An ACE2 decamer viral trap as a durable intervention solution for current and future SARS-CoV (preprint)

The capacity of SARS-CoV-2 to evolve poses challenges to conventional prevention and treatment options such as vaccination and monoclonal antibodies, as they rely on viral receptor binding domain (RBD) sequences from previous strains. Additionally, animal CoVs, especially those of the SARS family, are now appreciated as a constant pandemic threat. We present here a new antiviral approach featuring inhalation delivery of a recombinant viral trap composed of ten copies of angiotensin-converting enzyme 2 (ACE2) fused to the IgM Fc. This ACE2 decamer viral trap is designed to inhibit SARS-CoV-2 entry function, regardless of viral RBD sequence variations as shown by its high neutralization potency against all known SARS-CoV-2 variants, including Omicron BQ.1, BQ.1.1, XBB.1 and XBB.1.5. In addition, it demonstrates potency against SARS-CoV-1, human NL63, as well as bat and pangolin CoVs. The multivalent trap is effective in both prophylactic and therapeutic settings since a single intranasal dosing confers protection in human ACE2 transgenic mice against viral challenges. Lastly, this molecule is stable at ambient temperature for more than twelve weeks and can sustain physical stress from aerosolization. These results demonstrate the potential of a decameric ACE2 viral trap as an inhalation solution for ACE2-dependent coronaviruses of current and future pandemic concerns.

Title: A nanobody recognizes a unique conserved epitope and potently neutralizes against the SARS-CoV-2 omicron variants.

The SARS-CoV2 Omicron variant sub-lineages spread rapidly worldwide, mostly due to their immune-evasive properties. This has put a significant part of the population at risk for severe disease and underscores the need for effective anti-SARS-CoV-2 agents against emergent strains in vulnerable patients. Camelid nanobodies are attractive therapeutic candidates due to their high stability, ease of large-scale production and potential for delivery via inhalation. Here, we characterize the RBD-specific nanobody W25 and show superior neutralization activity towards Omicron sub-lineages in comparison to all other SARS-CoV2 variants. Structure analysis of W25 in complex with the SARS-CoV2 spike glycoprotein shows that W25 engages an RBD epitope not covered by any of the antibodies previously approved for emergency use. In vivo evaluation of W25 prophylactic and therapeutic treatments across multiple SARS-CoV-2 variant infection models, together with W25 biodistribution analysis in mice, demonstrates favorable pre-clinical properties. Together, these data endorse W25 for further clinical development.

State-level data on TANF policy changes during the COVID-19 pandemic.

OBJECTIVE: COVID-19 mitigation measures prompted many states to revise the administration of their welfare programs. States adopted policies that varied across the U.S. to respond to the difficulties in fulfilling program requirements, as well as increased financial need. This dataset captures the changes made to Temporary Assistance for Needy Families (TANF) programs during the COVID-19 pandemic, from March 2020 through December 2020. The authors created this dataset as part of a larger study that examined the health effects of TANF policy changes during the COVID-19 pandemic. DATA DESCRIPTION: TANF is the main cash assistance program for low-income families in the U.S., but benefits are often conditional on work requirements and can be revoked if an individual is deemed noncompliant. Structural factors during the COVID-19 pandemic made meeting these criteria more difficult, so some states relaxed their rules and increased their benefits. This dataset captures 24 types of policies that state TANF programs enacted, which of the states enacted each of them, when the policies went into effect, and when applicable, when the policies ended. These data can be used to study the effects of TANF policy changes on various health and programmatic outcomes.

Thrombectomy of an Acute Ischemic Stroke in a Child with COVID-19 and MIS-C: Case Analysis and Literature Context.

We describe a very young child who developed an acute ischemic stroke from a LAO, while affected by COVID-19 and MIS-C, and whom we treated successfully with thrombectomy. We compare his clinical and imaging findings with those of the existing case reports, and we explore the multifactorial nature of such a neurovascular complication, particularly in the context of the most recent publications regarding the multifactorial endothelial derangements produced by the illness.

COVID-19 Vaccination is Associated with Reduced Outpatient Antibiotic Prescribing In Older Adults with Confirmed SARS-CoV-2: A Population Wide Cohort Study.

