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

Communal orientation and attributions between the self and other

Prior research has shown that communally oriented interpersonal relationships are governed by other-oriented behaviors that take into account the needs and feelings of a partner. Communal orientation has been manipulated within interactions and has also been measured on a dispositional level. What is not known, however, are the consequences of being dispositionally communally oriented and how interacting with a communally oriented other might influence attributions for success and failure. To examine this issue, undergraduates completed the communal orientation scale and then participated in a joint decision-making task with a randomly assigned partner. Participants then assessed how communally oriented they thought their partner was and received success or failure feedback on the task. Then they were given the opportunity to attribute responsibility for the performance to themselves, their partner, or the relationship. Results indicate that communal orientation and the perception of the degree of communal orientation of the partner contributed to the attribution of responsibility for the performance. These data suggest that communal orientation and a perception of the communal orientation of another affects attributions even in short-term laboratory-based interactions

Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid

N-acetyl cysteine (NAC) supports the synthesis of glutathione (GSH), an essential substrate for fast, enzymatically catalyzed oxidant scavenging and protein repair processes. NAC is entering clinical trials for adrenoleukodystrophy, Parkinson’s disease, schizophrenia, and other disorders in which oxidative stress may contribute to disease progression. However, these trials are hampered by uncertainty about the dose of NAC required to achieve biological effects in human brain. Here we describe an approach to this issue in which mice are used to establish the levels of NAC in cerebrospinal fluid (CSF) required to affect brain neurons. NAC dosing in humans can then be calibrated to achieve these NAC levels in human CSF. The mice were treated with NAC over a range of doses, followed by assessments of neuronal GSH levels and neuronal antioxidant capacity in ex vivo brain slices. Neuronal GSH levels and antioxidant capacity were augmented at NAC doses that produced peak CSF NAC concentrations of ≥50 nM. Oral NAC administration to humans produced CSF concentrations of up to 10 μM, thus demonstrating that oral NAC administration can surpass the levels required for biological activity in brain. Variations of this approach may similarly facilitate and rationalize drug dosing for other agents targeting central nervous system disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13311-015-0404-4) contains supplementary material, which is available to authorized users

Association of macular pigment optical density with retinal layer thicknesses in eyes with and without manifest primary open-angle glaucoma

Objective To investigate associations between baseline macular pigment optical density (MPOD) and retinal layer thicknesses in eyes with and without manifest primary open-angle glaucoma (POAG) in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2).Methods and analysis MPOD was measured at CAREDS baseline (2001–2004) via heterochromatic flicker photometry (0.5° from foveal centre). Peripapillary retinal nerve fibre layer (RNFL), macular ganglion cell complex (GCC), ganglion cell layer (GCL), inner plexiform layer (IPL), and RNFL thicknesses were measured at CAREDS2 (2016–2019) via spectral-domain optical coherence tomography. Associations between MPOD and retinal thickness were assessed using multivariable linear regression.Results Among 742 eyes (379 participants), manifest POAG was identified in 50 eyes (32 participants). In eyes without manifest POAG, MPOD was positively associated with macular GCC, GCL and IPL thicknesses in the central subfield (P-trend ≤0.01), but not the inner or outer subfields. Among eyes with manifest POAG, MPOD was positively associated with macular GCC, GCL, IPL and RNFL in the central subfield (P-trend ≤0.03), but not the inner or outer subfields, and was positively associated with peripapillary RNFL thickness in the superior and temporal quadrants (P-trend≤0.006).Conclusion We observed a positive association between MPOD and central subfield GCC thickness 15 years later. MPOD was positively associated with peripapillary RNFL superior and temporal quadrant thicknesses among eyes with manifest POAG. Our results linking low MPOD to retinal layers that are structural indicators of early glaucoma provide further evidence that carotenoids may be protective against manifest POAG

Constitutional Law: A Contemporary Approach

The third edition of the casebook, which is suitable either for a one- or two-semester course, strives to make constitutional law easily teachable and readily accessible for students. The authors have selected the cases very carefully and provided extensive excerpts of the opinions so that students get a good sense of the Court\u27s reasoning. Text boxes call the students\u27 attention to important aspects of each opinion, and the book is filled with introductions, points for discussion, hypotheticals, and executive summaries. The authors present a diversity of views on every subject, and, reflecting some of their own disagreements, the authors have written point-counterpoint discussions on many disputed questions

Astro2020: Decadal Survey on Astronomy and Astrophysics : State of the Profession Considerations for Laboratory Astrophysics

International audienceAstrophysics advances, in part, through laboratory astrophysics studies of the underlying processes controlling the observed properties of the Cosmos. These studies encompass both theoretical and experimental research. Robust support for laboratory astrophysics is critically needed to maximize the scientific return of astronomical observations