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Introduction: Airway management is a key intervention during the resuscitation of critically ill trauma patients. Emergency surgical airway (ESA) placement is taught as a backup option when endotracheal intubation (ETI) fails. We sought to (1) describe the incidence of the emergency department (ED) ESA, (2) compare ESA versus ETI-only recipients, and (3) determine which factors were associated with receipt of an ESA., Methods: We searched within the Trauma Quality Improvement Program datasets from 2017 to 2022 for all emergency department surgical airway placement and/or endotracheal intubations recipients. We compared ESA versus ETI-only recipients., Results: From 2017 to 2022, there were 6,477,759 within the datasets, of which 238,128 met inclusion for this analysis. Within that, there were 236,292 ETIs, 2264 ESAs, with 428 (<1 %) having documentation of both. Of the ESAs performed, there were 82 documented in children <15 years of age with the youngest being 1 year of age. The ETI-only group had a lower proportion serious injuries to the head/neck (52 % versus 59 %), face (2 % versus 8 %), and skin (3 % versus 6 %). However, the ETI-only group had a higher proportion of serious injuries to the abdomen (15 % versus 9 %) and the extremities (19 % versus 12 %). Survival at 24-h was higher in the ETI-only group (83 % versus 76 %) as well as survival to discharge (70 % versus 67 %). In the subanaysis of children <15 years (n = 82), 34 % occurred in the 1-4 years age group, 35 % in the 5-9 years age group, and 30 % in the 10-14 years age group. In our multivariable logistic regression analysis, serious injuries to the head/neck (odds ratio [OR] 1.37, 95 % CI 1.23-1.54), face (OR 3.41, 2.83-4.11), thorax (OR 1.19, 1.06-1.33), and skin (OR 1.53, 1.15-2.05) were all associated with receipt of cricothyrotomy. Firearm (OR 3.62, 3.18-4.12), stabbing (2.85, 2.09-3.89), and other (OR 2.85, 2.09-3.89) were associated with receipt of ESA when using collision as the reference variable., Conclusions: ESA placement is a rarely performed procedure but frequently used as a primary airway intervention in this dataset. Penetrating mechanisms, and injuries to face were most associated with ESA placement. Our findings reinforce the need to maintain this critical airway skill for trauma management., Competing Interests: Declaration of competing interest DJD has received funding from the National Institute of Health and the Department of Defense. JMW has received honorariums from the Society of Critical Care Medicine for committee duties. DJD, FLW, MDA, and SGS have all received funding from the Department of Defense., (Published by Elsevier Inc.)

Objectives: We seek to describe the current practice pattern use of prothrombin complex concentrate (PCC) and fibrinogen concentrate (FC) in trauma patients., Background: Trauma-induced coagulopathy (TIC) and endotheliopathy of trauma (EOT) contribute significantly to mortality from traumatic haemorrhage. FC, and 4-factor PCC are potential treatments for EOT and TIC, respectively., Materials and Methods: We obtained data from the Trauma Quality Improvement Program (TQIP) registry and identified patients who received either PCC or FC using procedural codes. We used descriptive statistics to characterise practice patterns of these products., Results: There were 6 714 002 total encounters within the TQIP from 2017 to 2022, of which 10 589 received PCC and 3009 received FC. Of the recipients, there were 35 that received both products. There were 44 that received both. The median age of PCC recipients was 77 (69-84) with 19 patients <15 years of age with the youngest being 2 years of age. There was a general upward trend in the number of facilities with documented use of PCC: 155/744, 168/766, 189/764, 206/780, 234/795, and 235/816, respectively. The median age of FC recipients was 57 (32-75) with 48 patients <15 years of age with the youngest being 1 year of age. There was a minor downward trend in the number of facilities that had documented use of FC: 55, 44, 39, 32, 38 and 40., Conclusions: The administration of PCC and FC remains uncommon, although there appears to be an upward trend of PCC use. Most PCC use appeared to be for anticoagulation reversal in the setting of head trauma. Data guiding the use of these products are necessary as these products become more recognised as adjuncts to traumatic haemorrhage control., (© 2024 British Blood Transfusion Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Hypoxia and hyperoxia (pulse oximetry [SpO2] > 96%) are associated with increased mortality in critically ill patients. However, provider practices regarding oxygenation in traumatic brain injury (TBI) patients are unknown. This study assesses views on oxygenation of critically ill trauma patients with and without TBI and how this varies between Neurological ICU (NeuroICU) and Surgical-Trauma ICU (STICU) providers., Methods: This is a cross-sectional survey of Level I trauma center's NeuroICU and STICU providers. We used Likert scales, yes-no questions, and multiple-choice case-based scenarios to characterize provider views on oxygenation with descriptive statistics to characterize responses. Significant differences regarding TBI and non-TBI patients or NeuroICU and STICU providers were determined using Fisher's exact test and a P-value of .05., Results: A total of 83 providers initiated the survey, and 53 providers completed it. Most providers identified a threshold SpO2 < 92% for the administration of supplemental oxygen in critically ill TBI patients. A total of 9% of providers "somewhat or completely agreed" that they were more likely to give supplemental oxygen to a critically ill trauma patient with TBI than one without TBI and the same SpO2. A total of 48% of providers selected an SpO2 < 90% as the point at which supplemental oxygen should be initiated in patients without TBI, compared to 27% of providers in patients with TBI (P < .01). This threshold for supplemental oxygen use varied by provider type for non-TBI patients, but not for TBI patients (30% NeuroICU and 69% STICU providers selected SpO2 < 90% in non-TBI, P < .05; 30% NeuroICU and 35% STICU providers selected SpO2 < 90% in TBI, P = .85)., Conclusions: Critical care providers at UCHealth University of Colorado Hospital approach the oxygenation of critically ill trauma patients with and without TBI differently. Specifically, critical care respondents accepted a different lower oxygen saturation threshold for TBI and non-TBI patients. NeuroICU and STICU respondents differed in their threshold for the down-titration of supplemental oxygen. Targeted education for critical care providers may reduce these discrepancies and optimize oxygen use., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: Potential conflicts of interest. J. Ca. reports grants from National Institutes of Health (NIH) and Department of Defense (DoD), outside the submitted work. J. Ch. reports grants from the NIH, DoD, and Dolly Parton COVID-19 Research Fund, outside the submitted work. D. D. reports a grant from NIH, outside the submitted work. A. D. reports grants from the NIH and National Heart, Lung, and Blood Institute (NHLBI) for the ACTIV platform and PETAL network, respectively; and consulting fees for Alung Technologies, outside the submitted work. M. E. reports grants from NIH and Regeneron; personal funds for speaking at the ASPEN conference for Abbott Labs; and payment for testimony from Medical Legal Expert Witness, outside the submitted work. A. F. reports grants from NIH, outside the submitted work. M. G. reports grants from CDC, CDC-Abt Associates, and CDC-Westat; and served as cochair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. K. G. reports grants from NIH and DoD; and support for MHSRS 2022 travel from the DoD, outside the submitted work. A. G. reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. M. N. G. reports grants from NHLBI, CDC, and Agency for Healthcare Research and Quality; speaking at medicine grand rounds at New York Medical College; travel support for the American Thoracic Society (ATS) executive meeting and serving as ATS Chair Critical Care Assembly; data and safety monitoring board (DSMB) membership fees from Regeneron; and participating on the scientific advisory panel for Endpoint, outside the submitted work. C. G. reports grants from NIH, CDC, AHRQ, FDA, and Campbell Alliance/Syneos Health; and consulting fees from and participating on a DSMB for Merck, outside the submitted work. D. H. reports grants from NHLBI, outside the submitted work. N. H. reports grants from Sandofi and Quidel; and a Genentech educational grant to give a lecture, outside the submitted work. A. K. reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. A. L. reports grants from CDC, National Institute of Allergy and Infectious Diseases, and Burroughs Wellcome Fund; and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir, respectively, outside the submitted work. E. M. reports grants from Flu Lab, Merck, and NIH outside the submitted work. T. M. reports a grant from CDC; a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure; and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. I. D. P. reports grants from NIH and Janssen Pharmaceuticals; and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. W. B. S. reports grants and support for meetings/travel from the NIH/NHLBI, outside the submitted work. J. W. reports payment for the American College of Emergency Physicians speaker honorarium and participating on the American Board of Internal Medicine Critical Care Exam Committee, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Increased burnout and decreased professional fulfillment among intensive care physicians is partly due to intensive care unit (ICU) workload. Although the SARS-CoV-2 (COVID-19) pandemic increased ICU workload, it also may have increased feelings of personal fulfillment due to positive public perceptions of physicians caring for COVID patients. We surveyed critical care anesthesiologists to identify the effect of provider demographics, ICU workload, and COVID-19-related workload, on professional fulfillment and burnout., Methods: We performed an exploratory survey of 606 members of the Society of Critical Care Anesthesiologists (SOCCA) in January and February 2022. We used the Stanford Professional Fulfillment Index (PFI) to grade levels of professional fulfillment and markers of burnout (ie, work exhaustion and disengagement). Univariable and multivariable models were used to identify associations between provider demographics and practice characteristics and professional fulfillment and work exhaustion., Results: One hundred and seventy-five intensivists (29%) responded. A total of 65% were male and 49% were between 36 and 45 years old. The overall median PFI score-0 (none) to 24 (most professional fulfillment)-was 17 (IQR, 1-24), with a wide distribution of responses. In multivariable analysis, factors associated with higher professional fulfillment included age >45 years ( P =.004), ≤15 weeks full-time ICU coverage in 2020 ( P =.02), role as medical director ( P =.01), and nighttime home call with supervision of in-house ICU fellows ( P =.01)., Conclusions: Professional fulfillment and work exhaustion in this cross-sectional survey were associated with several demographic and practice characteristics but not COVID-19-related workload, suggesting that COVID-19 workload may not have either positive or negative perceptions on professional fulfillment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

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., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jonathan D. Casey reports grants from the National Institutes of Health (NIH) and the U.S. Department of Defense (DoD), and a travel grant from Fisher and Paykel, outside the submitted work. Steven Y. Chang reports consulting fees from PureTech Health and Kiniksa Pharmaceuticals, and participation as a Data Safety Monitoring Board (DSMB) member for a study at UCLA, outside the submitted work. Abhijit Duggal reports grants from NIH/National Heart, Lung, and Blood Institute (NHLBI), and consulting fees from Alung Technologies, outside the submitted work. David J. Douin reports a grant from NIH/National Institute of General Medical Sciences, outside the submitted work. Matthew C. Exline reports grants from NIH and Regeneron, honoria for speaking at the American Society for Parenteral and Enteral Nutrition conference from Abbott Labs, and payment for testimony as a medical legal expert witness, outside the submitted work. D. Clark Files reports receiving a grant from NIH and participating on the Medpace DSMB, outside the submitted work. Manjusha Gaglani reports having served as co-chair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. Kevin W. Gibbs reports grants from NIH and DoD, as well as support for travel to the 2022 Military Health System Research Symposium from DoD, outside the submitted work. Adit A. Ginde reports receiving grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NHLBI, the Agency for Healthcare Research and Quality (AHRQ), speaking at medicine grand rounds at Yale and Westchester Medical College, travel support from the American Thoracic Society (ATS) and serving on the ATS board, DSMB membership fees from Regeneron and the Replenish Trial, and participating on the scientific advisory panel for Endpoint, outside the submitted work. Carlos G. Grijalva reports grants from NIH, AHRQ, the Food and Drug Administration (FDA), Campbell Alliance/Syneos Health; receipt of consulting fees from and participation on a DSMB for Merck, outside the submitted work. David N. Hager reports receiving grants from NIH, outside the submitted work. Natasha Halasa reports receiving grants from Sanofi and Quidel, outside the submitted work. Akram Khan reports receiving grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. Adam S. Lauring reports receiving grants from FluLab, NIH/National Institute of Allergy and Infectious Diseases, and Burroughs Wellcome Fund, and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir respectively, outside the submitted work. Emily T. Martin reports grants from Merck and NIH, outside the submitted work. Tresa McNeal reports receiving a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure, and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. Arnold S. Monto reports a grant from NIH/NIAID, support for travel from the International Society for Influenza and other Respiratory Diseases, and participation on an advisory board for FDA, outside the submitted work. Ithan D. Peltan reports grants from NIH and Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Jay S. Steingrub reports a grant from NHLBI, outside the submitted work. Jennifer G. Wilson reports grants from NHLBI, outside the submitted work. No other potential conflicts of interest were disclosed.

