Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

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 legacy of Socrates (book review)

Review of: The Legacy of Socrates. By James Rachels (New York: Columbia University Press, 2007), xii, 248 pp

Ancient philosophy: a new history of western philosophy, volume 1 (book review)

Review of: Ancient Philosophy: A New History of Western Philosophy, Volume I. By Sir Anthony Kenny (Oxford: Oxford University Press, 2004), xxi + 341 pp

Imagine the Genii and the Historians: The Legacy of Marc Bloch and Lucien Febvre

Historians are not magicians though their insights when truly insightful have a touch of the magical or remarkable about them. With regard to Marc Bloch and Lucien Febvre this remains the case. Through the course of this essay the writings of Febvre will be deployed as gadfly and partner to those of Bloch

'The individual' in history and history in general: Alcibiades, philosophical history and ideas in contest

Alcibiades is, at once, an historical figure and an archetypal individual. Also, in an anthropological sense and in terms of traditions of thought, Alcibiades is a truly remarkable, individuated moment in history. Alcibiades the historical personage and philosophical character-as-actor has become a source for historical and philosophical memories, that is, a human gathering place, a focus, reference and a trans-historical persona for the passages of history and intellect - a place where singular and collective human actions and behaviours matter and where particular and general social forces remain; contentiously in play. With the classical world of the Athenian empire immediately behind the philosophical stage and dramatically present in the foreground of the Alcibiades I, and with the Spartan world still presenting intellectual and social puzzles, who better than the exiled, prodigal Athenian son, Alcibiades and Socrates to discuss the deep waters -the social anthropology of a once-real world and its strikingly individuated conduct. Significantly, these modes of human conduct must be clearly seen as situated within the broad agonistic context of Hellenic and Mediterr!ilnean civilisations. These 'particular' and 'general' ideas and arguments are swept by Mediterranean scenes and characters

Thucydides and the history of ideas: viewing Thucydides' Peloponnesian War anew : questions of qualitative understanding and insightfulness

Idealism, realism and history - Thucydides a complex amalgam of these notions and more. Thucydides' Peloponnesian War stands as a classical testament (an oftentimes argumentative testament) to the singular and general importance of the roles of perception, insight, and thoughtfulness as markstones of a true historian's craft - ancient modern and contemporary

Thucydides' war: accounting for the faces of conflict

The singular and general character of Thucydides’ War can be sighted, if not truly captured, by studying the movements and momentum of the rival alliances’ armies and naval forces and their related and smaller movements. These were sometimes opportunistic, other times deliberate and often swift or ruthless. If war is about power and ambition, chance and circumstance, surprise and opportunism, and pervasive hates and fears, then Thucydides’ War is timely with its focus upon the scale and size of forces committed to this period of protracted and interrupted warring. The study of general phenomenon which constitutes war and any attempt to comprehend or understand the phenomena and dimensions of any war remains as much a qualitative as it is a quantitative challenge. There are no simple answers in this arena. Thucydides’ War is an exploration of the complex interplay of the varying faces of conflict

The fluidity of the past and the present: historians and ways of perceiving/understanding: part 2

There are, of course, many paths to the study of the past. Given Thucydides' keen interest in the Great Athenian epidemic (the nosos ... or loimôdês nosos, the pestilential epidemic/sickness, 1.23.3) a further look at disease in history might well be useful both in terms of furthering historical understanding and thinking about disease-in-history, and as a way or rather ways to 'model' or further study human behaviour in time, across time and in situ- namely, in its urban/populous, warring and geographic environments. That is, the historical and potentially social anthropological utility of studying epidemic disease in Antiquity, rests in this distant world, or rather, these distant worlds, acting as both working historical model-like studies of the passage of epidemic disease/s as well as providing forensic, historical/socio-cultural zones for the study of ancient disease patterns, and their impact through time. Such studies can provide windows through which 'ancient' diseases and/or their 'modern' offspring might be better understood or viewed. Once contemporary experiences can have lives well beyond their immediate historical time, place and situation

Autarkeia and Aristotle's Politics: The Question of the Ancient Social Formation.

This thesis is concerned with the idea of the rise of the moral political economy. Whilst Aristotle did not invent the word 'economics' he came closer than many think. This thesis is an exploration in the field of the history of ideas. It views the origins of distant economic-like thinking as having a moral and political bases of existence.PhD Doctorat