BACKGROUND: Antibiotics are frequently prescribed unnecessarily in outpatients with COVID-19. We sought to evaluate factors associated with antibiotic prescribing in those with SARS-CoV-2 infection. METHODS: We performed a population-wide cohort study of outpatients 66 years or older with PCR-confirmed SARS-CoV-2 from January 1st 2020 to December 31st 2021 in Ontario, Canada. We determined rates of antibiotic prescribing within 1-week before (pre-diagnosis) and 1-week after (post-diagnosis) reporting of the positive SARS-CoV-2 result, compared to a self-controlled period (baseline). We evaluated predictors of prescribing, including a primary series COVID-19 vaccination, in univariate and multivariable analyses. RESULTS: We identified 13,529 eligible nursing home residents and 50,885 eligible community dwelling adults with SARS-CoV-2 infection. Of the nursing home and community residents, 3,020 (22%) and 6,372 (13%) received at least one antibiotic prescription within 1 week of a SARS-CoV-2 positive result, respectively. Antibiotic prescribing in nursing home and community residents occurred at 15.0 and 10.5 prescriptions per 1000 person-days pre-diagnosis and 20.9 and 9.8 per 1000 person-days post-diagnosis, higher than the baseline rates of 4.3 and 2.5 prescriptions per 1000 person-days. COVID-19 vaccination was associated with reduced prescribing in nursing home and community residents, with adjusted post-diagnosis IRRs of 0.7 (95%CI 0.4-1) and 0.3 (95%CI 0.3-0.4) respectively. CONCLUSIONS: Antibiotic prescribing was high and with little or no decline following SARS-CoV-2 diagnosis, though was reduced in COVID-19 vaccinated individuals, highlighting the importance of vaccination and antibiotic stewardship in older adults with COVID-19.

BRAIN AND BEHAVIOR PREDICTORS OF SARS-CoV-2 INFECTION AMONG PEOPLE WITH HIV

Background: Recent findings from the UK Biobank revealed that healthy adults who later became infected with SARS-CoV-2 had lower brain volumes in regions involved in risk-taking behavior and olfaction compared to individuals who did not become infected. We examined if similar pre-existing differences in brain regions correspond to SARS-CoV-2 infection among people with HIV (PWH) receiving suppressive ART. Method(s): Participants included adult Thai MSM enrolled in the acute HIV (AHI) cohort (RV254/SEARCH010) in Bangkok, Thailand. Participants underwent 3T MRI and clinical assessments (i.e., HIV disease metrics, cognitive testing, and self-reported mood and substance use). ART initiation occurred within 5 days of the MRI (median=same day). Regional brain volumes were summed across hemispheres and corrected for head size. Brain volumes and clinical indices were compared between participants with laboratory confirmed SARS-CoV-2 and those without a diagnosis of SARS-CoV-2 following ART initiation. Machine learning was utilized to identify variables at the time of enrollment into the cohort that predicted subsequent SARS-CoV-2 infection status. Result(s): 112 participants were included in the analysis. All study participants achieved viral suppression after ART and received SARS-CoV-2 vaccinations. Fifty-four participants became infected with SARS-CoV-2 during the observation period (median=79 weeks from ART initiation). Study participants who became infected with SARS-CoV-2 after ART had lower volumes at the time of enrollment in several subcortical brain regions with the most pronounced effect in the pallidum (p=.025). There were no associations between brain volumes and ratings of mood, demographics, or HIV disease indices. SARS-CoV-2 infection was two-fold higher among individuals who reported use of amyl nitrites (i.e., poppers) during chemsex. Machine learning with repeated cross validation revealed that lower orbital and medial frontal lobe, anterior cingulate, pallidum, vermis, and olfactory volumes, worse motor function, and higher education collectively predicted co-infection status (average AUC of 85%). Conclusion(s): Study findings point toward a risk phenotype for SARS-CoV-2 infection among PWH defined by pre-existing differences in brain volumes relevant to risk-taking behavior, emotion, and neuroHIV as well as behavioral factors such as inhalant use and lack of social distancing during chemsex. (Table Presented).