The use of hyperoxemia during cardiac surgery remains controversial. We hypothesized that intraoperative hyperoxemia during cardiac surgery is associated with an increased risk of postoperative pulmonary complications., Design: Retrospective cohort study., Setting: We analyzed intraoperative data from five hospitals within the Multicenter Perioperative Outcomes Group between January 1, 2014, and December 31, 2019. We assessed intraoperative oxygenation of adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Hyperoxemia pre and post CPB was quantified as the area under the curve (AUC) of Fio 2 above 0.21 in minutes when the corresponding peripheral oxygen saturation was greater than 92% measured by pulse oximetry. We quantified hyperoxemia during CPB as the AUC of Pao 2 greater than 200 mm Hg measured by arterial blood gas. We analyzed the association of hyperoxemia during all phases of cardiac surgery with the frequency of postoperative pulmonary complications within 30 days, including acute respiratory insufficiency or failure, acute respiratory distress syndrome, need for reintubation, and pneumonia., Patients: Twenty-one thousand six hundred thirty-two cardiac surgical patients., Interventions: None., Measurements and Main Results: During 21,632 distinct cardiac surgery cases, 96.4% of patients spent at least 1 minute in hyperoxemia (99.1% pre-CPB, 98.5% intra-CPB, and 96.4% post-CPB). Increasing exposure to hyperoxemia was associated with an increased risk of postoperative pulmonary complications throughout three distinct surgical periods. During CPB, increasing exposure to hyperoxemia was associated with an increased odds of developing postoperative pulmonary complications ( p < 0.001) in a linear manner. Hyperoxemia before CPB ( p < 0.001) and after CPB ( p = 0.02) were associated with increased odds of developing postoperative pulmonary complications in a U-shaped relationship., Conclusions: Hyperoxemia occurs almost universally during cardiac surgery. Exposure to hyperoxemia assessed continuously as an AUC during the intraoperative period, but particularly during CPB, was associated with an increased incidence of postoperative pulmonary complications., Competing Interests: Dr. Douin received research grant funding from the National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) T32GM135169. Dr. Clendenen received research grant funding from the NIH/NHLBI K23HL151882 (principal investigator: to Dr. Clendenen). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Massive trauma remains the leading cause of mortality among people aged younger than 45 years. In this review, we discuss the initial care and diagnosis of trauma patients followed by a comparison of resuscitation strategies. We discuss various strategies including use of whole blood and component therapy, examine viscoelastic techniques for management of coagulopathy, and consider the benefits and limitations of the resuscitation strategies and consider a series of questions that will be important for researchers to answer to provide the best and most cost-effective therapy for severely injured patients., Competing Interests: Disclosure None of the authors has any conflicts to disclose. Funding for this article was provided by R01GM127584 to B.M. Wagener., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Despite the growing contributions of critical care anesthesiologists to clinical practice, research, and administrative leadership of intensive care units (ICUs), relatively little is known about the subspecialty-specific clinical practice environment. An understanding of contemporary clinical practice is essential to recognize the opportunities and challenges facing critical care anesthesia, optimize staffing patterns, assess sustainability and satisfaction, and strategically plan for future activity, scope, and training. This study surveyed intensivists who are members of the Society of Critical Care Anesthesiologists (SOCCA) to evaluate practice patterns of critical care anesthesiologists, including compensation, types of ICUs covered, models of overnight ICU coverage, and relationships between these factors. We hypothesized that variability in compensation and practice patterns would be observed between individuals., Methods: Board-certified critical care anesthesiologists practicing in the United States were identified using the SOCCA membership distribution list and invited to take a voluntary online survey between May and June 2021. Multiple-choice questions with both single- and multiple-select options were used for answers with categorical data, and adaptive questioning was used to clarify stem-based responses. Respondents were asked to describe practice patterns at their respective institutions and provide information about their demographics, salaries, effort in ICUs, as well as other activities., Results: A total of 490 participants were invited to take this survey, and 157 (response rate 32%) surveys were completed and analyzed. The majority of respondents were White (73%), male (69%), and younger than 50 years of age (82%). The cardiothoracic/cardiovascular ICU was the most common practice setting, with 69.5% of respondents reporting time working in this unit. Significant variability was observed in ICU practice patterns. Respondents reported spending an equal proportion of their time in clinical practice in the operating rooms and ICUs (median, 40%; interquartile range [IQR], 20%-50%), whereas a smaller proportion-primarily those who completed their training before 2009-reported administrative or research activities. Female respondents reported salaries that were $36,739 less than male respondents; however, this difference was not statistically different, and after adjusting for age and practice type, these differences were less pronounced (-$27,479.79; 95% confidence interval [CI], -$57,232.61 to $2273.03; P = .07)., Conclusions: These survey data provide a current snapshot of anesthesiology critical care clinical practice patterns in the United States. Our findings may inform decision-making around the initiation and expansion of critical care services and optimal staffing patterns, as well as provide a basis for further work that focuses on intensivist satisfaction and burnout., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Objective: The role of hyperoxia in patients with traumatic brain injury (TBI) remains controversial. The objective of this study was to determine the association between hyperoxia and mortality in critically ill TBI patients compared to critically ill trauma patients without TBI., Design: Secondary analysis of a multicenter retrospective cohort study., Setting: Three regional trauma centers in Colorado, USA, between October 1, 2015, and June 30, 2018., Patients: We included 3464 critically injured adults who were admitted to an intensive care unit (ICU) within 24 h of arrival and qualified for inclusion into the state trauma registry. We analyzed all available SpO2 values during the first seven ICU days. The primary outcome was in-hospital mortality. Secondary outcomes included the proportion of time spent in hyperoxia (defined as SpO 2  > 96%) and ventilator-free days., Interventions: None., Measurements and Main Results: In-hospital mortality occurred in 163 patients (10.7%) in the TBI group and 101 patients (5.2%) in the non-TBI group. After adjusting for ICU length of stay, TBI patients spent a significantly greater amount of time in hyperoxia versus non-TBI patients ( p  = 0.024). TBI status significantly modified the effect of hyperoxia on mortality. At each specific SpO 2 level, the risk of mortality increases with increasing FiO 2 for both patients with and without TBI. This trend was more pronounced at lower FiO 2 and higher SpO 2 values, where a greater number of patient observations were obtained. Among patients who required invasive mechanical ventilation, TBI patients required significantly more days of ventilation to day 28 than non-TBI patients., Conclusions: Critically ill trauma patients with a TBI spend a greater proportion of time in hyperoxia compared to those without a TBI. TBI status significantly modified the effect of hyperoxia on mortality. Prospective clinical trials are needed to better assess a possible causal relationship.

Background: Coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE) studies are increasingly reporting relative VE (rVE) comparing a primary series plus booster doses with a primary series only. Interpretation of rVE differs from traditional studies measuring absolute VE (aVE) of a vaccine regimen against an unvaccinated referent group. We estimated aVE and rVE against COVID-19 hospitalization in primary-series plus first-booster recipients of COVID-19 vaccines., Methods: Booster-eligible immunocompetent adults hospitalized at 21 medical centers in the United States during December 25, 2021-April 4, 2022 were included. In a test-negative design, logistic regression with case status as the outcome and completion of primary vaccine series or primary series plus 1 booster dose as the predictors, adjusted for potential confounders, were used to estimate aVE and rVE., Results: A total of 2060 patients were analyzed, including 1104 COVID-19 cases and 956 controls. Relative VE against COVID-19 hospitalization in boosted mRNA vaccine recipients versus primary series only was 66% (95% confidence interval [CI], 55%-74%); aVE was 81% (95% CI, 75%-86%) for boosted versus 46% (95% CI, 30%-58%) for primary. For boosted Janssen vaccine recipients versus primary series, rVE was 49% (95% CI, -9% to 76%); aVE was 62% (95% CI, 33%-79%) for boosted versus 36% (95% CI, -4% to 60%) for primary., Conclusions: Vaccine booster doses increased protection against COVID-19 hospitalization compared with a primary series. Comparing rVE measures across studies can lead to flawed interpretations of the added value of a new vaccination regimen, whereas difference in aVE, when available, may be a more useful metric., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports serving as the data and safety monitoring board (DSMB) chair for Hamilton Ventilators outside the submitted work. Jonathan D. Casey reports grants from the National Institutes of Health (NIH) and Department of Defense (DoD), outside the submitted work. Steven Y. Chang consulted for PureTech Health in 2020 and Kiniksa Pharmaceuticals and is a DSMB member for an investigator-initiated study at UCLA. James D. Chappell reports grants from NIH and DoD during the conduct of the study. Cristie Columbus reports support from Baylor University Medical Center for meeting attendance, an advisory role to the Dallas County Public Health Committee, and other interests as the Chief of the Division of Infectious Diseases at Baylor University Medical Center and the Medical Director for Infection Prevention and Control/Healthcare epidemiology, outside the submitted work. David J. Douin reports grants received from NIH and the National Institute of General Medical Sciences, outside the submitted work. Abhijit Duggal reports grants from NIH and the National Heart, Lung, and Blood Institute (NHLBI), and participation on a Steering Committee for ALung technologies, outside the submitted work. Matthew C. Exline reports grants from NIH and Regeneron, as well as support from Abbott Labs and Medical Legal Expert Witness for sponsored talks, outside the submitted work. D. Clark Files reports personal consultant fees from Global Blood Therapeutics and is a DSMB member from Medpace, outside the submitted work. Manjusha Gaglani reports grants from CDC-Abt Associates, CDC-Westat, and Janssen, and participates as co-chair on the Infection Diseases and Immunizations Committee for the Texas Pediatric Society, outside the submitted work. Kevin W. Gibbs reports grants from NIH and DoD, and DoD funds for the Military Health System Research Symposium travel in 2022, outside the submitted work. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NHLBI and the Agency for Healthcare Research and Quality (AHRQ), speaking at medicine grand rounds at New York Medical College, travel support for the American Thoracic Society (ATS) executive meeting and serving as ATS Chair Critical Care Assembly, DSMB membership fees from Regeneron, and participating on the scientific advisory panel for Endpoint, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Merck; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, and AHRQ outside the submitted work. David N. Hager reports grants from NHLBI outside the submitted work. Natasha Halasa reports grants and nonfinancial support from Sanofi, and grants from Quidel outside the submitted work. Nicholas J. Johnson reports grants from NIH, DoD, University of Washington, and Medic One Foundation, outside the submitted work. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, Ely Lilly, 4D Medical, Dompe Pharmaceuticals and GlaxoSmithKline, and serves on the Guidelines committee for Chest, outside the submitted work. Jennie H. Kwon reports grants from NIH outside the submitted work. Adam S. Lauring reports personal fees from Sanofi and Roche and grants from the National Institute for Allergy and Infectious Diseases, Burroughs Wellcome Fund, Flu Lab, outside the submitted work. Emily T. Martin reports grants from Merck, Flu Lab, and NIH, outside the submitted work. Tresa McNeal reports grants from participating as a webinar invited panelist and a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals, and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Todd W. Rice reports grants from NIH and DoD, personal fees from Cumberland Pharmaceuticals, Inc., Cytovale, Inc., and Sanofi, Inc., outside the submitted work. William B. Stubblefield reports grants from NIH outside the submitted work. Jennifer G. Wilson reports personal funds from the American College of Emergency Physicians and American Board of Internal Medicine outside the submitted work. No other potential conflicts of interest were disclosed.

