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

Primary progressive aphasia: a clinical approach

This work was supported by the Alzheimer’s Society (AS-PG-16-007), the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the UCL Leonard Wolfson Experimental Neurology Centre (PR/ylr/18575). Individual authors were supported by the Leonard Wolfson Foundation (Clinical Research Fellowship to CRM), the National Institute for Health Research (NIHR Doctoral Training Fellowship to AV), the National Brain Appeal–Frontotemporal Dementia Research Fund (CNC) and the Medical Research Council (PhD Studentships to CJDH and RLB, MRC Research Training Fellowship to PDF, MRC Clinician Scientist to JDR). MNR and NCF are NIHR Senior Investigators. SJC is supported by Grants from ESRC-NIHR (ES/L001810/1), EPSRC (EP/M006093/1) and Wellcome Trust (200783). JDW was supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (091673/Z/10/Z)

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

Learning Firsthand: Vietnam War Digital Teaching Resource

: The Vietnam War Learning Firsthand Teaching and Learning Resource is an initiative of the Victorian Government. The resource complements thethe Vietnam Veterans Association of Australia (Victorian Branch)’s school guest speaker program, through which schools can host a veteran guest presenter.It is designed to provide a toolbox from which teachers can select topics and activities to support learning before or after a visit from a veteran, or as anindependent resource to engage with the Vietnam War in levels 9-10 History. The resource is therefore not designed as a sequenced unit but as a toolbox ofstand alone topics that can be accessed in any order. Each topic is its own entry point, so does not assume prior learning about other topics.The notion of learning firsthand informs the overall approach and use of historical sources. The resource seeks to stimulate conversation and further inquiryabout diverse perspectives on the Vietnam War and scaffold the development of historical thinking skills. The topics and activities speak directly to students.The historical knowledge section provides an anchor point and from there students can then select the activity or activities that best suit their needs andinterests. Some are quite structured, and others offer opportunities for more open-ended inquiry. A range of other online sources are embedded throughout,such as those from the Australian War Memorial, Department of Veterans Affairs and other key cultural institutions. The curriculum toolbox on the followingpage indicates the curriculum connections. The diagram below further explains the purpose of each component for each topic

Cycling and the city: a case study of how gendered, ethnic and class identities can shape healthy transport choices.

As a form of 'active transport', cycling has been encouraged as a route to improving population health. However, in many high-income countries, despite being widely seen as a 'healthy' choice, few people do cycle for transport. Further, where cycling is rare, it is not a choice made equally across the population. In London, for instance, cycling is disproportionately an activity of affluent, White, men. This paper takes London as a case study to explore why the meanings of cycling might resonate differently across urban, gendered, ethnic and class identities. Drawing on qualitative interview data with 78 individuals, we suggest first that the relative visibility of cycling when few do it means that it is publicly gendered in a way that more normalised modes of transport are not; conversely, the very invisibility of Black and Asian cyclists reduces their opportunities to see cycling as a candidate mode of transport. Second, following Bourdieu, we argue that the affinities different population groups have for cycling may reflect the locally constituted 'accomplishments' contained in cycling. In London, cycling represents the archetypal efficient mode for autonomous individuals to travel in ways that maximise their future-health gain, and minimise wasted time and dependence on others. However, it relies on the cultivation of a particular 'assertive' style to defend against the risks of road danger and aggression. While the identities of some professional (largely White) men and women could be bolstered by cycling, the aesthetic and symbolic goals of cycling were less appealing to those with other class, gendered and ethnic identities

Laser powder bed fusion of a β titanium alloy: Microstructural development, post-processing, and mechanical behaviour

β-Titanium alloys demonstrate unique properties, especially their low elastic modulus, good balance of strength and ductility, and strong heat treatment response. In this study, pre-alloyed powder of a β-Ti-alloy Ti–34Nb–13Ta–5Zr-0.3O (TNTZO) was processed using Laser Powder Bed Fusion (LPBF). Dense builds that demonstrate a full β microstructure with limited texture were achieved following process optimisation, with an elastic modulus of 56.5 GPa, tensile strength of 756 MPa, elongation-to-failure of 20 %, and recoverable strain of 1.3 %. Due to the high oxygen content, the β→α′′ deformation induced transformation was supressed, which resulted in a typical elastic-plastic stress-strain behaviour unlike the double-yielding behaviour typically experienced in superelastic Ti-alloys. The alloy was particularly sensitive to ageing heat treatments that resulted in needle α-precipitation, with tensile strengths exceeding 950 MPa, elastic modulus of ∼80 GPa, and recoverable strain of 1.5 %, yet at the expense of a reduced elongation-to-failure of 9 %. Transmission electron microscopy and electron backscattered diffraction investigations revealed the deformation mechanism was slip-dominated with no trace of twinning or stress induced phase transformation