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

Stéphane Benoist (Ed.), Rome, a City and its Empire in Perspective. The Impact of the Roman World through Fergus Millar’s Research. Leyde-Boston, Brill, 2012 (Impact of Empire, 16)

Wiseman Timothy Peter. Stéphane Benoist (Ed.), Rome, a City and its Empire in Perspective. The Impact of the Roman World through Fergus Millar’s Research. Leyde-Boston, Brill, 2012 (Impact of Empire, 16). In: L'antiquité classique, Tome 83, 2014. pp. 426-427

Stéphane Benoist (Ed.), Rome, a City and its Empire in Perspective. The Impact of the Roman World through Fergus Millar’s Research. Leyde-Boston, Brill, 2012 (Impact of Empire, 16)

Wiseman Timothy Peter. Stéphane Benoist (Ed.), Rome, a City and its Empire in Perspective. The Impact of the Roman World through Fergus Millar’s Research. Leyde-Boston, Brill, 2012 (Impact of Empire, 16). In: L'antiquité classique, Tome 83, 2014. pp. 426-427

Conspicui postes tectaque digna deo : the public image of aristocratic and imperial houses in the late Republic and early Empire

Like public buildings put up de manubiis, private houses were visible expressions of gloria in the Roman aristocracy, with triumphal spolia and ancestral statues displayed in the vestibulum. Against that background, the history of the imperial property on the Palatine may be read as a series of strategies by which the emperors projected their image of themselves. Octavian's house faced the river harbour and was approached from the Lupercal by the Clivus Victoriae. He may have planned to extend the property to the northern corner of the hill, to make his triumphal arch the entrance, but that was achieved only by Caligula. The mature Augustus was content with an entrance facing the Area Palatina, separated from the Forum by the vestibula of other aristocrats. When the fire of 64 destroyed the aristocratic houses, Nero created a new formal entrance with a grandiose approach from the Forum itself. Finally, Septimius Severus turned the facade of the palace towards the Porta Capena, the only topographical approach that had not yet been exploited.Wiseman Timothy Peter. Conspicui postes tectaque digna deo : the public image of aristocratic and imperial houses in the late Republic and early Empire. In: L'Urbs : espace urbain et histoire (Ier siècle av. J.-C. - IIIe siècle ap. J.-C.). Actes du colloque international de Rome (8-12 mai 1985) Rome : École Française de Rome, 1987. pp. 393-413. (Publications de l'École française de Rome, 98

Boletín del Servicio Meteorológico Español: Año XXXV Número 148 - 1927 Mayo 28

Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy the ability of genetic ATF6 activation to selectively reduce secretion and extracellular aggregation of amyloidogenic proteins. These results show that small molecule-dependent ER reprogramming, achieved through preferential activation of the ATF6 transcriptional program, is a promising strategy to ameliorate imbalances in ER function associated with degenerative protein aggregation diseases

Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation.

Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy the ability of genetic ATF6 activation to selectively reduce secretion and extracellular aggregation of amyloidogenic proteins. These results show that small molecule-dependent ER reprogramming, achieved through preferential activation of the ATF6 transcriptional program, is a promising strategy to ameliorate imbalances in ER function associated with degenerative protein aggregation diseases