Blood Pressure Management After Endovascular Therapy for Acute Ischemic Stroke: The BEST-II Randomized Clinical Trial.

Importance: The effects of moderate systolic blood pressure (SBP) lowering after successful recanalization with endovascular therapy for acute ischemic stroke are uncertain. Objective: To determine the futility of lower SBP targets after endovascular therapy (<140 mm Hg or 160 mm Hg) compared with a higher target (≤180 mm Hg). Design, Setting, and Participants: Randomized, open-label, blinded end point, phase 2, futility clinical trial that enrolled 120 patients with acute ischemic stroke who had undergone successful endovascular therapy at 3 US comprehensive stroke centers from January 2020 to March 2022 (final follow-up, June 2022). Intervention: After undergoing endovascular therapy, participants were randomized to 1 of 3 SBP targets: 40 to less than 140 mm Hg, 40 to less than 160 mm Hg, and 40 to 180 mm Hg or less (guideline recommended) group, initiated within 60 minutes of recanalization and maintained for 24 hours. Main Outcomes and Measures: Prespecified multiple primary outcomes for the primary futility analysis were follow-up infarct volume measured at 36 (±12) hours and utility-weighted modified Rankin Scale (mRS) score (range, 0 [worst] to 1 [best]) at 90 (±14) days. Linear regression models were used to test the harm-futility boundaries of a 10-mL increase (slope of 0.5) in the follow-up infarct volume or a 0.10 decrease (slope of -0.005) in the utility-weighted mRS score with each 20-mm Hg SBP target reduction after endovascular therapy (1-sided α = .05). Additional prespecified futility criterion was a less than 25% predicted probability of success for a future 2-group, superiority trial comparing SBP targets of the low- and mid-thresholds with the high-threshold (maximum sample size, 1500 with respect to the utility-weighted mRS score outcome). Results: Among 120 patients randomized (mean [SD] age, 69.6 [14.5] years; 69 females [58%]), 113 (94.2%) completed the trial. The mean follow-up infarct volume was 32.4 mL (95% CI, 18.0 to 46.7 mL) for the less than 140-mm Hg group, 50.7 mL (95% CI, 33.7 to 67.7 mL), for the less than 160-mm Hg group, and 46.4 mL (95% CI, 24.5 to 68.2 mL) for the 180-mm Hg or less group. The mean utility-weighted mRS score was 0.51 (95% CI, 0.38 to 0.63) for the less than 140-mm Hg group, 0.47 (95% CI, 0.35 to 0.60) for the less than 160-mm Hg group, and 0.58 (95% CI, 0.46 to 0.71) for the high-target group. The slope of the follow-up infarct volume for each mm Hg decrease in the SBP target, adjusted for the baseline Alberta Stroke Program Early CT score, was -0.29 (95% CI, -0.81 to ∞; futility P = .99). The slope of the utility-weighted mRS score for each mm Hg decrease in the SBP target after endovascular therapy, adjusted for baseline utility-weighted mRS score, was -0.0019 (95% CI, -∞ to 0.0017; futility P = .93). Comparing the high-target SBP group with the lower-target groups, the predicted probability of success for a future trial was 25% for the less than 140-mm Hg group and 14% for the 160-mm Hg group. Conclusions and Relevance: Among patients with acute ischemic stroke, lower SBP targets less than either 140 mm Hg or 160 mm Hg after successful endovascular therapy did not meet prespecified criteria for futility compared with an SBP target of 180 mm Hg or less. However, the findings suggested a low probability of benefit from lower SBP targets after endovascular therapy if tested in a future larger trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04116112.

Comparison of mRNA vaccine effectiveness against COVID-19-associated hospitalization by vaccination source: Immunization information systems, electronic medical records, and self-report-IVY Network, February 1-August 31, 2022.

BACKGROUND: Accurate determination of COVID-19 vaccination status is necessary to produce reliable COVID-19 vaccine effectiveness (VE) estimates. Data comparing differences in COVID-19 VE by vaccination sources (i.e., immunization information systems [IIS], electronic medical records [EMR], and self-report) are limited. We compared the number of mRNA COVID-19 vaccine doses identified by each of these sources to assess agreement as well as differences in VE estimates using vaccination data from each individual source and vaccination data adjudicated from all sources combined. METHODS: Adults aged ≥18 years who were hospitalized with COVID-like illness at 21 hospitals in 18 U.S. states participating in the IVY Network during February 1-August 31, 2022, were enrolled. Numbers of COVID-19 vaccine doses identified by IIS, EMR, and self-report were compared in kappa agreement analyses. Effectiveness of mRNA COVID-19 vaccines against COVID-19-associated hospitalization was estimated using multivariable logistic regression models to compare the odds of COVID-19 vaccination between SARS-CoV-2-positive case-patients and SARS-CoV-2-negative control-patients. VE was estimated using each source of vaccination data separately and all sources combined. RESULTS: A total of 4499 patients were included. Patients with ≥1 mRNA COVID-19 vaccine dose were identified most frequently by self-report (n = 3570, 79 %), followed by IIS (n = 3272, 73 %) and EMR (n = 3057, 68 %). Agreement was highest between IIS and self-report for 4 doses with a kappa of 0.77 (95 % CI = 0.73-0.81). VE point estimates of 3 doses against COVID-19 hospitalization were substantially lower when using vaccination data from EMR only (VE = 31 %, 95 % CI = 16 %-43 %) than when using all sources combined (VE = 53 %, 95 % CI = 41 %-62%). CONCLUSION: Vaccination data from EMR only may substantially underestimate COVID-19 VE.

