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

Healthcare utilization and adverse outcomes stratified by sex, age and long-term care residency using the Alberta COVID-19 Analytics and Research Database (ACARD): a population-based descriptive study

Abstract Background Understanding the epidemiology of Coronavirus Disease of 2019 (COVID-19) in a local context is valuable for both future pandemic preparedness and potential increases in COVID-19 case volume, particularly due to variant strains. Methods Our work allowed us to complete a population-based study on patients who tested positive for COVID-19 in Alberta from March 1, 2020 to December 15, 2021. We completed a multi-centre, retrospective population-based descriptive study using secondary data sources in Alberta, Canada. We identified all adult patients (≥ 18 years of age) tested and subsequently positive for COVID-19 (including only the first incident case of COVID-19) on a laboratory test. We determined positive COVID-19 tests, gender, age, comorbidities, residency in a long-term care (LTC) facility, time to hospitalization, length of stay (LOS) in hospital, and mortality. Patients were followed for 60 days from a COVID-19 positive test. Results Between March 1, 2020 and December 15, 2021, 255,037 adults were identified with COVID-19 in Alberta. Most confirmed cases occurred among those less than 60 years of age (84.3%); however, most deaths (89.3%) occurred among those older than 60 years. Overall hospitalization rate among those who tested positive was 5.9%. Being a resident of LTC was associated with substantial mortality of 24.6% within 60 days of a positive COVID-19 test. The most common comorbidity among those with COVID-19 was depression. Across all patients 17.3% of males and 18.6% of females had an unplanned ambulatory visit subsequent to their positive COVID-19 test. Conclusions COVID-19 is associated with extensive healthcare utilization. Residents of LTC were substantially impacted during the COVID-19 pandemic with high associated mortality. Further work should be done to better understand the economic burden associated with related healthcare utilization following a COVID-19 infection to inform healthcare system resource allocation, planning, and forecasting

The MADD-3 LAMMER Kinase Interacts with a p38 MAP Kinase Pathway to Regulate the Display of the EVA-1 Guidance Receptor in <i>Caenorhabditis elegans</i>

<div><p>The proper display of transmembrane receptors on the leading edge of migrating cells and cell extensions is essential for their response to guidance cues. We previously discovered that MADD-4, which is an ADAMTSL secreted by motor neurons in <i>Caenorhabditis elegans</i>, interacts with an UNC-40/EVA-1 co-receptor complex on muscles to attract plasma membrane extensions called muscle arms. In nematodes, the muscle arm termini harbor the post-synaptic elements of the neuromuscular junction. Through a forward genetic screen for mutants with disrupted muscle arm extension, we discovered that a LAMMER kinase, which we call MADD-3, is required for the proper display of the EVA-1 receptor on the muscle’s plasma membrane. Without MADD-3, EVA-1 levels decrease concomitantly with a reduction of the late-endosomal marker RAB-7. Through a genetic suppressor screen, we found that the levels of EVA-1 and RAB-7 can be restored in <i>madd-3</i> mutants by eliminating the function of a p38 MAP kinase pathway. We also found that EVA-1 and RAB-7 will accumulate in <i>madd-3</i> mutants upon disrupting CUP-5, which is a mucolipin ortholog required for proper lysosome function. Together, our data suggests that the MADD-3 LAMMER kinase antagonizes the p38-mediated endosomal trafficking of EVA-1 to the lysosome. In this way, MADD-3 ensures that sufficient levels of EVA-1 are present to guide muscle arm extension towards the source of the MADD-4 guidance cue.</p></div

A model of the relationship between MADD-3, EVA-1 and the p38 MAP kinase pathway.

<p>The EVA-1 receptor, which is required to guide muscle arm extension towards the MADD-4 guidance cue, is indicated in orange. RE, recycling endosome; EE, early endosome; LE, late endosome.</p

Mutations in p38 MAP kinase components and the mucolipin ortholog CUP-5 suppress the decrease in abundance of RAB-7 in <i>madd-3</i> mutants.

<p><b>A-I.</b> The muscle cells of animals of the indicated genotype expressing the indicated vesicle marker. <b>A-B.</b> mCherry::RAB-5 is specifically expressed in muscles from an extrachromsomal array harboring the pPRSAD950 plasmid. <b>C-F.</b> mCherry::RAB-7 is specifically expressed in muscles from the <i>huIs89</i> integrated transgene. <b>G-I.</b> mCherry::RAB-11 is specifically expressed in muscles from the <i>huIs97</i> integrated transgene. All RAB reagents were kind gifts from Rik Korswagen. The scale bars in A-H represent 50 μm. <b>J.</b> Western blot analyses of whole worm lysate from a mixed stage population of the indicated genotype probed with anti-RFP antibodies, which recognize mCherry (top), and anti-tubulin antibodies (bottom) as a loading control. <b>K.</b> Quantification of the RAB-7 vesicle phenotype in the indicated genetic background. <b>L.</b> Quantification of the RAB-11 vesicle phenotype in the indicated genetic background. MADD-3A is specifically in muscles from the <i>myo-3</i> promoter from an extra-chromosomal array (from the pPRSAD499 plasmid). For K-L, the presence of a wild type or <i>tr186</i> allele of MADD-3A is indicated with a respective (+) or (-) below the bars of the graph. An asterisk indicates a significant difference (<i>p</i><0.05) compared to the data point indicated with a closed circle of the same color as the asterisks.</p