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors have completed and submitted the International Committee of Medical Journal Editors (ICMJE) disclosure form. Funding for this work was provided to all participating sites by the United States Centers for Disease Control and Prevention. Samuel Brown reports grants from National Institutes of Health (NIH) and Department of Defense (DoD), participation as the DSMB chair for Hamilton Ventilators, and participation as a member of the DSMB for New York University COVID clinical trials. Jonathan Casey reports funding from NIH and DoD. Steven Chang reports consulting fees from La Jolla Pharmaceuticals, PureTech Health, and Kiniska Pharmaceuticals, payment/honoraria from La Jolla Pharmaceuticals, and participation on a DSMB for an investigator-initiated study conducted at UCLA. James Chappell reports grants and other support from NIH. Abhijit Duggal reports consulting fees from ALung technologies. Matthew Exline reports payment/honorariua from Abbott Lab for sponsored talks. D. Clark Files reports consulting fees from Cytovale and participation on a DSMB for Medpace. Anne Frosch reports grants from NIH. Manjusha Gaglani reports grants from Centers for Disease Control and Prevention (CDC), CDC-Abt Associates, CDC-Westat, and Janssen, and a leadership role as co-chair of the Infectious Disease and Immunization Committee of the Texas Pediatric Society, Texas Chapter of American Academy of Pediatrics. Kevin Gibbs reports funding from NIH/ National Heart, Lung, and Blood Institute (NHLBI) for the ACTIV-4HT NECTAR trial. Nicholas Mohr reports grants from the CDC (funded 2 other multicenter COVID-related projects separate from this work through payments to author’s institution). Adit Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals. Michelle Gong reports grants from NIH/NHLBI and Agency for Healthcare Research and Quality (AHRQ), consulting fees from Endpoint, a leadership role on the American Thoracic Society (ATS) executive committee and board as well as support from ATS for meeting travel expenses, and participation on a DSMB for Regeneron. Carlos Grijalva reports grants from NIH, CDC, Food and Drug Administration (FDA), AHRQ, Sanofi, and Syneos Health and consulting fees from Pfizer, Merck, and Sanofi. David Hager reports grants from NIH/NHLBI for the ACTIV-4HT NECTAR trial and Incyte Corporation and participation as a DSMB chair for the SAFE EVICT Trial of vitamin C in COVID-19. Jennifer Wilson reports grants from the CDC and NIH (ARREST Pneumonia Trial UH3HL141722, ACTIV3a and 3b trials, and ACTIV4a trial), and membership on the American Board of Internal Medicine Critical Care Medicine exam committee. Natasha Halasa reports grants from NIH, Quidel, and Sanofi and honoraria for speaking at the American Academy of Pediatrics (AAP) conference. Nicholas Johnson reports grants from NIH/NHLBI/NINDS and the University of Washington Royalty Research Fund and payment for expert testimony for the Washington Department of Health. Akram Khan reports grants from United Therapeutics, Gilead Sciences, and 4D Medical and a leadership role on the guidelines committee for Chest. Jennie Kwon reports grants from NIH/NIAID. Adam Lauring reports grants from CDC, NIH/NIAID, and Burroughs Wellcome Fund and consulting fees from Sanofi and Roche. Christopher Lindsell reports grants from NIH, DoD, CDC, bioMerieux, Entegrion Inc., Endpoint Health, and AbbVie, patents for risk stratification in sepsis and septic shock, participation on DSMBs for clinical trials unrelated to the current work, a leadership role on the executive committee for the Board of Directors of the Association for Clinical and Translational Science, and stock options in Bioscape Digita. Emily Martin reports grants from Merck, CDC, and NIH and payment/honoraria from the Michigan Infectious Disease Society. Tresa McNeal reports payment/honoraria from the Society of Hospital Medicine. Ithan Peltan reports grants from NIH, Janssen, Regeneron, and Asahi Kasei Pharma. Todd Rice reports grants from AbbVie Inc., consulting fees from Cumberland Pharmaceuticals, Inc. and Cytovale, Inc., membership on a DSMB for Sanofi, Inc., a leadership role as immediate past president of the American Society of Parenteral and Enteral Nutrition, and stock options in Cumberland Pharmaceuticals, Inc. Wesley Self reports receiving the primary funding for this project from the United States Centers for Disease Control and Prevention, and research funding from Merck and Gilead Sciences. William Stubblefield reports grants from the NIH/NHLBI., (Published by Elsevier Ltd.)

Background: Neutralizing monoclonal antibodies (mAbs) are highly effective in reducing hospitalization and mortality among early symptomatic COVID-19 patients in clinical trials and real-world data. While resistance to some mAbs has since emerged among new variants, characteristics associated with treatment failure of mAbs remain unknown., Methods: This multicenter, observational cohort study included patients with COVID-19 who received mAb treatment between November 20, 2020, and December 9, 2021. We utilized electronic health records from a statewide health system plus state-level vaccine and mortality data. The primary outcome was mAb treatment failure, defined as hospitalization or death within 28 days of a positive SARS-CoV-2 test., Results: COVID-19 mAb was administered to 7406 patients. Hospitalization within 28 days of positive SARS-CoV-2 test occurred in 258 (3.5%) of all patients who received mAb treatment. Ten patients (0.1%) died within 28 days, and all but one were hospitalized prior to death. Characteristics associated with treatment failure included having two or more comorbidities excluding obesity and immunocompromised status (adjusted odds ratio [OR] 3.71, 95% confidence interval [CI] 2.52-5.56), lack of SARS-CoV-2 vaccination (OR 2.73, 95% CI 2.01-3.77), non-Hispanic black race/ethnicity (OR 2.21, 95% CI 1.20-3.82), obesity (OR 1.79, 95% CI 1.36-2.34), one comorbidity (OR 1.68, 95% CI 1.11-2.57), age ≥ 65 years (OR 1.62, 95% CI 1.13-2.35), and male sex (OR 1.56, 95% CI 1.21-2.02). Immunocompromised status (none, mild, or moderate/severe), pandemic phase, and type of mAb received were not associated with treatment failure (all p > 0.05)., Conclusions: Comorbidities, lack of prior SARS-CoV-2 vaccination, non-Hispanic black race/ethnicity, obesity, age ≥ 65 years, and male sex are associated with treatment failure of mAbs., (© 2022. The Author(s).)

Background: Animal studies have shown that midazolam can increase vulnerability to cardiac ischemia, potentially via circadian-mediated mechanisms. We hypothesized that perioperative midazolam administration is associated with an increased incidence of myocardial injury in patients undergoing non-cardiac surgery (MINS) and that circadian biology may underlie this relationship., Methods: We analyzed intraoperative data from the Multicenter Perioperative Outcomes Group for the occurrence of MINS across 50 institutions from 2014 to 2019. The primary outcome was the occurrence of MINS. MINS was defined as having at least one troponin-I lab value ≥0.03 ng/ml from anesthesia start to 72 h after anesthesia end. To account for bias, propensity scores and inverse probability of treatment weighting were applied., Results: A total of 1,773,118 cases were available for analysis. Of these subjects, 951,345 (53.7%) received midazolam perioperatively, and 16,404 (0.93%) met criteria for perioperative MINS. There was no association between perioperative midazolam administration and risk of MINS in the study population as a whole (odds ratio (OR) 0.98, confidence interval (CI) [0.94, 1.01]). However, we found a strong association between midazolam administration and risk of MINS when surgery occurred overnight (OR 3.52, CI [3.10, 4.00]) or when surgery occurred in ASA 1 or 2 patients (OR 1.25, CI [1.13, 1.39])., Conclusion: Perioperative midazolam administration may not pose a significant risk for MINS occurrence. However, midazolam administration at night and in healthier patients could increase MINS, which warrants further clinical investigation with an emphasis on circadian biology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Prin, Pattee, Douin, Scott, Ginde and Eckle.)

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., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton Ventilators outside the submitted work. Jonathan D. Casey reports grants from the National Institutes of Health (NIH) and U.S. Department of Defense (DoD), outside the submitted work. Steven Y. Chang reports consulting for PureTech Health in 2020 and Kiniksa Pharmaceuticals and membership on the safety monitoring board (DSMB) for an investigator-initiated study at UCLA. James D. Chappell reports grants from NIH and DoD during the conduct of the study. David J. Douin reports grants received from NIH and National Institute of General Medical Sciences, outside the submitted work. Abhijit Duggal reports grants from NIH and participation on a steering committee for ALung technologies, outside the submitted work. Matthew C. Exline reports grants from the NIH and Regeneron, as well as support from Abbott Labs for sponsored talks, outside the submitted work. D. Clark Files reports personal consultant fees from Cytovale and membership on DSMB from Medpace, outside the submitted work. Anne P. Frosch reports grants from NIH, outside the submitted work. Manjusha Gaglani reports grants from Abt Associates, Westat, Janssen, and participation as co-chair on the Infection Diseases and Immunizations Committee for the Texas Pediatric Society, outside the submitted work. Kevin W. Gibbs reports grants from NIH and DoD, and DoD funds for Military Health System Research Symposium travel in 2022, outside the submitted work. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NIH, speaking at medicine grand rounds at New York Medical College, travel support for the American Thoracic Society executive meeting, DSMB membership fees from Regeneron, and participation on the scientific advisory panel for Endpoint, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, Agency for Healthcare Research and Quality, and Sanofi, outside the submitted work. David N. Hager grants from NIH, outside the submitted work. Natasha Halasa reports grants and nonfinancial support from Sanofi, and grants from Quidel outside the submitted work. Nicholas J. Johnson reports grants from the NIH, DoD, University of Washington, and Medic One Foundation, outside the submitted work. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, Ely Lilly, 4D Medical, Dompe Pharmaceuticals, and GlaxoSmithKline, outside the submitted work. Jennie H. Kwon reports grants from National Institute of Allergy and Infectious Diseases (NIAID), outside the submitted work. Adam S. Lauring reports personal fees from Sanofi and Roche and grants from NIAID, Burroughs Wellcome Fund, Flu Lab, outside the submitted work. Emily T. Martin reports grants from Merck, outside the submitted work. Tresa McNeal reports participation as a webinar invited panelist and a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Todd W. Rice reports grants from Abbvie Inc, and personal fees from Cumberland Pharmaceuticals, Inc, Cytovale, Inc., and Sanofi, Inc., outside the submitted work. William B. Stubblefield reports grants from NIH, outside the submitted work. Jennifer G. Wilson reports grants from NIH, and personal funds from the American College of Emergency Physicians and American Board of Internal Medicine, outside the submitted work. No other potential conflicts of interest were disclosed.

