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

Unexpected Crystallographic Phase Transformation in Nonstoichiometric SrUO 4– x : Reversible Oxygen Defect Ordering and Symmetry Lowering with Increasing Temperature

In situ synchrotron powder X-ray diffraction measurements have demonstrated that SrUO4 undergoes a reversible phase transformation under reducing conditions at high temperatures, associated with the ordering of oxygen defects resulting in a lowering of crystallographic symmetry. When substoichiometric rhombohedral α-SrUO4–x, in space group R3̅m with disordered in-plane oxygen defects, is heated above 200 °C in a hydrogen atmosphere it undergoes a first order phase transformation to a (disordered) triclinic polymorph, δ-SrUO4–x, in space group P1̅. Continued heating to above 450 °C results in the appearance of superlattice reflections, due to oxygen-vacancy ordering forming an ordered structure δ-SrUO4–x. Cooling δ-SrUO4–x toward room temperature results in the reformation of the rhombohedral phase α-SrUO4–x with disordered defects, confirming the reversibility of the transformation. This suggests that the transformation, resulting from oxygen vacancy ordering, is not a consequence of sample reduction or decomposition, but rather represents a change in the energetics of the system. A strong reducing atmosphere is required to generate a critical amount of oxygen defects in α-SrUO4–x to enable the transformation to δ-SrUO4–x but once formed the transformation between these two phases can be induced by thermal cycling. The structure of δ-SrUO4–x at 1000 °C was determined using symmetry representation analysis, with the additional reflections indexed to a commensurate distortion vector k = ⟨1/4 1/4 3/4⟩. The ordered 2D layered triclinic structure of δ-SrUO4–x can be considered a structural distortion of the disordered 2D layered rhombohedral α-SrUO4–x structure through the preferential rearrangement of the in-plane oxygen vacancies. Ab initio calculations using density functional theory with self-consistently derived Hubbard U parameter support the assigned ordered defect superstructure model. Entropy changes associated with the temperature dependent short-range ordering of the reduced U species are believed to be important and these are discussed with respect to the results of the ab initio calculations

Nonstoichiometry in Strontium Uranium Oxide: Understanding the Rhombohedral–Orthorhombic Transition in SrUO4_{4}

In situ neutron and synchrotron X-ray diffraction studies demonstrate that SrUO4 acts as an oxygen transfer agent, forming oxygen vacancies under both oxidizing and reducing conditions. Two polymorphs of SrUO4 are stable at room temperature, and the transformation between these is observed to be associated with thermally regulated diffusion of oxygen ions, with partial reduction of the U6+ playing a role in both the formation of oxygen deficient α-SrUO4−δ and its subsequent transformation to stoichiometric β-SrUO4. This is supported by ab initio calculations using density functional theory calculations. The oxygen vacancies play a critical role in the first order transition that SrUO4 undergoes near 830 °C. The changes in the oxidation states and U geometry associated with the structural phase transition have been characterized using X-ray absorption spectroscopy, synchrotron X-ray diffraction, and neutron diffraction

Unexpected Crystallographic Phase Transformation in Nonstoichiometric SrUO_4–<i>x</i>: Reversible Oxygen Defect Ordering and Symmetry Lowering with Increasing Temperature

In situ synchrotron powder X-ray diffraction measurements have demonstrated that SrUO₄ undergoes a reversible phase transformation under reducing conditions at high temperatures, associated with the ordering of oxygen defects resulting in a lowering of crystallographic symmetry. When substoichiometric rhombohedral α-SrUO_4–<i>x</i>, in space group <i>R</i>3̅<i>m</i> with disordered in-plane oxygen defects, is heated above 200 °C in a hydrogen atmosphere it undergoes a first order phase transformation to a (disordered) triclinic polymorph, δ-SrUO_4–<i>x</i>, in space group <i>P</i>1̅. Continued heating to above 450 °C results in the appearance of superlattice reflections, due to oxygen-vacancy ordering forming an ordered structure δ-SrUO_4–<i>x</i>. Cooling δ-SrUO_4–<i>x</i> toward room temperature results in the reformation of the rhombohedral phase α-SrUO_4–<i>x</i> with disordered defects, confirming the reversibility of the transformation. This suggests that the transformation, resulting from oxygen vacancy ordering, is not a consequence of sample reduction or decomposition, but rather represents a change in the energetics of the system. A strong reducing atmosphere is required to generate a critical amount of oxygen defects in α-SrUO_4–<i>x</i> to enable the transformation to δ-SrUO_4–<i>x</i> but once formed the transformation between these two phases can be induced by thermal cycling. The structure of δ-SrUO_4–<i>x</i> at 1000 °C was determined using symmetry representation analysis, with the additional reflections indexed to a commensurate distortion vector <b>k</b> = ⟨1/4 1/4 3/4⟩. The ordered 2D layered triclinic structure of δ-SrUO_4–<i>x</i> can be considered a structural distortion of the disordered 2D layered rhombohedral α-SrUO_4–<i>x</i> structure through the preferential rearrangement of the in-plane oxygen vacancies. Ab initio calculations using density functional theory with self-consistently derived Hubbard U parameter support the assigned ordered defect superstructure model. Entropy changes associated with the temperature dependent short-range ordering of the reduced U species are believed to be important and these are discussed with respect to the results of the ab initio calculations