Characteristics and Outcomes of Covid-19 in an Early-Treated Hiv Cohort in Thailand

Background: Emerging data indicate that people with HIV (PWH) are at risk of more severe outcomes from COVID-19. We described the clinical course and laboratory parameters pre-and post-COVID-19 in an early-treated HIV cohort in Thailand. Method(s): RV254 cohort participants were enrolled during Fiebig I-V acute HIV and initiated antiretroviral therapy (ART) within days. They underwent regular blood tests (CD4+ & CD8+ T-cell counts, HIV RNA), neuropsychiatric (NP) assessment (Color Trails 1 & 2, non-dominant hand Grooved Pegboard, Trails Making A), and mood questionnaires (Patient Health Questionnaire-9, Distress Thermometer) post-enrollment longitudinally. Their assessment outcomes pre-and post-COVID-19 were compared using Generalized Estimating Equations (GEE) with a normal distribution and identity link (CD4+, CD8+ T-cell counts, NP parameters) or binomial distribution with log link (HIV RNA), and autoregressive correlation structure. Result(s): Between 4/2021 and 9/2022, 295 participants on ART (98% male, median age 32 [IQR 28-37] were diagnosed with COVID-19. Of these, 16(5%), 38(13%) and 241(82%) were infected with alpha, delta and o variants, determined by the predominant strain circulating in Thailand at the time of infection;238(81%) received >=2 doses of COVID-19 vaccines prior to diagnosis;121(41%) received favipiravir. While 106 (36%) were managed in hospital or 'hospitel', including one intensive care unit admission, only 4(1.4%) received supplemental oxygen and none required mechanical ventilation (mean length of stay: 12 days). The participants were followed a median of 8 [IQR 5-15] weeks post-COVID. Comparing the outcomes pre-and post-COVID, plasma HIV suppression rate remained stable (98% vs. 96%, p=0.212). CD4+ (782 [IQR 708-856] vs. 823 [IQR 748-899], p=0.018) and CD8+ (622 [IQR 563-681] vs. 667 [IQR 605-728], p=0.023) T-cell counts were higher at follow-up after adjusting for age, sex, and duration between COVID-19 diagnosis and follow-up. The increasing trends of CD4+ and CD8+ T-cell were sustained on subsequent visits. Mood scores and NP performance (n=217) were stable at follow-up. Conclusion(s): In this cohort of young PWH on stable ART, we did not observe major clinical adverse events after COVID-19. Increases of CD4+ and CD8+ T-cell counts were observed while mood and NP parameters remained stable. More extensive NP assessment with incorporation of multimodal imaging outcomes and longer follow-up are needed to determine the long-term sequelae of COVID-19 in PWH.

Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging.

Length and quality of life are important to us all, yet identification of promising drug targets for human aging using genetics has had limited success. In the present study, we combine six European-ancestry genome-wide association studies of human aging traits-healthspan, father and mother lifespan, exceptional longevity, frailty index and self-rated health-in a principal component framework that maximizes their shared genetic architecture. The first principal component (aging-GIP1) captures both length of life and indices of mental and physical wellbeing. We identify 27 genomic regions associated with aging-GIP1, and provide additional, independent evidence for an effect on human aging for loci near HTT and MAML3 using a study of Finnish and Japanese survival. Using proteome-wide, two-sample, Mendelian randomization and colocalization, we provide robust evidence for a detrimental effect of blood levels of apolipoprotein(a) and vascular cell adhesion molecule 1 on aging-GIP1. Together, our results demonstrate that combining multiple aging traits using genetic principal components enhances the power to detect biological targets for human aging.

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

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: NCT02735707.

A systems approach evaluating the impact of SARS-CoV-2 variant of concern mutations on CD8+ T cell responses.

T cell recognition of SARS-CoV-2 antigens after vaccination and/or natural infection has played a central role in resolving SARS-CoV-2 infections and generating adaptive immune memory. However, the clinical impact of SARS-CoV-2-specific T cell responses is variable and the mechanisms underlying T cell interaction with target antigens are not fully understood. This is especially true given the virus' rapid evolution, which leads to new variants with immune escape capacity. In this study, we used the Omicron variant as a model organism and took a systems approach to evaluate the impact of mutations on CD8+ T cell immunogenicity. We computed an immunogenicity potential score for each SARS-CoV-2 peptide antigen from the ancestral strain and Omicron, capturing both antigen presentation and T cell recognition probabilities. By comparing ancestral vs. Omicron immunogenicity scores, we reveal a divergent and heterogeneous landscape of impact for CD8+ T cell recognition of mutated targets in Omicron variants. While T cell recognition of Omicron peptides is broadly preserved, we observed mutated peptides with deteriorated immunogenicity that may assist breakthrough infection in some individuals. We then combined our scoring scheme with an in silico mutagenesis, to characterise the position- and residue-specific theoretical mutational impact on immunogenicity. While we predict many escape trajectories from the theoretical landscape of substitutions, our study suggests that Omicron mutations in T cell epitopes did not develop under cell-mediated pressure. Our study provides a generalisable platform for fostering a deeper understanding of existing and novel variant impact on antigen-specific vaccine- and/or infection-induced T cell immunity.