Changing Severity and Epidemiology of Adults Hospitalized With Coronavirus Disease 2019 (COVID-19) in the United States After Introduction of COVID-19 Vaccines, March 2021-August 2022.

INTRODUCTION: Understanding the changing epidemiology of adults hospitalized with coronavirus disease 2019 (COVID-19) informs research priorities and public health policies. METHODS: Among adults (≥18 years) hospitalized with laboratory-confirmed, acute COVID-19 between 11 March 2021, and 31 August 2022 at 21 hospitals in 18 states, those hospitalized during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron-predominant period (BA.1, BA.2, BA.4/BA.5) were compared to those from earlier Alpha- and Delta-predominant periods. Demographic characteristics, biomarkers within 24 hours of admission, and outcomes, including oxygen support and death, were assessed. RESULTS: Among 9825 patients, median (interquartile range [IQR]) age was 60 years (47-72), 47% were women, and 21% non-Hispanic Black. From the Alpha-predominant period (Mar-Jul 2021; N = 1312) to the Omicron BA.4/BA.5 sublineage-predominant period (Jun-Aug 2022; N = 1307): the percentage of patients who had ≥4 categories of underlying medical conditions increased from 11% to 21%; those vaccinated with at least a primary COVID-19 vaccine series increased from 7% to 67%; those ≥75 years old increased from 11% to 33%; those who did not receive any supplemental oxygen increased from 18% to 42%. Median (IQR) highest C-reactive protein and D-dimer concentration decreased from 42.0 mg/L (9.9-122.0) to 11.5 mg/L (2.7-42.8) and 3.1 mcg/mL (0.8-640.0) to 1.0 mcg/mL (0.5-2.2), respectively. In-hospital death peaked at 12% in the Delta-predominant period and declined to 4% during the BA.4/BA.5-predominant period. CONCLUSIONS: Compared to adults hospitalized during early COVID-19 variant periods, those hospitalized during Omicron-variant COVID-19 were older, had multiple co-morbidities, were more likely to be vaccinated, and less likely to experience severe respiratory disease, systemic inflammation, coagulopathy, and death.

Effectiveness of Monovalent mRNA COVID-19 Vaccination in Preventing COVID-19-Associated Invasive Mechanical Ventilation and Death Among Immunocompetent Adults During the Omicron Variant Period - IVY Network, 19 U.S. States, February 1, 2022-January 31, 2023.

As of April 2023, the COVID-19 pandemic has resulted in 1.1 million deaths in the United States, with approximately 75% of deaths occurring among adults aged ≥65 years (1). Data on the durability of protection provided by monovalent mRNA COVID-19 vaccination against critical outcomes of COVID-19 are limited beyond the Omicron BA.1 lineage period (December 26, 2021-March 26, 2022). In this case-control analysis, the effectiveness of 2-4 monovalent mRNA COVID-19 vaccine doses was evaluated against COVID-19-associated invasive mechanical ventilation (IMV) and in-hospital death among immunocompetent adults aged ≥18 years during February 1, 2022-January 31, 2023. Vaccine effectiveness (VE) against IMV and in-hospital death was 62% among adults aged ≥18 years and 69% among those aged ≥65 years. When stratified by time since last dose, VE was 76% at 7-179 days, 54% at 180-364 days, and 56% at ≥365 days. Monovalent mRNA COVID-19 vaccination provided substantial, durable protection against IMV and in-hospital death among adults during the Omicron variant period. All adults should remain up to date with recommended COVID-19 vaccination to prevent critical COVID-19-associated outcomes.

