Global outbreak research: harmony not hegemony

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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

Advancing One Human-Environmental-Animal Health for Global Health Security: What does the evidence say?

The ongoing COVID-19 pandemic vividly illustrates that the emergence of a new lethal pathogen of probable animal origin in one part of the world affects public health everywhere. In this article, we review the contributions of human-animal-environmental (ONE-HEALTH [OH]) approaches to improving global health security (GHS) across a range of health hazards and summarise contemporary evidence of incremental benefits of an OH approach and impact on reporting to FAO, OIE and WHO. Using IHR (2005) Monitoring and Evaluation Framework and OIE Performance of Veterinary Services Pathway (PVS) reports, case studies and a narrative literature review, we assess progress of inter-sectoral OH approaches to build human capacity, bridges between stakeholders and institutional adaptation at national and international levels to contribute to global health security (GHS) across a range of health hazards. Examples from joint health services and infrastructure, surveillance-response, antimicrobial resistance (AMR) surveillance, food safety and food security, environmental hazards, water and sanitation, and zoonoses control clearly show incremental benefits of OH approaches. OH approaches appear to be most effective and sustainable in the prevention, preparedness and early detection of evolving risks/hazards and the evidence base for their application is strongest in the control of endemic and neglected tropical diseases. Significant gaps remain at the OH interface to rapidly detect and reduce the risk of widespread community transmission of new and re-emerging infections. For benefits to be maximised and extended, improved One Health Operationalisation (OHO) is needed with strengthening of multisectoral coordination mechanisms, for example by fostering a closer interaction between the IHR (2005) and OIE PVS Pathways. Case studies show evidence for OHO at the institutional and community level. The FAO, OIE and WHO currently play pivotal roles in stimulating OHO at the national and regional levels but will need increased support and allies to both strengthen current activities as well as address a wider set of health hazards across the Socio Ecological System. Progress in sustained OHO should be urgently prioritised at global, regional and national levels by building on, and inclusively broadening existing institutional collaborations at the wildlife-domestic animal-environmental-human interface to better reflect evolving risks and hazards across the Socio-Ecological System

Burden of hypertension and associated risks for cardiovascular mortality in Cuba: a prospective cohort study

Summary: Background: In Cuba, hypertension control in primary care has been prioritised as a cost-effective means of addressing premature death from cardiovascular disease. However, there is little evidence from large-scale studies on the prevalence and management of hypertension in Cuba, and no direct evidence of the expected benefit of such efforts on cardiovascular mortality. Methods: In a prospective cohort study, adults in the general population identified via local family medical practices were interviewed between Jan 1, 1996, and Nov 24, 2002, in five areas of Cuba, and a subset of participants were resurveyed between July 14, 2006, and Oct 19, 2008, in one area. During household visits, blood pressure was measured and information obtained on diagnosis and treatment of hypertension. We calculated the prevalence of hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or receiving treatment for hypertension) and the proportion of people with hypertension in whom it was diagnosed, treated, and controlled (systolic blood pressure <140 mm Hg, diastolic blood pressure <90 mm Hg). Deaths were identified through linkage by national identification numbers to the Cuban Public Health Ministry records, to Dec 31, 2016. We used Cox regression analysis to compare cardiovascular mortality between participants with versus without uncontrolled hypertension. Rate ratios (RRs) were used to estimate the fraction of cardiovascular deaths attributable to hypertension. Findings: 146 556 participants were interviewed in the baseline survey in 1996–2002 and 24 345 were interviewed in the resurvey in 2006–08. After exclusion for incomplete data and age outside the range of interest, 136 111 respondents aged 35–79 years (mean age 54 [SD 12] years; 75 947 [56%] women, 60 164 [44%] men) were eligible for inclusion in the analyses. 34% of participants had hypertension. Among these, 67% had a diagnosis of hypertension. 76% of participants with diagnosed hypertension were receiving treatment and blood pressure was controlled in 36% of those people. During 1·7 million person-years of follow-up there were 5707 cardiovascular deaths. In the age groups 35–59, 60–69, and 70–79 years, uncontrolled hypertension at baseline was associated with RRs of 2·15 (95% CI 1·88–2·46), 1·86 (1·69–2·05), and 1·41 (1·32–1·52), respectively, and accounted for around 20% of premature cardiovascular deaths. Interpretation: In this Cuban population, a third of people had hypertension. Although levels of hypertension diagnosis and treatment were commensurate with those in some high-income countries, the proportion of participants whose blood pressure was controlled was low. As well as reducing hypertension prevalence, improvement in blood pressure control among people with diagnosed hypertension is required to prevent premature cardiovascular deaths in Cuba. Funding: Medical Research Council, British Heart Foundation, Cancer Research UK