A modelling assessment of short- and medium-term risks of programme interruptions for gambiense human African trypanosomiasis in the DRC.

Gambiense human African trypanosomiasis (gHAT) is a deadly vector-borne, neglected tropical disease found in West and Central Africa targeted for elimination of transmission (EoT) by 2030. The recent pandemic has illustrated how it can be important to quantify the impact that unplanned disruption to programme activities may have in achieving EoT. We used a previously developed model of gHAT fitted to data from the Democratic Republic of the Congo, the country with the highest global case burden, to explore how interruptions to intervention activities, due to e.g. COVID-19, Ebola or political instability, could impact progress towards EoT and gHAT burden. We simulated transmission and reporting dynamics in 38 regions within Kwilu, Mai Ndombe and Kwango provinces under six interruption scenarios lasting for nine or twenty-one months. Included in the interruption scenarios are the cessation of active screening in all scenarios and a reduction in passive detection rates and a delay or suspension of vector control deployments in some scenarios. Our results indicate that, even under the most extreme 21-month interruption scenario, EoT is not predicted to be delayed by more than one additional year compared to the length of the interruption. If existing vector control deployments continue, we predict no delay in achieving EoT even when both active and passive screening activities are interrupted. If passive screening remains as functional as in 2019, we expect a marginal negative impact on transmission, however this depends on the strength of passive screening in each health zone. We predict a pronounced increase in additional gHAT disease burden (morbidity and mortality) in many health zones if both active and passive screening were interrupted compared to the interruption of active screening alone. The ability to continue existing vector control during medical activity interruption is also predicted to avert a moderate proportion of disease burden.

Elsberg Syndrome with Mixed Presentation as Meningitis Retention Syndrome: A Pediatric Case Report and Comprehensive Review of the Literature.

Elsberg syndrome is a typically infectious syndrome that may cause acute or subacute bilateral lumbosacral radiculitis and sometimes lower spinal cord myelitis. Patients often present with various neurological symptoms involving the lower extremities, including numbness, weakness, and urinary disturbances such as retention. A 9-year-old girl with no significant past medical history presented with altered mental status, fever, urinary retention, and anuria and was found to have encephalomyelitis. An extensive diagnostic workup led to ruling out possible etiologies until identifying Elsberg syndrome. In this report, we describe a case of Elsberg syndrome caused by West Nile virus (WNV). To the best of our knowledge, this is the first reported case of its kind in the pediatric population. Utilizing PubMed and Web of Science databases, we reviewed the literature to describe the neurogenic control of the urinary system in correlation to a multitude of neurologic pathologies.

Exploring Clinician Attitudes Towards Treating Eating Disorders: Bridging Counselor Training Gaps

Eating disorder (ED) clinicians may face various challenges in practice, including burnout and feelings of incompetence. Several deficits may contribute to these challenges, such as graduate education and treatment gaps. In this study, 109 interdisciplinary clinicians were surveyed regarding their personal attitudes, experiences, and challenges in treating EDs. Among the various results, quantitative and qualitative findings highlighted the lack of graduate education as the primary challenge to effectively treating EDs, as well as the need for more ED research and culturally responsive care. Recommendations to enhance ED education and counselor training are provided, including managing countertransference and advocating for specialized coursework. Lastly, critical directions for future research are discussed.

Leveraging federalism for flexible and robust management of social-ecological systems

Managing social-ecological systems (SES) requires balancing the need to tailor actions to local heterogeneity and the need to work over large areas to accommodate the extent of SES. This balance is particularly challenging for policy since the level of government where the policy is being developed determines the extent and resolution of action.We make the case for a new research agenda focused on ecological federalism that seeks to address this challenge by capitalizing on the flexibility afforded by a federalist system of governance. Ecological federalism synthesizes the environmental federalism literature from law and economics with relevant ecological and biological literature to address a fundamental question: What aspects of SES should be managed by federal governments and which should be allocated to decentralized state governments?This new research agenda considers the bio-geo-physical processes that characterize state-federal management tradeoffs for biodiversity conservation, resource management, infectious disease prevention, and invasive species control.Read the free Plain Language Summary for this article on the Journal blog.

