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

The heroic cult of the sovereign goddess in mediaeval India

This thesis examines why the cult of the sovereign goddess was considered important for the expression of royal power in mediaeval India. In literature and ritual, the goddess was conceptualized as the sovereign of heaven and earth. Her cult was heroic because it was primarily a cult of warriors: a good hero was one who worshipped the goddess for great powers, foremost among them being sovereignty. Certain ritual practices of the cult such as self-mutilation formed the criteria for a warrior- worshipper’s heroism. By assessing the available epigraphical, literary, scriptural and anthropological material, I will attempt to show that the association between Indic kingship and the cult’s belief-systems, also referred to as heroic Śāktism, was indeed an ancient one. Tracing its roots to non-Aryan religion, the cult of the sovereign goddess became a vital part of the Sanskritic kingdom, particularly from the latter half of the 6th c., when tribal kingdoms began to elevate themselves on the political map. One of the hallmarks of the cult, responsible for its pan-Indic popularity, was its syncretic nature: besides outcastes, its followers were from a number of sects. The goddess at its centre had no fixed identity but was formed of various personalities. The more public and well-attested of these was the martial goddess Durgā/Caṇḍī/Caṇḍikā, although other goddesses were also worshipped as her other aspects. In all these aspects the sovereign goddess was believed to grant the power of the king and the community. This idea was evoked in the mediaeval Indic world in an array of symbols: sacred statues, ritually empowered swords and insignia put on display for all to see, legends circulated throughout the kingdom, festivals where the sacred might of the realm was ritually reinforced. By assessing these symbols, I will attempt to show the vibrant forms whereby the connection of the cult with power was manifested in the mediaeval period.This thesis is not currently available in ORA

The Niśvāsatattvasaṃhitā. The Earliest Surviving Śaiva Tantra, Volume 1, A Critical Edition & Annotated Translation of the Mūlasūtra, Uttarasūtra & Nayasūtra

International audienc

The Niśvāsatattvasaṃhitā. The Earliest Surviving Śaiva Tantra, Volume 1, A Critical Edition & Annotated Translation of the Mūlasūtra, Uttarasūtra & Nayasūtra

International audienc