Background . Adults in the United States (US) began receiving the adenovirus vector coronavirus disease 2019 (COVID-19) vaccine, Ad26.COV2.S (Johnson & Johnson [Janssen]), in February 2021. We evaluated Ad26.COV2.S vaccine effectiveness (VE) against COVID-19 hospitalization and high disease severity during the first 10 months of its use. Methods . In a multicenter case-control analysis of US adults (≥18 years) hospitalized 11 March to 15 December 2021, we estimated VE against susceptibility to COVID-19 hospitalization (VEs), comparing odds of prior vaccination with a single dose Ad26.COV2.S vaccine between hospitalized cases with COVID-19 and controls without COVID-19. Among hospitalized patients with COVID-19, we estimated VE against disease progression (VEp) to death or invasive mechanical ventilation (IMV), comparing odds of prior vaccination between patients with and without progression. Results . After excluding patients receiving mRNA vaccines, among 3979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2229 controls (13% vaccinated with Ad26.COV2.S), VEs of Ad26.COV2.S against COVID-19 hospitalization was 70% (95% confidence interval [CI]: 63-75%) overall, including 55% (29-72%) among immunocompromised patients, and 72% (64-77%) among immunocompetent patients, for whom VEs was similar at 14-90 days (73% [59-82%]), 91-180 days (71% [60-80%]), and 181-274 days (70% [54-81%]) postvaccination. Among hospitalized COVID-19 case-patients, VEp was 46% (18-65%) among immunocompetent patients. Conclusions . The Ad26.COV2.S COVID-19 vaccine reduced the risk of COVID-19 hospitalization by 72% among immunocompetent adults without waning through 6 months postvaccination. After hospitalization for COVID-19, vaccinated immunocompetent patients were less likely to require IMV or die compared to unvaccinated immunocompetent patients., Competing Interests: Potential conflicts of interest. M. G.: CDC: Baylor Scott & White Health (BSWH) US Flu/COVID VE Network, HAIVEN, Synergy studies; CDC-Abt: BSWH FluVax Trial and RECOVER-PROTECT Cohort Studies; CDC-Westat: BSWH VISION COVID-Flu VE Study; Janssen: BSWH Respiratory Syncytial Virus (RSV) Severity App Birth Cohort Study; Co-Chair of Infectious Diseases and Immunization Committee—Texas Pediatric Society—Texas Chapter of American Academy of Pediatrics. A. G.: National Institutes of Health (NIH), Department of Defense; Faron Pharmaceuticals; AbbVie; D Douin: NIH/National Institute of General Medical Sciences (NIGMS) Institutional Training Grant. J. C.: NIH and Department of Defense grants unrelated to this work. T. A. M.: Panelist for Society of Hospital Medicine Updates in Heart Failure; Board member for Scott & White Clinic Physicians Board of Directors. K. G.: NECTAR Executive Committee member ACTIV4-HT; D. C. F.: Cytovale consulting fees; Medpace Data Safety Monitoring Board. D. N. H.: National Heart, Lung, and Blood Institute (NIHLBI) participant in the ACTIV4d-Host Tissue Trial; Chair DSMD—SAFE EVICT Trial of VIT C in COVID-19. M. N. G.: Grants from NHLBI and Agency for Healthcare Research and Quality (AHRQ); Consulting fees for Endpoint for scientific advisory panel; Honoraria—Medicine Grand Rounds from Westchester Medical Center; Support for attending ATS Board of Directors meeting; Data and Safety Monitoring Board (DSMB) for Regeneron study and REPLENISH trial. N. J. J.: IH grants paid to University of Washington Royalty Research Fund; Department of Defense grants; Medic One Foundation grants; WA Department of Health expert testimony payment; DSMB for Opticyte, Inc.; Chair, ACEP Critical Care Section. I. P.: NIH grants; Regeneron Pharmaceuticals grant; Intermountain Research & Medical Foundation grant; Asahi Kasei Pharma grant; Janssen Pharmaceuticals grant. S. B.: NIH grants and Department of Defense grants; DSMB for Hamilton ventilators and NYU. E. T. M.: Merck grant. A. S. M.: NIH grant. A. K.: NIH grants; United Therapeutics grants; Eli Lily grants; Johnson & Johnson—BOA Medical—4DMedical research grants; rA. D.: Center PI for PETAL network through NHLBI grant; on steering committee for A Lung technologies. J. G. W.: NIH/NHLBI funding for ACTIV-3 and ACTIV-4 trials; American Board of Internal Medicine—member of Critical Care Exam Committee. S. Y. C.: Consulting fees for PureTech Health and Kiniska Pharmaceuticals; Honoraria for La Jolla. H. M. B.: CDC grant for HCP COVID vaccine effectiveness. J. H. K.: NIAID grant. M. C. E.: Abbott Labs honoraria for speaking on ASPEN on nutrition in critical illness from COVID. A. L.: grants from CDC, NIH, and Burroughs Wellcome Fund; consulting fees from Sanofi on antiviral drugs and for Roche on baloxavir trial steering committee. N. H.: grants from NIH, Quidel, and Sanofi; Honoraria for speaking at CME event at AAP. C. G. G.: grants from Campbell Alliance/Syneos Health, Sanofi, CDC, AHRQ, NIH, and FDA; consulting fees from Merck, Pfizer, and Sanofi-Pasteur. T. W. R.: grants from NIH, Department of Defense and AbbVie; consulting fees for Cumberland Pharmaceuticals, Inc. and Cytovale, Inc.; DSMB for Sanofi, Inc.; Immediate Past President—ASPEN; Stock in Cumberland Pharmaceuticals, Inc. for consulting work. W. B. S.: NIH training grants. C. J. L.: grants from NIH, Department of Defense; CDC; bioMerieux; Entegrion, Inc.; Endpoint Health; AbbVie; Patents for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center; DSMBs for clinical trials for Study Principal Investigators; Association for Clinical and Translational Science (Executive Committee, Immediate Past President, and Board of Directors); stock options in Bioscape Digita. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2022.)

Mortality historically has been the primary outcome of choice for acute and critical care clinical trials. However, undue reliance on mortality can limit the scope of trials that can be performed. Large sample sizes are usually needed for trials powered for a mortality outcome, and focusing solely on mortality fails to recognize the importance that reducing morbidity can have on patients' lives. The COVID-19 pandemic has highlighted the need for rapid, efficient trials to rigorously evaluate new therapies for hospitalized patients with acute lung injury. Oxygen-free days (OFDs) is a novel outcome for clinical trials that is a composite of mortality and duration of new supplemental oxygen use. It is designed to characterize recovery from acute lung injury in populations with a high prevalence of new hypoxemia and supplemental oxygen use. In these populations, OFDs captures two patient-centered consequences of acute lung injury: mortality and hypoxemic lung dysfunction. Power to detect differences in OFDs typically is greater than that for other clinical trial outcomes, such as mortality and ventilator-free days. OFDs is the primary outcome for the Fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) Host Tissue platform, which evaluates novel therapies targeting the host response to COVID-19 among adults hospitalized with COVID-19 and new hypoxemia. This article outlines the rationale for use of OFDs as an outcome for clinical trials, proposes a standardized method for defining and analyzing OFDs, and provides a framework for sample size calculations using the OFD outcome., (Copyright © 2022 American College of Chest Physicians. All rights reserved.)

Rationale: Uncertainty regarding the natural history of coronavirus disease (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized patients with COVID-19. Objectives: Evaluate 90-day clinical course of patients hospitalized with COVID-19, comparing three distinct definitions of recovery. Methods: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1 ) the hospital discharge approach; 2 ) the TICO (Therapeutics for Inpatients with COVID-19) trials sustained recovery approach; and 3 ) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-ICU setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. Measurements and Main Results: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age, 68 vs. 59 years; P  < 0.001) and more had a comorbidity (84% vs. 70%; P  < 0.001). Of 170 discordant participants, 106 (62%) had postdischarge events captured by the TICO approach. Conclusions: Among patients hospitalized with COVID-19, 20% had clinically significant postdischarge events within 90 days after randomization in patients who would be considered "recovered" using the hospital discharge approach. Using the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should use follow-up times up to 90 days to assess clinical recovery more accurately.