The effect of COVID-19 outbreak on hospital admissions for dental infections

Cervicofacial infections of dental origin can cause life threatening emergency and we were anticipating that the prevalence of hospital admissions for this reason between the 26 th of March 2020 until the 8 th of June 2020 that the dental practices were closed would increase. We conducted a retrospective analysis of the hospital admissions for cervicfacial infections of dental origin during this period and the results were compared with the admissions the same period last year. Surprisingly there were less admissions in 2020 compared to 2019 which can be attributed to the government guidance to ''Stay at home", "Save lives", "Protect the NHS'' and the treatment provided by the Urgent Dental Care Centers that reduced the pressure on the country's health care system. Proportionately more admissions in 2020 were attributed to dental abscess from mandibular teeth compared to 2019 but there was a small decrease in the incision and drainage under general anesthetic and a small increase in the length of the hospital stay in 2020.Copyright © 2021

Enhancing the student learning experience: Co-teaching biochemistry and clinical sciences within the dental curriculum.

Basic knowledge of biochemistry underpins oral and dental care. Undergraduate dental students do not always engage well with basic science teaching due to not appreciating its clinical relevance. Co-teaching provides one approach to overcome students' disengagement and involves two lecturers, with complementary expertise, presenting the curriculum together. This study investigated student experiences and engagement using co-teaching to integrate biochemistry with clinical sciences in the students' second-year dental curriculum. Two successive second year dental student cohorts were co-taught. Content was delivered by a biochemist and an oral biologist, either online (during the 2020 COVID lockdown) or in-person (2021). Each cohort was surveyed at the end of the teaching module using an online questionnaire containing both interval scale and free-text questions. Responses were received from 39 (42%) and 64 (85%) of students in 2020 and 2021, respectively. Students from both cohorts preferred the co-teaching approach with a mean of 8.74 on a 10-point interval scale. In 2020 and 2021, 77% and 76% of participants, respectively, preferred a combined biochemistry and clinical dentistry delivery, either in-person (37%), via Zoom (19%) or via video recording (14%). Thematic analysis of responses revealed students experienced enhanced engagement when co-taught and they attributed this to integration of the curriculum making the content more relevant and stimulating. Students preferred co-teaching to individual subjects being taught by a single teacher. Co-teaching established the relevance of theoretical biochemistry to clinical dental sciences and enhanced the students' learning experience.

Perspectives of Physicians with Experience in Nursing Home Care on Telehealth Use During the COVID-19 Public Health Emergency.

BACKGROUND: Despite expanded access to telehealth services for Medicare beneficiaries in nursing homes (NHs) during the COVID-19 public health emergency, information on physicians' perspectives on the feasibility and challenges of telehealth provision for NH residents is lacking. OBJECTIVE: To examine physicians' perspectives on the appropriateness and challenges of providing telehealth in NHs. PARTICIPANTS: Medical directors or attending physicians in NHs. APPROACH: We conducted 35 semistructured interviews with members of the American Medical Directors Association from January 18 through January 29, 2021. Outcomes of the thematic analysis reflected perspectives of physicians experienced in NH care on telehealth use. MAIN MEASURES: The extent to which participants used telehealth in NHs, the perceived value of telehealth for NH residents, and barriers to telehealth provision. KEY RESULTS: Participants included 7 (20.0%) internists, 8 (22.9%) family physicians, and 18 (51.4%) geriatricians. Five common themes emerged: (1) direct care is needed to adequately care for residents in NHs; (2) telehealth may allow physicians to reach NH residents more flexibly during offsite hours and other scenarios when physicians cannot easily reach patients; (3) NH staff and other organizational resources are critical to the success of telehealth, but staff time is a major barrier to telehealth provision; (4) appropriateness of telehealth in NHs may be limited to certain resident populations and/or services; (5) conflicting views about whether telehealth use will be sustained over time in NHs. Subthemes included the role of resident-physician relationships in facilitating telehealth and the appropriateness of telehealth for residents with cognitive impairment. CONCLUSIONS: Participants had mixed views on the effectiveness of telehealth in NHs. Staff resources to facilitate telehealth and the limitations of telehealth for NH residents were the most raised issues. These findings suggest that physicians in NHs may not view telehealth as a suitable substitute for most in-person services.

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.