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Rationale: Acute lung injury (ALI) is a debilitating condition associated with severe skeletal muscle weakness that persists in humans long after lung injury has resolved. The molecular mechanisms underlying this condition are unknown.Objectives: To identify the muscle-specific molecular mechanisms responsible for muscle wasting in a mouse model of ALI.Methods: Changes in skeletal muscle weight, fiber size, in vivo contractile performance, and expression of mRNAs and proteins encoding muscle atrophy-associated genes for muscle ring finger-1 (MuRF1) and atrogin1 were measured. Genetic inactivation of MuRF1 or electroporation-mediated transduction of miRNA-based short hairpin RNAs targeting either MuRF1 or atrogin1 were used to identify their role in ALI-associated skeletal muscle wasting.Measurements and Main Results: Mice with ALI developed profound muscle atrophy and preferential loss of muscle contractile proteins associated with reduced muscle function in vivo. Although mRNA expression of the muscle-specific ubiquitin ligases, MuRF1 and atrogin1, was increased in ALI mice, only MuRF1 protein levels were up-regulated. Consistent with these changes, suppression of MuRF1 by genetic or biochemical approaches prevented muscle fiber atrophy, whereas suppression of atrogin1 expression was without effect. Despite resolution of lung injury and down-regulation of MuRF1 and atrogin1, force generation in ALI mice remained suppressed.Conclusions: These data show that MuRF1 is responsible for mediating muscle atrophy that occurs during the period of active lung injury in ALI mice and that, as in humans, skeletal muscle dysfunction persists despite resolution of lung injury. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective cohort study., Objective: To characterize variation in dexamethasone and remdesivir use over time among hospitals., Background: Little is known about hospital-level variation in COVID-19 drug treatments in a large and diverse network in the United States., Methods: We selected individuals hospitalized with COVID-19 across 163 hospitals between February 23, 2020 and October 31, 2021 from using the HCA CHARGE, an electronic health record repository from a network of community health care facilities in the United States. We quantified receipt of dexamethasone, remdesivir, and combined use of dexamethasone and remdesivir during the hospital stay. We used 2-level logistic regression models to determine the intraclass correlation coefficient (ICC) at the hospital level, adjusting for patient and hospital characteristics. The ICC shows the proportion of total variation in drug use accounted for by hospitals., Results: Among 161,667 individuals hospitalized with COVID-19, 73.0% were treated with dexamethasone, 49.1% with remdesivir, and 45.0% with both dexamethasone and remdesivir. The proportion of variation in dexamethasone use was 12.7% (adjusted ICC: 0.127), 8.5% for remdesivir, and 11.3% for combined drug use, indicating low interhospital variation. In the fully adjusted models, between-facility variation in dexamethasone use declined from 34.1% in February-March 2020 to 11.3% in January-March 2021 and then increased to 17.3% in July-October 2021. The variation in remdesivir use remained relatively stable during the study period., Conclusions: During the first 2 years of the pandemic, there was relatively consistent use of dexamethasone and remdesivir across the hospitals examined. Consistent adoption and implementation of treatment guidelines across the hospitals examined may have led to a decrease in variation in drug usage over time., Competing Interests: K.M.A. was supported by a National Heart, Lung, and Blood Institute Pharmacoepidemiology T32 Training Program (T32HL139426). After the completion of her involvement in this work, she joined Pfizer Inc. as a full-time employee and holds stock in Pfizer Inc. B.T.G. reports receiving funding from the John Templeton Foundation. Also, is a member of the FDA Pulmonary-Asthma Drug Advisory Committee, and reports personal fees from Janssen Research and Development LLC, Gilead Sciences Inc, and Atea Pharmaceuticals. H.B.M. was supported by the National Institute on Aging (K01 AG070329). G.C.A. is the past Chair of the U.S. Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee and a co-founding Principal and equity holder in Stage Analytics. A.W.W. reports personal fees from Gore and grants to the institution from Genentech and Pfizer. J.F.B. reports equity and entitlement to future royalties from miDiagnostics. These arrangements have been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. The remaining authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with diabetes have higher mortality from COVID-19 compared to the general population. Dexamethasone, a potent glucocorticoid used for moderate to severe COVID-19, can worsen hyperglycemia in patients with diabetes, potentially leading to worse outcomes. The efficacy and safety of use of dexamethasone for COVID-19 in patients with diabetes needs further evaluation., Objective: The study aimed to assess the efficacy and safety of dexamethasone in patients with diabetes hospitalized for COVID-19 infection., Design: This retrospective study analyzed data from five hospitals in the Johns Hopkins Health System (JHHS) collected between March 3, 2020 and June 25, 2022. Propensity score matching was applied to a cohort of patients with diabetes who received dexamethasone and those who did not (controls), and outcomes were compared using Cox proportional hazards regression models., Outcomes: The primary outcome was time to death within 28 days. The secondary outcome was time to clinical improvement. Additional outcomes included the incidence of hyperglycemic emergencies and subgroup analysis of primary outcomes by clinical severity., Results: Out of 10,329 patients admitted for COVID-19, 3,679 had diabetes, and 2,361 met the inclusion criteria. After propensity score matching, 529 patients were analyzed in each group. Survival rates between the dexamethasone and control groups during the 0-6 day and 7-28-day periods and time to clinical improvement at 28 days did not differ significantly. There was no difference in the incidence of diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS) between the groups., Conclusion: Dexamethasone treatment did not significantly improve survival or time to clinical improvement in patients with diabetes and COVID-19 infection. Further prospective studies are needed to confirm these findings and determine potential mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Few studies have assessed the ability of internal medicine residents to perform a cardiovascular physical examination using real