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., Competing Interests: Potential conflicts of interest. All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. J. H. K. reports grant support from National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (1K23 AI137321-01A1). M. G. reports grant support from CDC, CDC-Abt, CDC-Westat, and Janssen and a role as the Co-Chair of the Infectious Diseases and Immunization Committee, Texas Pediatric Society, Texas Chapter of American Academy of Pediatrics (AAP). H. K. T. reports a grant from CDC. A. A. G. reports grant support from CDC, NIH, US Department of Defense (DOD), AbbVie, and Faron Pharmaceuticals. T. M. reports payments as a panelist for the Society of Hospital Medicine Updates in Heart Failure (August 25, 2021) and as a board member of the Scott & White Clinic Physicians Board of Directors. D. J. D. reports grant support from NIH/National Institute of General Medical Sciences (T32GM135169). J. D. C. reports grants from the NIH and DOD. K. W. G. reports grant support as a NECTAR Executive Committee member ACTIV-4HT. D. C. F. reports consultant fees from Cytovale and membership on a Medpace Data Safety Monitoring Board (DSMB). D. N. H. reports a contract from CDC and grant support from National Heart, Lung, and Blood Institute (NHLBI) for participation in the ACTIV4d-Host Tissue Trial. M. C. E. reports talks on nutrition in COVID pneumonia at ASPEN conference sponsored by Abbott Laboratories. M. N. G. reports grant support from the CDC, funding from NHLBI and Agency for Healthcare Research and Quality (AHRQ), and fees from Endpoint for participating on a scientific advisory panel, payment for Medicine Grand Rounds at Westchester Medical Center, travel support for attending the ATS Board of Directors meeting, and participation on a DSMB for Regeneron and REPLINISH trial. N. J. J. reports grants from the NIH, DOD, and Medic One Foundation, payment for expert testimony from the Washington Department of Health, participation on DSMBs for Opticyte Inc., Multi-Center, Randomized Control Trial to Study the Effectiveness of Hyperbaric Oxygen for COVID-19 patients with Moderate to Severe Hypoxemia (NCT04619719), and Remote Ischemic Conditioning to Enhance Resuscitation (RICE) Pilot (NCT04265807), and participation as Chair of the ACEP Critical Care Section. I. D. P. reports grants from the CDC, NIH, Janssen Pharmaceuticals, and Intermountain Research & Medical Foundation, institutional fees from Asahi Kasei Pharma and from Regeneron Pharmaceuticals. S. M. B. reports grants from the CDC, NIH, and DOD, fees from Hamilton ventilators for chairing a DSMB, and personal fees from New York University for service on a DSMB. E. T. M. reports a grant from Merck outside the submitted work. A. K. reports grants from the NIH, Ely Lily, United Therapeutics, Johnson & Johnson, BOA Medical, and 4D Medical. A. D. reports funding as the Center PI for PETAL network through NHLBI grant and for participation on a steering committee for ALung technologies. J. G. W. reports grant support from NIH/NHLBI for ACTIV-3 and ACTIV-4 trials and membership on the American Board of Internal Medicine Critical Care Exam Committee. S. Y. C. reports payment as a speaker for La Jolla Pharmaceuticals and consultant fees for PureTech Health and Kiniska Pharmaceuticals. H. M. B. reports grants from the CDC. A. S. L. reports grants from the CDC, NIH, and Burroughs Wellcome Fund, consultant fees from Sanofi, and fees from Roche for membership on a trial steering committee. N. H. reports grants from the CDC, NIH, Sanofi, and Quidel and honoraria for speaking at Continuing Medical Education event at AAP. J. D. C. reports grant support from the CDC. C. G. G. reports consultant fees from Pfizer, Merck, and Sanofi-Pasteur and grants from Campbell Alliance/Syneos Health, CDC, NIH, US Food and Drug Administration, AHRQ, and Sanofi. T. W. R. reports grants from the NIH, DOD, and AbbVie, personal fees from Cumberland Pharmaceuticals as the Director of Medical Affairs, consultant fees from Cytovale, Inc., personal fees from Sanofi, Inc. for serving as a DSMB board member, a role as the Immediate Past President of the American Society of Parenteral and Enteral Nutrition (ASPEN), and stock from Cumberland Pharmaceuticals for consulting work. C J. L. reports grants/contracts from the CDC, NIH, DOD, bioMerieux, Endpoint LLC, Entegrion, Inc., and AbbVie, a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock, participation on DSMBS for Study Principal Investigators, roles on the Executive Committee, Immediate Past President, Member, Board of Directors for the Association of Clinical and Translational Science, and stock options in Bioscape Digita. W. H. S. reports grant funding from the CDC for this work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Vaccine effectiveness (VE) against COVID-19 hospitalization was evaluated among immunocompetent adults (≥18 years) during March-August 2021 using a case-control design. Among 1669 hospitalized COVID-19 cases (11% fully vaccinated) and 1950 RT-PCR-negative controls (54% fully vaccinated), VE was 96% (95% confidence interval [CI], 93%-98%) among patients with no chronic medical conditions and 83% (95% CI, 76%-88%) among patients with ≥ 3 categories of conditions. VE was similar between those aged 18-64 years versus ≥65 years (P > .05). VE against severe COVID-19 was very high among adults without chronic conditions and lessened with increasing comorbidity burden., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Background: As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination coverage increases in the United States, there is a need to understand the real-world effectiveness against severe coronavirus disease 2019 (COVID-19) and among people at increased risk for poor outcomes., Methods: In a multicenter case-control analysis of US adults hospitalized March 11-May 5, 2021, we evaluated vaccine effectiveness to prevent COVID-19 hospitalizations by comparing odds of prior vaccination with a messenger RNA (mRNA) vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with COVID-19 and hospital-based controls who tested negative for SARS-CoV-2., Results: Among 1212 participants, including 593 cases and 619 controls, median age was 58 years, 22.8% were Black, 13.9% were Hispanic, and 21.0% had immunosuppression. SARS-CoV-2 lineage B0.1.1.7 (Alpha) was the most common variant (67.9% of viruses with lineage determined). Full vaccination (receipt of 2 vaccine doses ≥14 days before illness onset) had been received by 8.2% of cases and 36.4% of controls. Overall vaccine effectiveness was 87.1% (95% confidence interval [CI], 80.7-91.3). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.4%; 95% CI, 79.3-9.7). Among 45 patients with vaccine-breakthrough COVID hospitalizations, 44 (97.8%) were ≥50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (62.9%; 95% CI,20.8-82.6) than without immunosuppression (91.3%; 95% CI, 85.6-94.8)., Conclusion: During March-May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing COVID-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Early in the COVID-19 pandemic, the World Health Organization stressed the importance of daily clinical assessments of infected patients, yet current approaches frequently consider cross-sectional timepoints, cumulative summary measures, or time-to-event analyses. Statistical methods are available that make use of the rich information content of longitudinal assessments. We demonstrate the use of a multistate transition model to assess the dynamic nature of COVID-19-associated critical illness using daily evaluations of COVID-19 patients from 9 academic hospitals. We describe the accessibility and utility of methods that consider the clinical trajectory of critically ill COVID-19 patients., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Dr Ginde reports grants from CDC, during the conduct of the study; grants from NIH, grants from Department of Defense, grants from AbbVie, grants from Faron Pharmaceuticals, outside the submitted work. Matthew C. Exline reports talks on nutrition in COVID pneumonia at APEN conference sponsored by Abbott Labs. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Lung LLC, and Reata Pharmaceuticals. D. Clark Files reports consultant fees from Cytovale and membership on a Medpace Data Safety Monitoring Board (DSMB). Dr Rice reports grants from Centers for Disease Control (CDC), during the conduct of the study; personal fees from Cumberland Pharmaceuticals, Inc., personal fees from Cytovale, Inc., personal fees from Sanofi, Inc., outside the submitted work. Jonathan D. Casey reports a grant (N23HL153584) from the National Institutes of Health (NIH). Daniel J. Henning reports consulting fees from Cytovale and Opticyte. Samuel M. Brown reports fees from Hamilton for chairing a DSMB, and institutional fees from Faron, Sedana, and Janssen; grants from Sedana, Janssen, NIH, and the Department of Defense (DoD); book royalties from Oxford University and Brigham Young University; and personal fees from New York University for service on a DSMB. Wesley H. Self reports grant funding from CDC for this work; grants and consultant fees from Merck outside this work and consultant fees from Aerpio Pharmaceuticals outside this work. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; organizational contract fees from bioMerieux, Endpoint LLC, and Entegrion, Inc.; and a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock. No other potential conflicts of interest were disclosed., (© The Author(s) 2022.)

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) are effective at preventing COVID-19-associated hospitalization (1-3). However, how well mRNA vaccines protect against the most severe outcomes of these hospitalizations, including invasive mechanical ventilation (IMV) or death is uncertain. Using a case-control design, mRNA vaccine effectiveness (VE) against COVID-19-associated IMV and in-hospital death was evaluated among adults aged ≥18 years hospitalized at 21 U.S. medical centers during March 11, 2021-January 24, 2022. During this period, the most commonly circulating variants of SARS-CoV-2, the virus that causes COVID-19, were B.1.1.7 (Alpha), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Previous vaccination (2 or 3 versus 0 vaccine doses before illness onset) in prospectively enrolled COVID-19 case-patients who received IMV or died within 28 days of hospitalization was compared with that among hospitalized control patients without COVID-19. Among 1,440 COVID-19 case-patients who received IMV or died, 307 (21%) had received 2 or 3 vaccine doses before illness onset. Among 6,104 control-patients, 4,020 (66%) had received 2 or 3 vaccine doses. Among the 1,440 case-patients who received IMV or died, those who were vaccinated were older (median age = 69 years), more likely to be immunocompromised* (40%), and had more chronic medical conditions compared with unvaccinated case-patients (median age = 55 years; immunocompromised = 10%; p<0.001 for both). VE against IMV or in-hospital death was 90% (95% CI = 88%-91%) overall, including 88% (95% CI = 86%-90%) for 2 doses and 94% (95% CI = 91%-96%) for 3 doses, and 94% (95% CI = 88%-97%) for 3 doses during the Omicron-predominant period. COVID-19 mRNA vaccines are highly effective in preventing COVID-19-associated death and respiratory failure treated with IMV. CDC recommends that all persons eligible for vaccination get vaccinated and stay up to date with COVID-19 vaccination (4)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton ventilators, and grants from the National Institutes of Health (NIH) and the U.S. Department of Defense (DoD). Jonathan D. Casey reports grants from the NIH and DoD. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals in 2018, consulted for PureTech Health in 2020, and consulted for Kiniska Pharmaceuticals in December 2021. David J. Douin reports a grant from NIH/National Institute of General Medical Sciences. Abhijit Duggal reports grants from NIH and participation on a Steering Committee for ALung Technologies. Matthew C. Exline reports support from Abbott Labs for sponsored talks. D. Clark Files reports personal consultant fees from Cytovale and membership on a data and safety monitoring board (DSMB) from Medpace. Anne E. Frosch reports grants from NIH/National Institute of Allergy and Infectious Diseases (NIAID), NIH/National Heart, Lung, and Blood Institute (NHLBI), and NIH/INSIGHT/ICC. Manjusha Gaglani reports grants from Abt Associates, Westat, and Janssen. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals. Michelle N. Gong reports grants from NIH and the Agency for Healthcare Research and Quality (AHRQ), and DSMB membership fees from Regeneron, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHRQ, and Sanofi. David N. Hager reports grants from NIH/NHLBI. Natasha Halasa reports grants and nonfinancial support from Sanofi, and grants from Quidel and NIH. Nicholas J. Johnson reports grants from NIH, DoD, and Medic One Foundation. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, and Eli Lilly. Jennie H. Kwon reports grants from NIH/NIAID. Adam S. Lauring reports personal fees from Sanofi and Roche, and grants from NIH and Burroughs Wellcome Fund. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; contract fees from bioMerieux, Endpoint Health, Entegrion Inc, and AbbVie; and a patent for risk stratification in sepsis and septic shock. Emily T. Martin reports grants from Merck. Arnold S. Monto reports a grant from NIH. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals, and Intermountain Research and Medical Foundation, and institutional support from Asahi Kasei Pharma and Regeneron. Todd W. Rice reports grants from NIH, DoD, and AbbVie and personal fees from Cumberland Pharmaceuticals, Inc., and Cytovale, Inc. No other potential conflicts of interest were disclosed.

