Defining representativeness of study samples in medical and population health research.

Medical and population health science researchers frequently make ambiguous statements about whether they believe their study sample or results are representative of some (implicit or explicit) target population. This article provides a comprehensive definition of representativeness, with the goal of capturing the different ways in which a study can be representative of a target population. It is proposed that a study is representative if the estimate obtained in the study sample is generalisable to the target population (owing to representative sampling, estimation of stratum specific effects, or quantitative methods to generalise or transport estimates) or the interpretation of the results is generalisable to the target population (based on fundamental scientific premises and substantive background knowledge). This definition is explored in the context of four covid-19 studies, ranging from laboratory science to descriptive epidemiology. All statements regarding representativeness should make clear the way in which the study results generalise, the target population the results are being generalised to, and the assumptions that must hold for that generalisation to be scientifically or statistically justifiable.

Clinically stable covid-19 patients presenting to acute unscheduled episodic care venues have increased risk of hospitalization: secondary analysis of a randomized control trial.

BACKGROUND: Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. METHODS: A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. RESULTS: Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p < 0.001, compared with patients enrolled at a MC setting. Upon Cox regression analysis adjustment patients enrolled at an AUEC setting remained at significant risk of the primary composite outcome, HR 3.40 (95% CI 1.46, 7.94). CONCLUSIONS: Patients with clinically stable COVID-19 presenting to an AUEC enrollment setting represent a population at increased risk of arterial and venous thrombosis complications, hospitalization for cardiopulmonary events, or death, when adjusted for other risk factors, compared with patients enrolled at a MC setting. Future outpatient therapeutic trials and clinical therapeutic delivery programs of clinically stable COVID-19 patients may focus on inclusion of higher-risk patient populations from AUEC engagement locations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273.

Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.

Importance: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. Objective: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. Design, Setting, and Participants: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Interventions: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. Results: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Conclusions and Relevance: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. Trial Registration: ClinicalTrials.gov Identifier: NCT04498273.

The psychiatric sequelae of the COVID-19 pandemic in adolescents, adults, and health care workers.

BACKGROUND: The COVID-19 pandemic is the most serious global public health crisis since the 1918 influenza pandemic. This study is the first to assess its mental health impact across the lifespan in the United States in adolescents, adults, and health care workers. METHODS: We recruited 4909 participants through an online survey advertising on Facebook and Instagram to assess exposure to COVID-19 and psychiatric symptoms from April 27 to July 13. We also recruited through the University of Pittsburgh, University of Pittsburgh Medical Center, and other health care systems around Pittsburgh. The primary outcomes were clinically significant depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms, suicidal ideation or behavior, and grief reactions since COVID-19. RESULTS: Adolescents were significantly more likely to report moderate to severe symptoms of depression (55% vs. 29%; χ2 = 122, df = 1; p < .001), anxiety (48% vs. 29%; χ2 = 73; df = 1; p < .001), PTSD (45% vs. 33%; χ2 = 12; df = 1; p < .001), suicidal ideation or behavior (38% vs. 16%; χ2 = 117; df = 1; p < .001), and sleep problems (69% vs. 57%; χ2 = 26; df = 1; p < .001) compared to adults. The rates of intense grief reactions among those who lost someone to COVID-19 was 55%. Loneliness was the most common predictor across outcomes and higher number of hours spent on social media and exposure to media about COVID-19 predicted depression symptoms and suicidal ideation or behavior in adolescents. CONCLUSIONS: The COVID-19 pandemic is associated with increased rates of clinically significant psychiatric symptoms. Loneliness could put individuals at increased risk for the onset of psychiatric disorders.