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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Lithospheric dismemberment and magmatic processes of the Great Basin-Colorado Plateau transition, Utah, implied from magnetotellurics

To illuminate rifting processes across the Transition Zone between the extensional Great Basin and stable Colorado Plateau interior, we collected an east-west profile of 117 wideband and 30 long-period magnetotelluric (MT) soundings along latitude 38.5°N from southeastern Nevada across Utah to the Colorado border. Regularized two-dimensional inversion shows a strong lower crustal conductor below the Great Basin and its Transition Zone in the 15–35 km depth range interpreted as reflecting modern basaltic underplating, hybridization, and hydrothermal fluid release. This structure explains most of the geomagnetic variation anomaly in the region first measured in the late 1960s. Hence, the Transition Zone, while historically included with the Colorado Plateau physiographically, possesses a deep thermal regime and tectonic activity like that of the Great Basin. The deep crustal conductor is consistent with a rheological profile of a brittle upper crust over a weak lower crust, in turn on a stronger upper mantle (jelly sandwich model). Under the incipiently faulted Transition Zone, the conductor implies a vertically nonuniform mode of extension resembling early stages of continental margin formation. Colorado Plateau lithosphere begins sharply below the western boundary of Capitol Reef National Park as a resistive keel in the deep crust and upper mantle, with only a thin and weak Moho-level crustal conductor near 45 km depth. Several narrow, steep conductors connect conductive lower crust with major surface faulting, some including modern geothermal systems, and in the context of other Great Basin MT surveying suggest connections between deep magma-sourced fluids and the upper crustal meteoric regime. The MT data also suggest anisotropically interconnected melt over a broad zone in the upper mantle of the eastern Great Basin which has supplied magma to the lower crust, consistent with extensional mantle melting models and local shear wave splitting observations. We support a hypothesis that the Transition Zone location and geometry ultimately reflect the middle Proterozoic suturing between the stronger Yavapai lithosphere to the east and the somewhat weaker Mojave terrane to the west. We conclude that strength heterogeneity is the primary control on locus of deformation across the Transition Zone, with modulating force components.Philip E. Wannamaker, Derrick P. Hasterok, Jeffery M. Johnston, John A. Stodt, Darrell B. Hall, Timothy L. Sodergren, Louise Pellerin, Virginie Maris, William M. Doerner, Kim A. Groenewold, and Martyn J. Unswort