Objective: Recent clinical trials confirmed the corticosteroid dexamethasone as an effective treatment for patients with COVID-19 requiring mechanical ventilation. However, limited attention has been given to potential adverse effects of corticosteroid therapy. The objective of this study was to determine the association between corticosteroid administration and impaired glycemic control among COVID-19 patients requiring mechanical ventilation and/or veno-venous extracorporeal membrane oxygenation., Design: Multicenter retrospective cohort study between March 9 and May 17, 2020. The primary outcome was days spent with at least 1 episode of blood glucose either >180 mg/dL or <80 mg/dL within the first 28 days of admission., Setting: Twelve hospitals in a United States health system., Patients: Adults diagnosed with COVID-19 requiring invasive mechanical ventilation and/or veno-venous extracorporeal membrane oxygenation., Interventions: None., Measurements and Main Results: We included 292 mechanically ventilated patients. We fitted a quantile regression model to assess the association between steroid administration ≥320 mg methylprednisolone (equivalent to 60 mg dexamethasone) and impaired glycemic control. Sixty-six patients (22.6%) died within 28 days of intensive care unit admission. Seventy-one patients (24.3%) received a cumulative dose of least 320 mg methylprednisolone equivalents. After adjustment for gender, history of diabetes mellitus, chronic liver disease, sequential organ failure assessment score on intensive care unit day 1, and length of stay, administration of ≥320 mg methylprednisolone equivalent was associated with 4 additional days spent with glucose either <80 mg/dL or >180 mg/dL (B = 4.00, 95% CI = 2.15-5.85, P < .001)., Conclusions: In this cohort study of 292 mechanically ventilated COVID-19 patients, we found an association between corticosteroid administration and higher incidence of both hyperglycemia and hypoglycemia.

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) provide protection against infection with SARS-CoV-2, the virus that causes COVID-19, and are highly effective against COVID-19-associated hospitalization among eligible persons who receive 2 doses (1,2). However, vaccine effectiveness (VE) among persons with immunocompromising conditions* is lower than that among immunocompetent persons (2), and VE declines after several months among all persons (3). On August 12, 2021, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for a third mRNA vaccine dose as part of a primary series ≥28 days after dose 2 for persons aged ≥12 years with immunocompromising conditions, and, on November 19, 2021, as a booster dose for all adults aged ≥18 years at least 6 months after dose 2, changed to ≥5 months after dose 2 on January 3, 2022 (4,5,6). Among 2,952 adults (including 1,385 COVID-19 case-patients and 1,567 COVID-19-negative controls) hospitalized at 21 U.S. hospitals during August 19-December 15, 2021, effectiveness of mRNA vaccines against COVID-19-associated hospitalization was compared between adults eligible for but who had not received a third vaccine dose (1,251) and vaccine-eligible adults who received a third dose ≥7 days before illness onset (312). Among 1,875 adults without immunocompromising conditions (including 1,065 [57%] unvaccinated, 679 [36%] 2-dose recipients, and 131 [7%] 3-dose [booster] recipients), VE against COVID-19 hospitalization was higher among those who received a booster dose (97%; 95% CI = 95%-99%) compared with that among 2-dose recipients (82%; 95% CI = 77%-86%) (p <0.001). Among 1,077 adults with immunocompromising conditions (including 324 [30%] unvaccinated, 572 [53%] 2-dose recipients, and 181 [17%] 3-dose recipients), VE was higher among those who received a third dose to complete a primary series (88%; 95% CI = 81%-93%) compared with 2-dose recipients (69%; 95% CI = 57%-78%) (p <0.001). Administration of a third COVID-19 mRNA vaccine dose as part of a primary series among immunocompromised adults, or as a booster dose among immunocompetent adults, provides improved protection against COVID-19-associated hospitalization., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton, institutional fees from Faron Pharmaceuticals and Sedana, grants from Janssen, the National Institutes of Health (NIH), the Department of Defense (DoD), book royalties from Oxford University and Brigham Young University, outside the submitted work. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals in 2018 and consulted for PureTech Health in 2020. James D. Chappell reports grants from NIH during the conduct of the study. Abhijit Duggal reports grants from NIH and participation on a steering committee for ALung Technologies, Inc., outside the submitted work. Matthew C. Exline reports support from Abbott Labs for sponsored talks, outside the submitted work. D. Clark Files reports personal consultant fees from Cytovale and is a data and safety monitoring board (DSMB) member from Medpace, outside the submitted work. Manjusha Gaglani reports grants from CDC-Vanderbilt University Medical Center for the submitted work, CDC-Abt Associates, CDC-Westat, Janssen and Pfizer, outside the submitted work. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NIH and the Agency for Healthcare Research and Quality (AHRQ), DSMB membership fees from Regeneron, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHRQ, and Sanofi, outside the submitted work. David N. Hager reports salary support from Incyte Corporation and EMPACT Precision Medicine via Vanderbilt University Medical Center and grants from NHLBI, outside the submitted work. Natasha Halasa reports grants and nonfinancial support from Sanofi, and grants from Quidel outside the submitted work. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, Ely Lilly, and GlaxoSmithKline, outside the submitted work. Adam S. Lauring reports personal fees from Sanofi and Roche, outside the submitted work. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; contract fees from bioMerieux, Endpoint LLC, and Entegrion Inc, outside the submitted work; in addition, Dr. Lindsell has a patent for risk stratification in sepsis and septic shock issued. Emily T. Martin reports personal fees from Pfizer and grants from Merck, outside the submitted work. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc, Cytovale, Inc., and Sanofi, Inc., outside the submitted work. Wesley H. Self reports consulting fees from Aeprio Pharmaceuticals and Merck, outside the submitted work. No other potential conflicts of interest were disclosed.

Importance: A comprehensive understanding of the benefits of COVID-19 vaccination requires consideration of disease attenuation, determined as whether people who develop COVID-19 despite vaccination have lower disease severity than unvaccinated people., Objective: To evaluate the association between vaccination with mRNA COVID-19 vaccines-mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech)-and COVID-19 hospitalization, and, among patients hospitalized with COVID-19, the association with progression to critical disease., Design, Setting, and Participants: A US 21-site case-control analysis of 4513 adults hospitalized between March 11 and August 15, 2021, with 28-day outcome data on death and mechanical ventilation available for patients enrolled through July 14, 2021. Date of final follow-up was August 8, 2021., Exposures: COVID-19 vaccination., Main Outcomes and Measures: Associations were evaluated between prior vaccination and (1) hospitalization for COVID-19, in which case patients were those hospitalized for COVID-19 and control patients were those hospitalized for an alternative diagnosis; and (2) disease progression among patients hospitalized for COVID-19, in which cases and controls were COVID-19 patients with and without progression to death or mechanical ventilation, respectively. Associations were measured with multivariable logistic regression., Results: Among 4513 patients (median age, 59 years [IQR, 45-69]; 2202 [48.8%] women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), 1983 were case patients with COVID-19 and 2530 were controls without COVID-19. Unvaccinated patients accounted for 84.2% (1669/1983) of COVID-19 hospitalizations. Hospitalization for COVID-19 was significantly associated with decreased likelihood of vaccination (cases, 15.8%; controls, 54.8%; adjusted OR, 0.15; 95% CI, 0.13-0.18), including for sequenced SARS-CoV-2 Alpha (8.7% vs 51.7%; aOR, 0.10; 95% CI, 0.06-0.16) and Delta variants (21.9% vs 61.8%; aOR, 0.14; 95% CI, 0.10-0.21). This association was stronger for immunocompetent patients (11.2% vs 53.5%; aOR, 0.10; 95% CI, 0.09-0.13) than immunocompromised patients (40.1% vs 58.8%; aOR, 0.49; 95% CI, 0.35-0.69) (P < .001) and weaker at more than 120 days since vaccination with BNT162b2 (5.8% vs 11.5%; aOR, 0.36; 95% CI, 0.27-0.49) than with mRNA-1273 (1.9% vs 8.3%; aOR, 0.15; 95% CI, 0.09-0.23) (P < .001). Among 1197 patients hospitalized with COVID-19, death or invasive mechanical ventilation by day 28 was associated with decreased likelihood of vaccination (12.0% vs 24.7%; aOR, 0.33; 95% CI, 0.19-0.58)., Conclusions and Relevance: Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and disease progression to death or mechanical ventilation. These findings are consistent with risk reduction among vaccine breakthrough infections compared with absence of vaccination.

Background: Targeted normoxia (SpO 2 90-96% or PaO 2 60-100 mmHg) may help to conserve oxygen and improve outcomes in critically ill patients by avoiding potentially harmful hyperoxia. However, the role of normoxia for critically ill trauma patients remains uncertain. The objective of this study is to describe the study protocol and statistical analysis plan for the Strategy to Avoid Excessive Oxygen for Critically Ill Trauma Patients (SAVE-O2) clinical trial., Methods: Design, setting, and participants: Protocol for a multicenter cluster randomized, stepped wedge implementation trial evaluating the effectiveness of a multimodal intervention to target normoxia in critically ill trauma patients at eight level 1 trauma centers in the USA. Each hospital will contribute pre-implementation (control) and post-implementation (intervention) data. All sites will begin in the control phase with usual care. When sites reach their randomly assigned time to transition, there will be a one-month training period, which does not contribute to data collection. Following the 1-month training period, the site will remain in the intervention phase for the duration of the trial., Main Outcome Measures: The primary outcome will be supplemental oxygen-free days, defined as the number of days alive and not on supplemental oxygen. Secondary outcomes include in-hospital mortality to day 90, hospital-free days to day 90, ventilator-free days (VFD) to day 28, time to room air, Glasgow Outcome Score (GOS), and duration of time receiving supplemental oxygen., Discussion: SAVE-O2 will determine if a multimodal intervention to improve compliance with targeted normoxia will safely reduce the need for concentrated oxygen for critically injured trauma patients. These data will inform military stakeholders regarding oxygen requirements for critically injured warfighters, while reducing logistical burden in prolonged combat casualty care., Trial Registration: ClinicalTrials.gov NCT04534959 . Registered September 1, 2020., (© 2021. The Author(s).)

