Efficacy and safety of oral methazolamide in patients with type 2 diabetes: A 24-week, placebo-controlled, double-blind study

OBJECTIVE To evaluate the safety and efficacy of methazolamide as a potential therapy for type 2 diabetes. RESEARCH DESIGN AND METHODS This double-blind, placebo-controlled study randomized 76 patients to oral methazolamide (40 mg b.i.d.) or placebo for 24 weeks. The primary efficacy end point for methazolamide treatment was a placebo-corrected reduction in HbA1c from baseline after 24 weeks (ΔHbA1c). RESULTS Mean ± SD baseline HbA1c was 7.1 ± 0.7% (54 ± 5 mmol/mol; n = 37) and 7.4 ± 0.6% (57 ± 5 mmol/mol; n = 39) in the methazolamide and placebo groups, respectively. Methazolamide treatment was associated with a ΔHbA1c of –0.39% (95% CI –0.82, 0.04; P < 0.05) (–4.3 mmol/mol [–9.0, 0.4]), an increase in the proportion of patients achieving HbA1c ≤6.5% (48 mmol/mol) from 8 to 33%, a rapid reduction in alanine aminotransferase (∼10 units/L), and weight loss (2%) in metformin-cotreated patients. CONCLUSIONS Methazolamide is the archetype for a new intervention in type 2 diabetes with clinical benefits beyond glucose control

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

Violence and Racial Discrimination in South African Youth: Profiles of a Continuum of Exposure

Objectives: In high-violence countries with limited resources, it can be difficult to identify youth who are at greatest risk for poor health outcomes due to violence exposure. Profile analysis can help achieve this goal by identifying at-risk groups based on multi-variable patterns, especially if the indicators of violence exposure are sensitive enough to identify most of the youth who are at-risk for poor health, but specific enough to identify subpopulations of youth who might benefit most from intervention programs. Methods: We conducted profile analyses to identify subgroups of secondary school students in South Africa (N = 1,317; 54% female; 40% Black; 50% Coloured; 8% White; 2% other races) who were at highest risk for substance use and risky sexual behaviors based on their exposure to different forms of violence, including witnessing violence in the community, at home, and at school, and directly experiencing community violence and racial discrimination. Results: Our analyses yielded five profiles: youth with (1) low-violence exposure; (2) average violence exposure ; (3) high exposure to violence at home; (4) high community victimization; and (5) very high violence exposure characterized by high to very high direct and indirect violence exposure at home, school, and in the community, and moderate levels of personal racial discrimination. Profiles were differentially associated with risk behavior. Conclusions: These data underscore the need to examine racial discrimination on the continuum of exposure to violence, as it may exacerbate the effects of exposure to other types of violence and the likelihood of risky behaviors

Exposure to violence across multiple contexts and health risk behaviours in South African adolescents: the moderating role of emotion dysregulation

Objective: The association between violence exposure and health risk behaviours in South African adolescents, and the moderating role of emotion dysregulation were investigated. Design: A multiethnic sample of adolescents (N¼925: boy: 47.3%, girl: 52.7%, M age ¼ 16 years, SD¼1.54) completed a survey. Main outcome measures: Violence exposure across different contexts (home-, school-, community-, political victimisation), emotion dysregulation (inability to regulate sadness and anger) and a composite measure of health risk behaviours (smoking, substance use, risky sexual behaviour) were examined. Results: Boys reported more risk behaviours than girls, t (844) ¼ 5.25, p<0.001. Direct community victimisation was a predictor for boys’ risk behaviours, B¼0.22, p<0.001. Indirect school victimisation and direct community victimisation were predictors for girls’ risk behaviours, B’s ¼ 0.19, p’s < 0.01. Girls reported higher emotion dysregulation than boys, t (748) ¼ _2.95, p<0.01. Only for girls, emotion dysregulation moderated the associations of indirect home victimisation, B¼16, p<0.01, and direct community victimisation, B¼15, p<0.05, with risk behaviours. Conclusion: Interventions may target emotion regulation skills, particularly for girls, to enhance resilience to the negative effects of violence on behaviours