Total and Subgenomic RNA Viral Load in Patients Infected With SARS-CoV-2 Alpha, Delta, and Omicron Variants.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic and subgenomic RNA levels are frequently used as a correlate of infectiousness. The impact of host factors and SARS-CoV-2 lineage on RNA viral load is unclear. METHODS: Total nucleocapsid (N) and subgenomic N (sgN) RNA levels were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in specimens from 3204 individuals hospitalized with coronavirus disease 2019 (COVID-19) at 21 hospitals. RT-qPCR cycle threshold (Ct) values were used to estimate RNA viral load. The impact of time of sampling, SARS-CoV-2 variant, age, comorbidities, vaccination, and immune status on N and sgN Ct values were evaluated using multiple linear regression. RESULTS: Mean Ct values at presentation for N were 24.14 (SD 4.53) for non-variants of concern, 25.15 (SD 4.33) for Alpha, 25.31 (SD 4.50) for Delta, and 26.26 (SD 4.42) for Omicron. N and sgN RNA levels varied with time since symptom onset and infecting variant but not with age, comorbidity, immune status, or vaccination. When normalized to total N RNA, sgN levels were similar across all variants. CONCLUSIONS: RNA viral loads were similar among hospitalized adults, irrespective of infecting variant and known risk factors for severe COVID-19. Total N and subgenomic RNA N viral loads were highly correlated, suggesting that subgenomic RNA measurements add little information for the purposes of estimating infectivity.

Lopinavir/ritonavir for treatment of non-hospitalized patients with COVID-19: a randomized clinical trial.

OBJECTIVES: Effective and widely available therapies are still needed for outpatients with COVID-19. We aimed to evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) for early treatment of non-hospitalized individuals diagnosed with COVID-19. METHODS: This randomized, placebo (Plb)-controlled, double-blind, multi-site decentralized clinical trial enrolled non-hospitalized adults with confirmed SARS-CoV-2 infection and six or fewer days of acute respiratory infection symptoms who were randomized to either twice-daily oral LPV/r (400 mg/100 mg) or Plb for 14 days. Daily surveys on study days 1 through 16 and again on study day 28 evaluated symptoms, daily activities, and hospitalization status. The primary outcome was longitudinal change in an ordinal scale based on a combination of symptoms, activity, and hospitalization status through day 15 and was analyzed by use of a Bayesian longitudinal proportional odds logistic regression model for estimating the probability of a superior recovery for LPV/r over Plb (odds ratio >1). RESULTS: Between June 2020 and December 2021, 448 participants were randomized to receive either LPV/r (n = 216) or Plb (n = 221). The mean symptom duration before randomization was 4.3 days (SD 1.3). There were no differences between treatment groups through the first 15 days for the ordinal primary outcome (odds ratio 0.96; 95% credible interval: 0.66 to 1.41). There were 3.2% (n = 7) of LPV/r and 2.7% (n = 6) of Plb participants hospitalized by day 28. Serious adverse events did not differ between groups. CONCLUSION: LPV/r did not significantly improve symptom resolution or reduce hospitalization in non-hospitalized participants with COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04372628.

Vaccine Effectiveness Against Influenza A(H3N2)-Associated Hospitalized Illness: United States, 2022.

BACKGROUND: The COVID-19 pandemic was associated with historically low influenza circulation during the 2020-2021 season, followed by an increase in influenza circulation during the 2021-2022 US season. The 2a.2 subgroup of the influenza A(H3N2) 3C.2a1b subclade that predominated was antigenically different from the vaccine strain. METHODS: To understand the effectiveness of the 2021-2022 vaccine against hospitalized influenza illness, a multistate sentinel surveillance network enrolled adults aged ≥18 years hospitalized with acute respiratory illness and tested for influenza by a molecular assay. Using the test-negative design, vaccine effectiveness (VE) was measured by comparing the odds of current-season influenza vaccination in influenza-positive case-patients and influenza-negative, SARS-CoV-2-negative controls, adjusting for confounders. A separate analysis was performed to illustrate bias introduced by including SARS-CoV-2-positive controls. RESULTS: A total of 2334 patients, including 295 influenza cases (47% vaccinated), 1175 influenza- and SARS-CoV-2-negative controls (53% vaccinated), and 864 influenza-negative and SARS-CoV-2-positive controls (49% vaccinated), were analyzed. Influenza VE was 26% (95% CI: -14% to 52%) among adults aged 18-64 years, -3% (-54% to 31%) among adults aged ≥65 years, and 50% (15-71%) among adults aged 18-64 years without immunocompromising conditions. Estimated VE decreased with inclusion of SARS-CoV-2-positive controls. CONCLUSIONS: During a season where influenza A(H3N2) was antigenically different from the vaccine virus, vaccination was associated with a reduced risk of influenza hospitalization in younger immunocompetent adults. However, vaccination did not provide protection in adults ≥65 years of age. Improvements in vaccines, antivirals, and prevention strategies are warranted.

Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Hospitalization Among Immunocompetent Adults Aged ≥65 Years - IVY Network, 18 States, September 8-November 30, 2022.