Three COVID-19 vaccines are authorized or approved for use among adults in the United States (1,2). Two 2-dose mRNA vaccines, mRNA-1273 from Moderna and BNT162b2 from Pfizer-BioNTech, received Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020 for persons aged ≥18 years and aged ≥16 years, respectively. A 1-dose viral vector vaccine (Ad26.COV2 from Janssen [Johnson & Johnson]) received EUA in February 2021 for persons aged ≥18 years (3). The Pfizer-BioNTech vaccine received FDA approval for persons aged ≥16 years on August 23, 2021 (4). Current guidelines from FDA and CDC recommend vaccination of eligible persons with one of these three products, without preference for any specific vaccine (4,5). To assess vaccine effectiveness (VE) of these three products in preventing COVID-19 hospitalization, CDC and collaborators conducted a case-control analysis among 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states during March 11-August 15, 2021. An additional analysis compared serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2, the virus that causes COVID-19, among 100 healthy volunteers enrolled at three hospitals 2-6 weeks after full vaccination with the Moderna, Pfizer-BioNTech, or Janssen COVID-19 vaccine. Patients with immunocompromising conditions were excluded. VE against COVID-19 hospitalizations was higher for the Moderna vaccine (93%; 95% confidence interval [CI] = 91%-95%) than for the Pfizer-BioNTech vaccine (88%; 95% CI = 85%-91%) (p = 0.011); VE for both mRNA vaccines was higher than that for the Janssen vaccine (71%; 95% CI = 56%-81%) (all p<0.001). Protection for the Pfizer-BioNTech vaccine declined 4 months after vaccination. Postvaccination anti-spike IgG and anti-RBD IgG levels were significantly lower in persons vaccinated with the Janssen vaccine than the Moderna or Pfizer-BioNTech vaccines. Although these real-world data suggest some variation in levels of protection by vaccine, all FDA-approved or authorized COVID-19 vaccines provide substantial protection against COVID-19 hospitalization., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Wesley H. Self reports grants and consultant fees from Merck and consultant fees from Aerpio Pharmaceuticals. Adit A. Ginde reports grant support from AbbVie and Faron Pharmaceuticals. Jonathan D. Casey reports a grant (N23HL153584) from the National Institutes of Health (NIH). D. Clark Files reports consultant fees from Cytovale and membership on a Medpace Data Safety Monitoring Board (DSMB). David N. Hager reports salary support from Incyte Corporation, EMPACT Precision Medicine, and the Marcus Foundation. Michelle N. Gong reports grant support from NIH and the Agency for Healthcare Research and Quality (AHRQ) and fees for participating on a DSMB for Regeneron and for participating on a scientific advisory panel for Philips Healthcare. Daniel J. Henning reports consulting fees from Cytovale and Opticyte. Ithan D. Peltan reports grants from NIH and Janssen Pharmaceuticals, institutional fees from Asahi Kasei Pharma and from Regeneron. Samuel M. Brown reports fees from Hamilton for chairing a DSMB, and institutional fees from Faron, Sedana, and Janssen; grants from Sedana, Janssen, NIH, and the Department of Defense (DoD); book royalties from Oxford University and Brigham Young University; and personal fees from New York University for service on a DSMB. Emily T. Martin reports personal fees from Pfizer for unrelated work and a grant from Merck for unrelated work. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Lung LLC, and Reata Pharmaceuticals. Arnold S. Monto reports consulting fees from Sanofi-Pasteur and Seqirus. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals and a Consultant for PureTech Health. Jennie H. Kwon reports grant support from NIH. Matthew C. Exline reports talks on nutrition in COVID pneumonia at APEN conference sponsored by Abbott Labs. Natasha Halasa reports grants from Sanofi and Quidel. James D. Chappell reports a grant from the National Center for Advancing Translational Sciences, NIH. Adam S. Lauring reports consultant fees from Sanofi and fees from Roche for membership on a trial steering committee. Carlos G. Grijalva reports consultant fees from Pfizer, Merck, and Sanofi-Pasteur and grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHRQ, and Sanofi. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc., as the Director of Medical Affairs, consultant fees from Avisa Pharma, LLC; and DSMB membership fees from Sanofi. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; organizational contract fees from bioMerieux, Endpoint LLC, and Entegrion, Inc.; and a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock. No other potential conflicts of interest were disclosed.

Real-world evaluations have demonstrated high effectiveness of vaccines against COVID-19-associated hospitalizations (1-4) measured shortly after vaccination; longer follow-up is needed to assess durability of protection. In an evaluation at 21 hospitals in 18 states, the duration of mRNA vaccine (Pfizer-BioNTech or Moderna) effectiveness (VE) against COVID-19-associated hospitalizations was assessed among adults aged ≥18 years. Among 3,089 hospitalized adults (including 1,194 COVID-19 case-patients and 1,895 non-COVID-19 control-patients), the median age was 59 years, 48.7% were female, and 21.1% had an immunocompromising condition. Overall, 141 (11.8%) case-patients and 988 (52.1%) controls were fully vaccinated (defined as receipt of the second dose of Pfizer-BioNTech or Moderna mRNA COVID-19 vaccines ≥14 days before illness onset), with a median interval of 65 days (range = 14-166 days) after receipt of second dose. VE against COVID-19-associated hospitalization during the full surveillance period was 86% (95% confidence interval [CI] = 82%-88%) overall and 90% (95% CI = 87%-92%) among adults without immunocompromising conditions. VE against COVID-19- associated hospitalization was 86% (95% CI = 82%-90%) 2-12 weeks and 84% (95% CI = 77%-90%) 13-24 weeks from receipt of the second vaccine dose, with no significant change between these periods (p = 0.854). Whole genome sequencing of 454 case-patient specimens found that 242 (53.3%) belonged to the B.1.1.7 (Alpha) lineage and 74 (16.3%) to the B.1.617.2 (Delta) lineage. Effectiveness of mRNA vaccines against COVID-19-associated hospitalization was sustained over a 24-week period, including among groups at higher risk for severe COVID-19; ongoing monitoring is needed as new SARS-CoV-2 variants emerge. To reduce their risk for hospitalization, all eligible persons should be offered COVID-19 vaccination., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton, institutional fees from Faron Pharmaceuticals and Sedana, grants from Janssen, the National Institutes of Health (NIH), and the Department of Defense (DoD), book royalties from Oxford University and Brigham Young University, outside the submitted work. Jonathan D. Casey reports grants from NIH, outside the submitted work. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals in 2018 and consulted for PureTech Health in 2020. James D. Chappell reports grants from NIH during the conduct of the study. Matthew C. Exline reports support from Abbott Labs for sponsored talks, outside the submitted work. D. Clark Files reports personal consultant fees from Cytovale and is a data and safety monitoring board (DSMB) member from Medpace, outside the submitted work. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NIH and the Agency for Healthcare Research and Quality (AHRQ), DSMB membership fees from Regeneron, and personal fees from Philips Healthcare, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHQR, and Sanofi, outside the submitted work. David N. Hager reports salary support from Incyte Corporation, the Marcus Foundation, and EMPACT Precision Medicine via Vanderbilt University Medical Center, outside the submitted work. Natasha Halasa reports grants and nonfinancial support from Sanofi, and Quidel outside the submitted work. Daniel J. Henning reports personal consultant fees from Cytovale and Opticyte. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Lung LLC, and Reata Pharmaceuticals, outside the submitted work. Adam S. Lauring reports personal fees from Sanofi and Roche, outside the submitted work. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; contract fees from bioMerieux, Endpoint LLC, and Entegrion Inc, outside the submitted work and has a patent for risk stratification in sepsis and septic shock issued. Emily T. Martin reports personal fees from Pfizer and grants from Merck, outside the submitted work. Arnold S. Monto reports consulting fees from Sanofi-Pasteur and Seqirus outside the submitted work. Ithan D. Peltan reports grants from NIH and Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc. and personal fees from Avisa Pharma, LLC and Sanofi, outside the submitted work. Wesley H. Self reports consulting fees from Aeprio Pharmaceuticals and Merck outside the submitted work. No other potential conflicts of interest were disclosed.

Background: Surgery is required for cure of most solid tumors, and general anesthesia is required for most cancer surgery. The vast majority of cancer surgery is facilitated by general anesthesia using volatile inhalational agents such as isoflurane and sevoflurane. Only recently have the immunologic and oncologic effect of inhalational agents, and their alternative, propofol-based total intravenous anesthesia (TIVA), come under investigation., Methods: Between January 2019 and June 2020, English language articles on PubMed were searched for the keywords "Propofol" "TIVA" or "IV anesthesia" and either "cancer surgery" or "surgical oncology." Duplicates were removes, manuscripts classified as either in vitro, animal, translational, or clinical studies, and their results summarized within these categories., Results: In-vitro and translational data suggest that inhalational anesthetics are potent immunosuppressive and tumorigenic agents that promote metastasis, while propofol is anti-inflammatory, anti-tumorigenic, and prevents metastasis development. Clinically there is a recurring association, based largely on retrospective, single institution series, that TIVA is associated with significant improvements in disease-free interval and overall survival in a number of, but not all, solid tumors. The longer the surgery is, the more intense the surgical trauma is, the more aggressive the malignancy is, and the higher likelihood of an association is., Discussion: Prospective randomized trials, coupled with basic science and translational studies, are needed to further define this association., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background: Avoidance of hypoxia and hyperoxia may reduce morbidity and mortality in critically ill civilian and military trauma patients. The objective of this study was to determine if a multimodal quality improvement intervention increases adherence to a consensus-based, targeted normoxia strategy. We hypothesized that this intervention would safely improve compliance with targeted normoxia., Methods: This is a pre/postquasiexperimental pilot study to improve adherence to normoxia, defined as a pulse oximetry (SpO2) of 90% to 96% or an arterial partial pressure oxygen (PaO2) of 60 to 100 mm Hg. We used a multimodal informatics and educational intervention guiding clinicians to safely titrate supplemental oxygen to normoxia based on SpO2 monitoring in critically ill trauma patients admitted to the surgical-trauma or neurosurgical intensive care unit within 24 hours of emergency department arrival. The primary outcome was effectiveness in delivering targeted normoxia (i.e., an increase in the probability of being in the targeted normoxia range and/or a reduction in the probability of being on a higher fraction-inspired oxygen concentration [FiO2])., Results: Analysis included 371 preintervention subjects and 201 postintervention subjects. Preintervention and postintervention subjects were of similar age, race/ethnicity, and sex and had similar comorbidities and Acute Physiologic and Chronic Health Evaluation II scores. Overall, the adjusted probability of being hyperoxic while on supplemental oxygen was reduced during the postintervention period (adjusted odds ratio, 0.74; 95% confidence interval, 0.57-0.97). There was a higher probability of being on room air (FiO2, 0.21) in the postintervention period (adjusted odds ratio, 1.38; 95% confidence interval, 0.83-2.30). In addition, there was a decreased amount of patient time spent on higher levels of FiO2 (FiO2, >40%) without a concomitant increase in hypoxia., Conclusion: A multimodal intervention targeting normoxia in critically ill trauma patients increased normoxia and lowered the use of supplemental oxygen. A large clinical trial is needed to validate the impact of this protocol on patient-centered clinical outcomes., Level of Evidence: Therapeutic/care management, level II., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Because of the increased risk for severe coronavirus disease 2019 (COVID-19), the Advisory Committee on Immunization Practices (ACIP) initially prioritized COVID-19 vaccination for persons in long-term care facilities (LTCF), persons aged ≥65 years, and persons aged 16-64 years with high-risk medical conditions when there is limited vaccine supply. We compared characteristics and severe outcomes of hospitalized patients with COVID-19 in the United States between early and later in the pandemic categorized by groups at higher risk of severe COVID-19., Methods: Observational study of sampled patients aged ≥18 years who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and admitted to one of 14 academic hospitals in the United States during March-June and October-December 2020. Demographic and clinical information were gathered from electronic health record data., Results: Among 647 patients, 91% met ≥1 of the following risk factors for severe COVID-19 [91% March-June (n = 434); 90% October-December (n = 213)]; 19% were LTCF residents, 45% were aged ≥65-years, and 84% had ≥1 high-risk condition. The proportion of patients who resided in a LTCF declined significantly (25% vs 6%) from early to later pandemic periods. Compared with patients at lower risk for severe COVID-19, in-hospital mortality was higher among patients at high risk for severe COVID-19 (20% vs 7%); these differences were consistently observed between March-June and October-December., Conclusions: Most adults hospitalized with COVID-19 were those recommended to be prioritized for vaccination based on risk for developing severe COVID-19. These findings highlight the continued urgency to vaccinate patients at high risk for severe COVID-19 and monitor vaccination impact on hospitalizations and outcomes., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Objectives: Hyperoxia is common among critically ill patients and may increase morbidity and mortality. However, limited evidence exists for critically injured patients. The objective of this study was to determine the association between hyperoxia and in-hospital mortality in adult trauma patients requiring ICU admission., Design Setting and Participants: This multicenter, retrospective cohort study was conducted at two level I trauma centers and one level II trauma center in CO between October 2015 and June 2018. All adult trauma patients requiring ICU admission within 24 hours of emergency department arrival were eligible. The primary exposure was oxygenation during the first 7 days of hospitalization., Interventions: None., Measurements and Main Results: Primary outcome was in-hospital mortality. Secondary outcomes were hospital-free days and ventilator-free days. We included 3,464 critically injured patients with a mean age of 52.6 years. Sixty-five percent were male, and 66% had blunt trauma mechanism of injury. The primary outcome of in-hospital mortality occurred in 264 patients (7.6%). Of 226,057 patient-hours, 46% were spent in hyperoxia (oxygen saturation > 96%) and 52% in normoxia (oxygen saturation 90-96%). During periods of hyperoxia, the adjusted risk for mortality was higher with greater oxygen administration. At oxygen saturation of 100%, the adjusted risk scores for mortality (95% CI) at Fio 2 of 100%, 80%, 60%, and 50% were 6.4 (3.5-11.8), 5.4 (3.4-8.6), 2.7 (1.7-4.1), and 1.5 (1.1-2.2), respectively. At oxygen saturation of 98%, the adjusted risk scores for mortality (95% CI) at Fio 2 of 100%, 80%, 60%, and 50% were 7.7 (4.3-13.5), 6.3 (4.1-9.7), 3.2 (2.2-4.8), and 1.9 (1.4-2.7), respectively., Conclusions: During hyperoxia, higher oxygen administration was independently associated with a greater risk of mortality among critically injured patients. Level of evidence: Cohort study, level III., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

