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 electropolishing on the room-temperature low-cycle fatigue behaviour of AISI 304LN stainless steel

The surfaces of specimens of AISI 304LN stainless steel were given different levels of finish by means of electropolishing and mechanical polishing with emery papers of different grit sizes. They were subjected to total strain-controlled low-cycle fatigue (LCF) deformation at room temperature. The cyclic stress response and the strain-life plots were recorded. As opposed to the mechanically polished specimens, the electropolished specimens displayed secondary hardening in the later stages of deformation even at low strain amplitudes. This behaviour could be attributed to increased martensite formation in the latter case because of the enhanced life. The effect of electropolishing in enhancing the LCF life was more pronounced at the lower strain amplitudes

A comparison of the room-temperature behaviour of AISI 304LN stainless steel and Nimonic 90 under strain cycling

The influence of room-temperature low-cycle fatigue (LCF) deformation on the microstructure and the consequent modification of the LCF behaviour were examined in the case of AISI 304LN stainless steel and the superalloy Nimonic 90. Secondary hardening due to martensite formation in AISI 304LN enhanced its resistance to plastic flow. On the other hand, in Nimonic 90 shearing of γ' particles led to cyclic softening. A change in the number of operating slip systems as well as the fracture mode was responsible for the observed two-slope behaviour in the Coffin-Manson, the cyclic stress-strain and the energy-life plots in Nimonic 90. While Nimonic 90 resisted the applied strain elastically on the basis of its strength, AISI 304LN resisted the strain plastically on the basis of its ductility. Nimonic 90 had a much higher plastic strain energy absorption capacity than AISI 304LN

Room-temperature low-cycle fatigue behaviour of a Ni-base superalloy

A nickel-base superalloy, Nimonic 90, was subjected to room-temperature low-cycle fatigue under constant total strain control. Cyclic stress response was investigated as a function of the total strain range. Hardening was attributed to slip band formation and softening to the shearing of γ' precipitates Slip band spacing decreased with increasing strain range. Two-slope behaviour or bilinearity seen in Coffin-Manson and cyclic stress-strain plots has been attributed to a change in the deformation mode with increasing strain range

Some studies on the incremental step (fatigue) test

Cylindrical specimens of AISI 304LN austenitic strainless stael and Nimonic 90 were deformed under strain cycling at room temperature by repeated application of strain blocks consisting of waveforms in which the amplitude gradually increased and then decreased. The dependence of the cyclic stress-strain (CSS) curve on the number of waveforms in the applied strain block was found to be considerably less for Nimonic 90 than for the stainless steel. The CSS curves generated using blocks having lower maximum strain amplitudes were below the CSS curves obtained using blocks having higher maximum strain amplitudes. The difference between the CSS curves generated using blocks of different maximum strain amplitudes was greater in stainless steel than in Nimonic 90 due to strain-induced martensite formation in the former

Influence of martensite formation and grain size on room temperature low cycle fatigue behaviour of AISI 304LN austenitic stainless steel

The effects of strain induced martensite formation and grain size on the room temperature low cycle fatigue behaviour of AISI 304LN austenitic stainless steel were considered. Two grain sizes, namely, 60 and 350 µm, were developed via suitable solution annealing treatments. Microstructural changes before and after low cycle fatigue testing were identified. The martensitic transformation was studied using aferritescope, X-ray diffractometry, and optical microscopy. The mechanical response was correlated with the microstructural changes. Secondary hardening as well as a crossover in the strain-life plots for the two grain sizes resulted from martensite formation. Dislocation configurations depended on the strains imposed

Effect of surface roughness on the room temperature low cycle fatigue life of alloy Nimonic 90

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