Monovalent COVID-19 mRNA vaccines, designed against the ancestral strain of SARS-CoV-2, successfully reduced COVID-19-related morbidity and mortality in the United States and globally (1,2). However, vaccine effectiveness (VE) against COVID-19-associated hospitalization has declined over time, likely related to a combination of factors, including waning immunity and, with the emergence of the Omicron variant and its sublineages, immune evasion (3). To address these factors, on September 1, 2022, the Advisory Committee on Immunization Practices recommended a bivalent COVID-19 mRNA booster (bivalent booster) dose, developed against the spike protein from ancestral SARS-CoV-2 and Omicron BA.4/BA.5 sublineages, for persons who had completed at least a primary COVID-19 vaccination series (with or without monovalent booster doses) ≥2 months earlier (4). Data on the effectiveness of a bivalent booster dose against COVID-19 hospitalization in the United States are lacking, including among older adults, who are at highest risk for severe COVID-19-associated illness. During September 8-November 30, 2022, the Investigating Respiratory Viruses in the Acutely Ill (IVY) Network§ assessed effectiveness of a bivalent booster dose received after ≥2 doses of monovalent mRNA vaccine against COVID-19-associated hospitalization among immunocompetent adults aged ≥65 years. When compared with unvaccinated persons, VE of a bivalent booster dose received ≥7 days before illness onset (median = 29 days) against COVID-19-associated hospitalization was 84%. Compared with persons who received ≥2 monovalent-only mRNA vaccine doses, relative VE of a bivalent booster dose was 73%. These early findings show that a bivalent booster dose provided strong protection against COVID-19-associated hospitalization in older adults and additional protection among persons with previous monovalent-only mRNA vaccination. All eligible persons, especially adults aged ≥65 years, should receive a bivalent booster dose to maximize protection against COVID-19 hospitalization this winter season. Additional strategies to prevent respiratory illness, such as masking in indoor public spaces, should also be considered, especially in areas where COVID-19 community levels are high (4,5).

Comparison of test-negative and syndrome-negative controls in SARS-CoV-2 vaccine effectiveness evaluations for preventing COVID-19 hospitalizations in the United States.

BACKGROUND: Test-negative design (TND) studies have produced validated estimates of vaccine effectiveness (VE) for influenza vaccine studies. However, syndrome-negative controls have been proposed for differentiating bias and true estimates in VE evaluations for COVID-19. To understand the use of alternative control groups, we compared characteristics and VE estimates of syndrome-negative and test-negative VE controls. METHODS: Adults hospitalized at 21 medical centers in 18 states March 11-August 31, 2021 were eligible for analysis. Case patients had symptomatic acute respiratory infection (ARI) and tested positive for SARS-CoV-2. Control groups were test-negative patients with ARI but negative SARS-CoV-2 testing, and syndrome-negative controls were without ARI and negative SARS-CoV-2 testing. Chi square and Wilcoxon rank sum tests were used to detect differences in baseline characteristics. VE against COVID-19 hospitalization was calculated using logistic regression comparing adjusted odds of prior mRNA vaccination between cases hospitalized with COVID-19 and each control group. RESULTS: 5811 adults (2726 cases, 1696 test-negative controls, and 1389 syndrome-negative controls) were included. Control groups differed across characteristics including age, race/ethnicity, employment, previous hospitalizations, medical conditions, and immunosuppression. However, control-group-specific VE estimates were very similar. Among immunocompetent patients aged 18-64 years, VE was 93 % (95 % CI: 90-94) using syndrome-negative controls and 91 % (95 % CI: 88-93) using test-negative controls. CONCLUSIONS: Despite demographic and clinical differences between control groups, the use of either control group produced similar VE estimates across age groups and immunosuppression status. These findings support the use of test-negative controls and increase confidence in COVID-19 VE estimates produced by test-negative design studies.

Effectiveness of Monovalent mRNA Vaccines Against COVID-19-Associated Hospitalization Among Immunocompetent Adults During BA.1/BA.2 and BA.4/BA.5 Predominant Periods of SARS-CoV-2 Omicron Variant in the United States - IVY Network, 18 States, December 26, 2021-August 31, 2022.

