary outcome was suicide-related visits to the ED or hospital within 3 months of baseline; both were assessed by an interviewer blinded to baseline information. The ASQ is a 4-item questionnaire that surveys suicidal ideation and lifetime SAs. A positive response or nonresponse on any item indicates suicidal risk. The CASSY is a computerized adaptive screening tool that always includes 3 ASQ items and a mean of 8 additional items. The CASSY\u27s continuous outcome is the predicted probability of an SA. RESULTS: Of 6513 adolescents available, 4050 were enrolled, 3965 completed baseline assessments, and 2740 (1705 girls [62.2%]; mean [SD] age at enrollment, 15.0 [1.7] years; 469 Black participants [17.1%], 678 Hispanic participants [24.7%], and 1618 White participants [59.1%]) completed both screenings and follow-ups. The ASQ and the CASSY showed a similar sensitivity (0.951 [95% CI, 0.918-0.984] vs 0.945 [95% CI, 0.910-0.980]), specificity (0.588 [95% CI, 0.569-0.607] vs 0.643 [95% CI, 0.625-0.662]), positive predictive value (0.127 [95% CI, 0.109-0.146] vs 0.144 [95% CI, 0.123-0.165]), and negative predictive value (both 0.995 [95% CI, 0.991-0.998], respectively). Area under the receiver operating characteristic curve findings were similar among patients with physical symptoms (ASQ, 0.88 [95% CI, 0.81-0.95] vs CASSY, 0.94 [95% CI, 0.91-0.96]). Among patients with psychiatric symptoms, the CASSY performed better than the ASQ (0.72 [95% CI, 0.68-0.77] vs 0.57 [95% CI, 0.55-0.59], respectively). CONCLUSIONS AND RELEVANCE: This study suggests that both the ASQ and the CASSY are appropriate for universal screening of patients in pediatric EDs. For the small subset of patients with psychiatric symptoms, the CASSY shows greater predictive validity