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

NanoSIMS analysis of an isotopically labelled organometallic ruthenium(II) drug to probe its distribution and state in vitro

The in vitro inter-and intra-cellular distribution of an isotopically labelled ruthenium(II)-arene (RAPTA) anti-metastatic compound in human ovarian cancer cells was imaged using nano-scale secondary ion mass spectrometry (NanoSIMS). Ultra-high resolution isotopic images of C-13, N-15, and Ru indicate that the phosphine ligand remains coordinated to the ruthenium(II) ion whereas the arene detaches. The complex localizes mainly on the membrane or at the interface between cells which correlates with its anti-metastatic effects

Consolidation and Future Upgrades to the CLEAR User Facility at CERN

International audienceThe CERN Linear Electron Accelerator for Research (CLEAR) at CERN has been operating since 2017 as a dedicated user facility providing beams for a varied range of experiments. CLEAR consists of a 20 m long linear accelerator (linac), able to produce beams from a Cs₂Te photocathode and accelerate them to energies of between 60 MeV and 220 MeV. Following the linac, an experimental beamline is located, in which irradiation tests, wakefield and impedances tudies, plasma lens experiments, beam diagnostics development, and terahertz (THz) emission studies, are performed. In this paper, we present recent upgrades to the entire beamline, as well as the design of future upgrades, such as a dogleg section connecting to an additional proposed experimental beamline. The gain in performance due to these upgrades is presented with a full range of available beam properties documented

A 12 GHz RF Power Source for the CLIC Study

The CLIC RF frequency has been changed in 2008 from the initial 30 GHz to the European X-band 11.9942 GHz permitting beam independent power production using klystrons for CLIC accelerating structure testing. A design and fabrication contract for five klystrons at that frequency has been signed by different parties with SLAC. France (IRFU, CEA Saclay) is contributing a solid state modulator purchased in industry and specific 12 GHz RF network components to the CLIC study. RF pulses over 120 MW peak at 230 ns length will be obtained by using a novel SLED-I type pulse compression scheme designed and fabricated by IAP, Nizhny Novgorod, Russia. The X-band power test stand is being installed in the CLIC Test Facility CTF3 for independent structure and component testing in a bunker, but allowing, in a later stage, for powering RF components in the CTF3 beam lines. The design of the facility, results from commissioning of the RF power source and the expected performance of the Test Facility are reported

First Experiments at the CLEAR User Facility

The new "CERN Linear Electron Accelerator for Research" (CLEAR) facility at CERN started its operation in fall 2017. CLEAR results from the conversion of the CALIFES beam line of the former CLIC Test Facility (CTF3) into a new testbed for general accelerator R&D; and component studies for existing and possible future accelerator applications. CLEAR can provide a stable and reliable electron beam from 60 to 220 MeV in single or multi bunch configuration at 1.5 GHz. The experimental program includes studies for high gradient acceleration methods, e.g. for CLIC X-band and plasma technology, prototyping and validation of accelerator components, e.g. for the HL-LHC upgrade, and irradiation test capabilities for characterization of electronic components and for medical applications. An overview of the facility capabilities and a summary of the latest results will be presented

Status of the CLEAR electron beam user facility at CERN

The CERN Linear Electron Accelerator for Research (CLEAR) has now finished its second year of operation, providing a testbed for new accelerator technologies and a versatile radiation source. Hosting a varied experimental program, this beamline provides a flexible test facility for users both internal and external to CERN, as well as being an excellent accelerator physics training ground. The energy can be varied between 60 and 220 MeV, bunch length between 1 and 4 ps, bunch charge in the range 10 pC to 2 nC, and number of bunches in the range 1 to 200, at a repetition rate of 0.8 to 10 Hz. The status of the facility with an overview of the recent experimental results is presented

Oxidation of CaMKII determines the cardiotoxic effects of aldosterone

Excessive activation of β-adrenergic, angiotensin II, and aldosterone (Aldo) signaling pathways promotes mortality after myocardial infarction (MI), while antagonist drugs targeting these pathways are core therapies for treating post-MI patients. Catecholamines and angiotensin II activate the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), and CaMKII inhibition prevents isoproterenol- and angiotensin II-mediated cardiomyopathy. Here we show that Aldo exerts direct toxic actions on myocardium by oxidative activation of CaMKII, causing cardiac rupture and increased mortality in mice after MI. Aldo oxidizes CaMKII by recruiting NADPH oxidase, and oxidized CaMKII promotes matrix metalloproteinase 9 (Mmp9) expression in cardiomyocytes. Myocardial CaMKII inhibition, over-expression of methionine sulfoxide reductase A, an enzyme that reduces oxidized CaMKII, or NADPH oxidase inhibition prevented Aldo-enhanced post-MI cardiac rupture. These findings show oxidized myocardial CaMKII mediates cardiotoxic effects of Aldo on cardiac matrix and establish CaMKII as a nodal signal for the neurohumoral pathways associated with poor outcomes after MI