The SARS-CoV-2 Omicron variant (B.1.1.529 or BA.1) became predominant in the United States by late December 2021 (1). BA.1 has since been replaced by emerging lineages BA.2 (including BA.2.12.1) in March 2022, followed by BA.4 and BA.5, which have accounted for a majority of SARS-CoV-2 infections since late June 2022 (1). Data on the effectiveness of monovalent mRNA COVID-19 vaccines against BA.4/BA.5-associated hospitalizations are limited, and their interpretation is complicated by waning of vaccine-induced immunity (2-5). Further, infections with earlier Omicron lineages, including BA.1 and BA.2, reduce vaccine effectiveness (VE) estimates because certain persons in the referent unvaccinated group have protection from infection-induced immunity. The IVY Network† assessed effectiveness of 2, 3, and 4 doses of monovalent mRNA vaccines compared with no vaccination against COVID-19-associated hospitalization among immunocompetent adults aged ≥18 years during December 26, 2021-August 31, 2022. During the BA.1/BA.2 period, VE 14-150 days after a second dose was 63% and decreased to 34% after 150 days. Similarly, VE 7-120 days after a third dose was 79% and decreased to 41% after 120 days. VE 7-120 days after a fourth dose was 61%. During the BA.4/BA.5 period, similar trends were observed, although CIs for VE estimates between categories of time since the last dose overlapped. VE 14-150 days and >150 days after a second dose was 83% and 37%, respectively. VE 7-120 days and >120 days after a third dose was 60%and 29%, respectively. VE 7-120 days after the fourth dose was 61%. Protection against COVID-19-associated hospitalization waned even after a third dose. The newly authorized bivalent COVID-19 vaccines include mRNA from the ancestral SARS-CoV-2 strain and from shared mRNA components between BA.4 and BA.5 lineages and are expected to be more immunogenic against BA.4/BA.5 than monovalent mRNA COVID-19 vaccines (6-8). All eligible adults aged ≥18 years§ should receive a booster dose, which currently consists of a bivalent mRNA vaccine, to maximize protection against BA.4/BA.5 and prevent COVID-19-associated hospitalization.

Ascertainment of vaccination status by self-report versus source documentation: Impact on measuring COVID-19 vaccine effectiveness.

BACKGROUND: During the COVID-19 pandemic, self-reported COVID-19 vaccination might facilitate rapid evaluations of vaccine effectiveness (VE) when source documentation (e.g., immunization information systems [IIS]) is not readily available. We evaluated the concordance of COVID-19 vaccination status ascertained by self-report versus source documentation and its impact on VE estimates. METHODS: Hospitalized adults (≥18 years) admitted to 18 U.S. medical centers March-June 2021 were enrolled, including COVID-19 cases and SARS-CoV-2 negative controls. Patients were interviewed about COVID-19 vaccination. Abstractors simultaneously searched IIS, medical records, and other sources for vaccination information. To compare vaccination status by self-report and documentation, we estimated percent agreement and unweighted kappa with 95% confidence intervals (CIs). We then calculated VE in preventing COVID-19 hospitalization of full vaccination (2 doses of mRNA product ≥14 days prior to illness onset) independently using data from self-report or source documentation. RESULTS: Of 2520 patients, 594 (24%) did not have self-reported vaccination information to assign vaccination group; these patients tended to be more severely ill. Among 1924 patients with both self-report and source documentation information, 95.0% (95% CI: 93.9-95.9%) agreement was observed, with a kappa of 0.9127 (95% CI: 0.9109-0.9145). VE was 86% (95% CI: 81-90%) by self-report data only and 85% (95% CI: 81-89%) by source documentation data only. CONCLUSIONS: Approximately one-quarter of hospitalized patients could not provide self-report COVID-19 vaccination status. Among patients with self-report information, there was high concordance with source documented status. Self-report may be a reasonable source of COVID-19 vaccination information for timely VE assessment for public health action.

mRNA Vaccine Effectiveness Against Coronavirus Disease 2019 Hospitalization Among Solid Organ Transplant Recipients.

BACKGROUND: The study objective was to evaluate 2- and 3-dose coronavirus disease 2019 (COVID-19) mRNA vaccine effectiveness (VE) in preventing COVID-19 hospitalization among adult solid organ transplant (SOT) recipients. METHODS: We conducted a 21-site case-control analysis of 10 425 adults hospitalized in March to December 2021. Cases were hospitalized with COVID-19; controls were hospitalized for an alternative diagnosis (severe acute respiratory syndrome coronavirus 2-negative). Participants were classified as follows: SOT recipient (n = 440), other immunocompromising condition (n = 1684), or immunocompetent (n = 8301). The VE against COVID-19-associated hospitalization was calculated as 1-adjusted odds ratio of prior vaccination among cases compared with controls. RESULTS: Among SOT recipients, VE was 29% (95% confidence interval [CI], -19% to 58%) for 2 doses and 77% (95% CI, 48% to 90%) for 3 doses. Among patients with other immunocompromising conditions, VE was 72% (95% CI, 64% to 79%) for 2 doses and 92% (95% CI, 85% to 95%) for 3 doses. Among immunocompetent patients, VE was 88% (95% CI, 87% to 90%) for 2 doses and 96% (95% CI, 83% to 99%) for 3 doses. CONCLUSIONS: Effectiveness of COVID-19 mRNA vaccines was lower for SOT recipients than immunocompetent adults and those with other immunocompromising conditions. Among SOT recipients, vaccination with 3 doses of an mRNA vaccine led to substantially greater protection than 2 doses.

Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT NOW) for COVID-19: a summary of the protocol and analysis plan for a decentralized randomized controlled trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has a heterogeneous outcome in individuals from remaining asymptomatic to death. In a majority of cases, mild symptoms are present that do not require hospitalization and can be successfully treated in the outpatient setting, though symptoms may persist for a long duration. We hypothesize that drugs suitable for decentralized study in outpatients will have efficacy among infected outpatients METHODS: The TREAT NOW platform is designed to accommodate testing multiple agents with the ability to incorporate new agents in the future. TREAT NOW is an adaptive, blinded, multi-center, placebo-controlled superiority randomized clinical trial which started with two active therapies (hydroxychloroquine and lopinavir/ritonavir) and placebo, with the hydroxychloroquine arm dropped shortly after enrollment began due to external evidence. Each arm has a target enrollment of 300 participants who will be randomly assigned in an equal allocation to receive either an active therapy or placebo twice daily for 14 days with daily electronic surveys collected over days 1 through 16 and on day 29 to evaluate symptoms and a modified COVID-19 ordinal outcome scale. Participants are enrolled remotely by telephone and consented with a digital interface, study drug is overnight mailed to study participants, and data collection occurs electronically without in-person interactions. DISCUSSION: If effective treatments for COVID-19 can be identified for individuals in the outpatient setting before they advance to severe disease, it will prevent progression to more severe disease, reduce the need for hospitalization, and shorten the duration of symptoms. The novel decentralized, "no touch" approach used by the TREAT NOW platform has distinction advantages over traditional in-person trials to reach broader populations and perform study procedures in a pragmatic yet rigorous manner. TRIAL REGISTRATION: ClinicalTrials.gov NCT04372628. Registered on April 30, 2020. First posted on May 4, 2020.

Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged ≥65 Years - United States, January-March 2021.

Adults aged ≥65 years are at increased risk for severe outcomes from COVID-19 and were identified as a priority group to receive the first COVID-19 vaccines approved for use under an Emergency Use Authorization (EUA) in the United States (1-3). In an evaluation at 24 hospitals in 14 states,* the effectiveness of partial or full vaccination† with Pfizer-BioNTech or Moderna vaccines against COVID-19-associated hospitalization was assessed among adults aged ≥65 years. Among 417 hospitalized adults aged ≥65 years (including 187 case-patients and 230 controls), the median age was 73 years, 48% were female, 73% were non-Hispanic White, 17% were non-Hispanic Black, 6% were Hispanic, and 4% lived in a long-term care facility. Adjusted vaccine effectiveness (VE) against COVID-19-associated hospitalization among adults aged ≥65 years was estimated to be 94% (95% confidence interval [CI] = 49%-99%) for full vaccination and 64% (95% CI = 28%-82%) for partial vaccination. These findings are consistent with efficacy determined from clinical trials in the subgroup of adults aged ≥65 years (4,5). This multisite U.S. evaluation under real-world conditions suggests that vaccination provided protection against COVID-19-associated hospitalization among adults aged ≥65 years. Vaccination is a critical tool for reducing severe COVID-19 in groups at high risk.

External Corroboration That Corticosteroids May Be Harmful to Septic Shock Endotype A Patients.

OBJECTIVES: We previously reported gene expression-based endotypes of pediatric septic shock, endotypes A and B, and that corticosteroid exposure was independently associated with increased mortality among pediatric endotype A patients. The Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial tested the efficacy of vasopressin as initial vasopressor therapy for septic shock among adult patients, when compared with norepinephrine. Patients who reached a prespecified dose of either vasopressor were further randomized to receive hydrocortisone or placebo. A proportion of patients in the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial had transcriptomic data generated at baseline using whole blood-derived messenger RNA. We used the publicly available transcriptomic data from the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial to assign the study subjects to pediatric septic shock endotype A or B, and tested the hypothesis that hydrocortisone treatment is associated with increased mortality among patients in endotype A. DESIGN: Secondary analysis of publicly available transcriptomic data. SETTING: Multiple adult ICUs. PATIENTS: Adults with septic shock randomized to hydrocortisone (n = 47) or placebo (n = 50). INTERVENTIONS: Randomization to the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial experimental arms. MEASUREMENTS AND MAIN RESULTS: Endotype A patients receiving hydrocortisone had a mortality rate of 46%, whereas endotype A patients receiving placebo had a mortality rate of 22% (p = 0.105). In contrast, the mortality rates for endotype B patients receiving hydrocortisone or placebo were 19% and 22%, respectively. The odds of death were more than three times greater in endotype A patients receiving hydrocortisone than endotype A patients receiving placebo (p = 0.05). CONCLUSIONS: This exploratory analysis provides further evidence that corticosteroid exposure may be associated with increased mortality among septic shock endotype A patients.

Clarifying the volume of estimated need for public health and prevention services within an emergency department population.