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., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Christopher J. Lindsell reports grants from National Institutes of Health, U.S. Department of Defense, Marcus Foundation, Endpoint Health, Entegrion, bioMerieux, and Bioscape Digital, outside the submitted work. Jay S. Steingrub reports grants from National Institutes of Health, outside the submitted work. Akram Khan reports grants from United Therapeutics, Actelion Pharmaceuticals, Regeneron, and Reata Pharmaceuticals, outside the submitted work. Samuel M. Brown reports grants from National Institutes of Health, U.S. Department of Defense, Intermountain Research and Medical Foundation, and Janssen, and consulting fees paid to his employer from Faron and Sedana, all outside the submitted work. Ithan D. Peltan reports grants from National Institutes of Health and, outside the submitted work, grants from Asahi Kasei Pharma, Janssen Pharmaceuticals, and Regeneron. Adit A. Ginde reports grants from National Institutes of Health, U.S. Department of Defense and AbbVie, outside the submitted work. Carlos G. Grijalva reports consulting fees from Pfizer, Merck, and Sanofi-Pasteur, grants from Campbell Alliance/Syneos Health, National Institutes of Health, Food and Drug Administration, and Agency for Health Care Research and Quality, outside the submitted work. Michelle N. Gong reports grants from National Institutes of Health, Agency for Healthcare Research and Quality, and consulting fees from Regeneron, Philips Healthcare, all outside the submitted work. Steven Y. Chang reports consulting fees from PureTech Health and speaker fees from La Jolla Pharmaceuticals, both outside the submitted work. Jonathan D. Casey reports grants from National Institutes of Health, outside the submitted work. Todd W. Rice reports grants from National Institutes of Health and Endpoint Health, consulting work for Cumberland Pharmaceuticals, Inc, and Sanofi, Inc., outside the submitted work. Manjusha Gaglani reports grants from CDC-Abt Associates, outside the submitted work. Emily T. Martin reports personal fees from Pfizer and grants from Merck, outside the submitted work. Anurag Malani reports shareholder of Pfizer pharmaceuticals. Arnold S. Monto reports personal fees from Sanofi Pasteur and Seqirus, outside the submitted work. Fernanda P. Silveira reports grants from Shire, Qiagen, Ansun, and Novartis, outside the submitted work. Richard K. Zimmerman reports grants from Sanofi Pasteur, outside the submitted work. Donald B. Middleton reports grants and personal fees from Pfizer and personal fees from Seqirus, Sanofi Pasteur, and GlaxoSmithKline, outside the submitted work. No other potential conflicts of interest were disclosed.

Objectives: Given finite ICU bed capacity, knowledge of ICU bed utilization during the coronavirus disease 2019 pandemic is critical to ensure future strategies for resource allocation and utilization. We sought to examine ICU census trends in relation to ICU bed capacity during the rapid increase in severe coronavirus disease 2019 cases early during the pandemic., Design: Observational cohort study., Setting: Thirteen geographically dispersed academic medical centers in the United States., Patients/subjects: We obtained daily ICU censuses from March 26 to June 30, 2020, as well as prepandemic ICU bed capacities. The primary outcome was daily census of ICU patients stratified by coronavirus disease 2019 and mechanical ventilation status in relation to ICU capacity., Interventions: None., Measurements and Main Results: Prepandemic overall ICU capacity ranged from 62 to 225 beds (median 109). During the study period, the median daily coronavirus disease 2019 ICU census per hospital ranged from 1 to 84 patients, and the daily ICU census exceeded overall ICU capacity for at least 1 day at five institutions. The number of critically ill patients exceeded ICU capacity for a median (interquartile range) of 17 (12-50) of 97 days at these five sites. All 13 institutions experienced decreases in their noncoronavirus disease ICU population, whereas local coronavirus disease 2019 cases increased. Coronavirus disease 2019 patients reached their greatest proportion of ICU capacity on April 12, 2020, when they accounted for 44% of ICU patients across all participating hospitals. Maximum ICU census ranged from 52% to 289% of overall ICU capacity, with three sites less than 80%, four sites 80-100%, five sites 100-128%, and one site 289%., Conclusions: From March to June 2020, the coronavirus disease 2019 pandemic led to ICU censuses greater than ICU bed capacity at fives of 13 institutions evaluated. These findings demonstrate the short-term adaptability of U.S. healthcare institutions in redirecting limited resources to accommodate a public health emergency., Competing Interests: Dr. Lindsell reports grants from National Institutes of Health and the Department of Defense and other support from Marcus Foundation, Endpoint Health, Entegrion, bioMerieux, and Bioscape Digital, outside the submitted work. Dr. Brown reports grants from National Institutes of Health, Department of Defense, Intermountain Research and Medical Foundation, and Janssen and consulting fees paid to his employer from Faron and Sedana, outside the submitted work. Dr. Peltan reports grants from the National Institutes of Health, Asahi Kasei Pharma, Immunexpress Inc., Janssen Pharmaceuticals, and Regeneron, outside the submitted work. Dr. Rice reports grants from the National Institutes of Health, personal fees from Cumberland Pharmaceuticals, Inc, Cytovale, Inc, and Avisa, LLC, outside the submitted work. Dr. Henning reports personal fees from CytoVale and grants from Baxter, outside the submitted work. Dr. Self reports research funding for the current work from the Centers for Disease Control and Prevention. Dr. Ginde reports grants from the National Institutes of Health and Department of Defense, outside the submitted work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: The United States currently has more confirmed cases of COVID-19 than any other country in the world. Given the variability in COVID-19 testing and prevention capability, identifying factors associated with mortality in patients requiring mechanical ventilation is critical. This study aimed to identify which demographics, comorbidities, markers of disease progression, and interventions are associated with 30-day mortality in COVID-19 patients requiring mechanical ventilation., Methods: Adult patients with a confirmed diagnosis of COVID-19 admitted to one of the health system's intensive care units and requiring mechanical ventilation between March 9, 2020 and April 1, 2020, were included in this observational cohort study. We used Chi-Square and Mann-Whitney U tests to compare patient characteristics between deceased and living patients and multiple logistic regression to assess the association between independent variables and the likelihood of 30-day mortality., Results: We included 85 patients, of which 20 died (23.5%) within 30 days of the first hospital admission. In the univariate analysis, deceased patients were more likely ≥60 years of age (p < 0.001), non-Hispanic (p = 0.026), and diagnosed with a solid malignant tumor (p = 0.003). Insurance status also differed between survivors and non-survivors (p = 0.019). Age ≥60 and malignancy had a 9.5-fold (95% confidence interval 1.4-62.3, p = 0.020) and 5.8-fold higher odds ratio (95% confidence interval 1.2-28.4, p = 0.032) for 30-day mortality after adjusted analysis using multivariable logistic regression, while other independent variables were no longer significant., Conclusions: In our observational cohort study of 85 mechanically ventilated COVID-19 patients, age, and a diagnosis of a solid malignant tumor were associated with 30-day mortality. Our findings validate concerns for the survival of elderly and cancer patients in the face of the COVID-19 pandemic in the United States, where testing capabilities and preventative measures have been inconsistent. Preventative efforts geared to patients at risk for intensive care unit mortality from COVID-19 should be explored.

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness., Objective: To test whether tocilizumab decreases mortality in this population., Design, Setting, and Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding., Exposures: Treatment with tocilizumab in the first 2 days of ICU admission., Main Outcomes and Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences., Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%)., Conclusions and Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.

Competing Interests: Conflict of Interest None.

Background: Patients diagnosed with COVID-19 frequently require mechanical ventilation. Knowledge of laboratory tests associated with the prolonged need for mechanical ventilation may guide resource allocation. We hypothesized that an elevated plasma procalcitonin level (>0.1 ng/ml) would be associated with the duration of invasive mechanical ventilation., Methods: Patients diagnosed with COVID-19, who were admitted to any of our health system's hospitals between March 9th-April 20th, 2020 and required invasive mechanical ventilation, were eligible for this observational cohort study. Demographics, comorbidities, components of the Sequential Organ Failure Assessment score, and procalcitonin levels on admission were obtained from the electronic health record. The primary outcome was the duration of mechanical ventilation; secondary outcomes included 28-day mortality and time to intubation. Outcomes were assessed within the first 28 days of admission. Baseline demographics and comorbidities were summarized by descriptive statistics. Univariate comparisons were made using Pearson's chi-square test for binary outcomes and Mann-Whitney U test for continuous outcomes. A multiple linear regression was fitted to assess the association between procalcitonin levels and the duration of mechanical ventilation., Results: Patients with an initial procalcitonin level >0.1 ng/ml required a significantly longer duration of mechanical ventilation than patients with a level of ≤0.1 ng/ml (p = 0.021) in the univariate analysis. There was no significant difference in 28-day mortality or time to intubation between the two groups. After adjusted analysis using multivariable linear regression, the duration of mechanical ventilation was, on average, 5.6 (p = 0.016) days longer in patients with an initial procalcitonin level >0.1 ng/ml., Conclusion: In this cohort of 93 mechanically ventilated COVID-19 patients, we found an association between an initial plasma procalcitonin level >0.1 ng/ml and the duration of mechanical ventilation. These findings may help to identify patients at risk for prolonged mechanical ventilation upon admission., Competing Interests: Dr. Muhammad Aftab is a consultant and has received research devices support (non-monetary) for W.L. Gore and Associates (Newark, DE). He is also a consultant for LivaNova, PLC (London, England). This does not alter our adherence to PLOS ONE policies on sharing data and materials. Otherwise, the authors declare that they have no competing interests.