OBJECTIVES: Emergency departments (EDs) are called to implement public health and prevention initiatives, such as infectious disease screening. The perception that ED resources are insufficient is a primary barrier. Resource needs are generally conceptualized in terms of total number of ED encounters, without formal calculation of the number of encounters for which a service is required. We illustrate potential differences in the estimated volume of service need relative to ED census using the examples of HIV and hepatitis C (HCV) screening. METHODS: This cross-sectional analysis adjusted the proportion of ED encounters in which patients are eligible for HIV and HCV screening according to a cascade of successively more restrictive patient selection criteria, presuming full implementation of each criterion. Parameter estimates for the proportion satisfying each selection criterion were derived from the electronic health records of an urban academic facility and its ED HIV and HCV screening program during 2 time periods. The primary outcome was the estimated reduction in proportion of ED visits eligible for screening after application of the entire cascade. RESULTS: There were 76,104 ED encounters during the study period. Applying all selection criteria reduced the number of required screens by 97.1% (95% confidence interval, 97.0-97.2) for HIV and 86.1% (95% confidence interval, 85.9-86.3) for HCV. CONCLUSIONS: Using the example of HIV and HCV screening, the application of eligibility metrics reduces the volume of service need to a smaller, more feasible number than estimates from ED census alone. This approach might be useful for clarifying perceived service need and guiding operational planning.

Mechanical Ventilation of Severe Traumatic Brain Injury Patients in the Prehospital Setting.

OBJECTIVE: Suboptimal ventilation may impact outcomes in patients with traumatic brain injury (TBI). This study compares the incidence of eucapnia between manually and mechanically ventilated patients with severe TBI during helicopter transport. METHODS: This retrospective chart review included consecutive intubated adults with severe TBI (Glasgow Coma Scale score < 9) transported by helicopter from the scene of injury to a level 1 trauma center between 2009 and 2015. The primary outcome was the first venous partial pressure of carbon dioxide obtained in the emergency department. Hypocapnia, eucapnia, and hypercapnia were defined based on the normal range for the testing instrument. The Fisher exact test was used to compare groups. RESULTS: Of 1,070 trauma patients intubated and transported, 93 met the inclusion criteria with full data. The mean age was 43 years, 81 of 93 were white, and 70 of 93 were men. The mean Injury Severity Score was 29, and 26 of 93 were mechanically ventilated. Hypocapnia occurred in 4 of 93 and hypercapnia in 56 of 93. There was no difference in the rate of eucapnia in manually ventilated compared with mechanically ventilated patients (36% vs. 35%, P = 1.00). CONCLUSION: Eucapnia at emergency department arrival occurred in 36% of patients and was unaffected by whether ventilation was manually or mechanically controlled. Few patients were hypocapnic, indicating a low incidence of hyperventilation during helicopter transport.

Global Differences in Characteristics, Precipitants, and Initial Management of Patients Presenting With Acute Heart Failure.

Importance: Acute heart failure (AHF) precipitates millions of hospital admissions worldwide, but previous registries have been country or region specific. Objective: To conduct a prospective contemporaneous comparison of AHF presentations, etiologic factors and precipitants, treatments, and in-hospital outcomes among global regions through the International Registry to Assess Medical Practice with Longitudinal Observation for Treatment of Heart Failure (REPORT-HF). Design, Setting, and Participants: A total of 18 553 adults were enrolled during a hospitalization for AHF. Patients were recruited from the acute setting in Western Europe (WE), Eastern Europe (EE), Eastern Mediterranean and Africa (EMA), Southeast Asia (SEA), Western Pacific (WP), North America (NA), and Central and South America (CSA). Patients with AHF were approached for consent and excluded only if there was recent participation in a clinical trial. Patients were enrolled from July 23, 2014, to March 24, 2017. Statistical analysis was conducted from April 18 to June 29, 2018; revised analyses occurred between August 6 and 29, 2019. Main Outcomes and Measures: Heart failure etiologic factors and precipitants, treatments, and in-hospital outcomes among global regions. Results: A total of 18 553 patients were enrolled at 358 sites in 44 countries. The median age was 67.0 years (interquartile range [IQR], 57-77), 11 372 were men (61.3%), 9656 were white (52.0%), 5738 were Asian (30.9%), and 867 were black (4.7%). A history of HF was present in more than 50% of the patients and 40% were known to have a prior left-ventricular ejection fraction lower than 40%. Ischemia was a common AHF precipitant in SEA (596 of 2329 [25.6%]), WP (572 of 3354 [17.1%]), and EMA (364 of 2241 [16.2%]), whereas nonadherence to diet and medications was most common in NA (306 of 1592 [19.2%]). Median time to the first intravenous therapy was 3.0 (IQR, 1.4-5.6) hours in NA; no other region had a median time above 1.2 hours (P < .001). This treatment delay remained after adjusting for severity of illness (P < .001). Intravenous loop diuretics were the most common medication administered in the first 6 hours of AHF management across all regions (65.4%-89.9%). Despite similar initial blood pressure across all regions, inotropic agents were used approximately 3 times more often in SEA, WP, and EE (11.3%-13.5%) compared with NA and WE (3.1%-4.3%) (P < .001). Older age (odds ratio [OR], 1.0; 95% CI, 1.00-1.02), HF etiology (ischemia: OR, 1.65; 95% CI, 1.11-2.44; valvular: OR, 2.10; 95% CI, 1.36-3.25), creatinine level greater than 2.75 mg/dL (OR, 1.85; 95% CI, 0.71-2.40), and chest radiograph signs of congestion (OR, 2.03; 95% CI, 1.39-2.97) were all associated with increased in-hospital mortality. Similarly, younger age (OR, -0.04; 95% CI, -0.05 to -0.02), HF etiology (ischemia: OR, 0.77; 95% CI, 0.26-1.29; valvular: OR, 2.01; 95% CI, 1.38-2.65), creatinine level greater than 2.75 mg/dL (OR, 1.16; 95% CI, 0.31-2.00), and chest radiograph signs of congestion (OR, 1.02; 95% CI, 0.57-1.47) were all associated with increased in-hospital LOS. Conclusions and Relevance: Data from REPORT-HF suggest that patients are similar across regions in many respects, but important differences in timing and type of treatment exist, identifying region-specific gaps in medical management that may be associated with patient outcomes.

Emergency department evaluation of patients with angiotensin converting enzyme inhibitor associated angioedema.

INTRODUCTION: Angiotensin converting enzyme inhibitor (ACEi) associated angioedema is frequently encountered in the emergency department. Airway management is the primary treatment, but published evidence supporting the decision to intubate patients with this condition is extremely limited. METHOD: We performed a retrospective study of all cases of ACEi associated angioedema encountered in a large, urban, tertiary referral emergency department. We classified demographics, duration of symptoms before presentation, physical exam findings and nasopharyngoscopy findings in patients that did and did not require intubation. RESULTS: We identified a total of 190 separate encounters from 183 unique patients who presented during the 3-year period of the study. Eighteen (9.5%) of these patients required intubation. Patients requiring intubation were more likely to present within 6 h of the onset of angioedema symptoms. Anterior tongue swelling, vocal changes, drooling, and dyspnea were significantly more common in patients requiring intubation. Isolated lip swelling was present in 54% of all patients and was the only finding significantly more common in the group that did not require intubation. CONCLUSIONS: Rapid progression of symptoms within the first 6 h of angioedema onset, anterior tongue swelling, vocal changes, drooling and dyspnea are associated with intubation for ACEi associated angioedema. Isolated lip swelling is significantly more common in patients that do not require intubation. Our data provide risk stratification guidance for providers treating patients with suspected ACEi associated angioedema in the emergency department.

A randomized controlled field trial of iBsafe-a novel child safety game app.

BACKGROUND: Injury is a leading cause of child morbidity and mortality worldwide. Delivering injury prevention programs via mobile platforms, such as applications (apps), may reduce risky behaviors. iBsafe is an "interactive Bike and Bite safety" mobile game app founded in behavioral theory and designed to educate kindergarten-aged children about bicycle and dog-related safety. This study assessed the relationship of iBsafe game play and child safety knowledge and skills; hypothesizing that iBsafe increases safety knowledge with translation to practice. METHODS: This single-blinded, randomized, controlled field trial included sixty 5-6-year-old children. Parent-child dyads were randomly assigned to receive a weeklong field trial of iBsafe or control. Pre- and post-intervention safety knowledge tests were completed; post-intervention safety skills assessments occurred in a simulated safety lab using real props (i.e., safety street, bicycles, and live dogs). The primary outcome was child bicycle and dog-related safety knowledge and skills performance. Performance was assessed by blinded reviewers. Secondary outcomes included frequency of safety discussion in groups and iBsafe acceptability. RESULTS: Thirty children were randomized to each group; there were no substantial demographic differences between groups. Compared to controls, post-intervention iBsafe children had higher bicycle and dog-related safety knowledge scores (9.2±0.9 vs. 8.7±1.0, P=0.029 and 8.2±2.1 vs. 6.7±1.8, P=0.003, respectively); and they exhibited more safety skills (median number bicycle skills 5 vs. 4, P=0.007; median number dog-related skills 5 vs. 3, P<0.001, respectively). Frequency of safety conversations increased among intervention families during the trial, and iBsafe acceptability was near universal. CONCLUSIONS: iBsafe was effective at increasing child safety knowledge and improving safety skills. Child injury prevention programs that embrace interactive mobile platforms may expand reach and possibly decrease injury outcomes.