patients., Methods: First year internal medicine interns from 2 large academic medical centers in Maryland examined the same patient with aortic insufficiency as part of the Assessment of Physical Examination and Communication Skills (APECS). Interns were assessed on 5 clinical domains: physical exam technique, identifying physical signs, generating a differential diagnosis, clinical judgment, and maintaining patient welfare. Spearman's correlation test was used to describe associations between clinical domains. Preceptor comments were examined to identify common errors in physical exam technique and identifying physical signs., Results: One hundred nine interns examined the same patient with aortic insufficiency across 14 APECS sessions. Only 58 interns (53.2%) correctly identified the presence of a diastolic murmur, and only 52 interns (47.7%) included aortic insufficiency on their differential diagnosis. There was a significant and positive correlation between physical exam technique and identification of the correct physical findings (r = 0.42, P < .001). Both technique (r = 0.34, P = .003) and identifying findings (r = 0.42, P < .001) were significantly associated with generating an appropriate differential diagnosis. Common errors in technique included auscultating over the gown, timing the cardiac cycle with the radial pulse, and failing to palpate for the apical impulse., Conclusions: Internal medicine interns had variable skills in performing and interpreting the cardiovascular physical exam. Improving cardiovascular exam skills would likely lead to increased identification of relevant cardiovascular findings, inform clinical decision making and improve overall patient care., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In response to the growing number of outbreaks of emerging infectious diseases, the US Administration for Strategic Preparedness and Response (ASPR) has embarked on a plan to improve and expand special pathogen patient care capabilities. To achieve this, ASPR is developing a coordinated network of Regional Emerging Special Pathogen Treatment Centers (RESPTCs) to serve as state-of-the-art facilities staffed by a highly trained workforce to care for and manage special pathogen patients across the lifespan. The RESPTC network represents the operational arm of a broader US National Special Pathogen System of care to prevent and prepare for the next infectious disease outbreak. RESPTCs are strategically located in every region across the country and form a network linking local and regional healthcare partners to enhance national preparedness through training in best practices for detection, isolation, and treatment of individuals suspected of or known to be infected with a special pathogen. This local, regional, and national network is also designed to lead a coordinated response that includes the dissemination of accurate and trustworthy information to responders and the public. The overarching goal of the RESPTCs is to serve as a valuable resource for clinical care, training, and material support to meet current and future major infectious diseases challenges. In this case study, 2 new RESPTCs, MedStar Washington Hospital Center and the University of North Carolina, describe their experiences related to designing a biocontainment unit, creating clinical teams, building staff resiliency, receiving mentoring from regional RESPTC partners, and developing opportunities for innovation.

Abstract: A central goal of precision education (PE) is efficiently delivering the right educational intervention to the right learner at the right time. This can be achieved through a PE cycle that involves gathering inputs, using analytics to generate insights, planning and implementing interventions, learning and assessing outcomes, and then using lessons learned to inform modifications to the cycle. In this paper, the authors describe 3 PE initiatives utilizing this cycle. The Graduate Medical Education Laboratory (GEL) uses longitudinal data on graduate trainee behavior, clinical skills, and wellness to improve clinical performance and professional fulfillment. The Transition to Residency Advantage (TRA) program uses learner data from medical school coupled with individualized coaching to improve the transition to residency. The Anesthesia Research Group for Educational Technology (TARGET) is developing an automated tool to deliver individualized education to anesthesia residents based on a longitudinal digital representation of the learner. The authors discuss strengths of the PE cycle and transferrable learnings for future PE innovations. Common challenges are identified, including related to data (e.g., volume, variety, sharing across institutions, using the electronic health record), analytics (e.g., validating augmented intelligence models), and interventions (e.g., scaling up learner assessments with limited resources). PE developers need to share their experiences in order to overcome these challenges, develop best practices, and ensure ethical development of future systems. Adapting a common framework to develop and assess PE initiatives will lead to a clearer understanding of their impact, help to mitigate potential risks, and allow deployment of successful practices on a larger scale., (Copyright © 2023 the Association of American Medical Colleges.)

Several genetic variants linked to COVID-19 have been identified by host genomics researchers. Further advances in this research will likely play a role in the clinical management and public health control of future infectious disease outbreaks. The implementation of genetic testing to identify host genomic risk factors associated with infectious diseases raises several ethical, legal, and social implications (ELSIs). As an important stakeholder group, health professionals can provide key insights into these ELSI issues. In 2021, a cross-sectional online survey was fielded to US health professionals. The survey explored how they view the value and ethical acceptability of using COVID-19 host genomic information in three main decision-making settings: (1) clinical, (2) public health, and (3) workforce. The survey also assessed participants' personal and professional experience with genomics and infectious diseases and collected key demographic data. A total of 603 participants completed the survey. A majority (84%) of participants agreed that it is ethically acceptable to use host genomics to make decisions about clinical care and 73% agreed that genetic screening has an important role to play in the public health control of COVID-19. However, more than 90% disagreed that it is ethically acceptable to use host genomics to deny resources or admission to individuals when hospital resources are scarce. Understanding stakeholder perspectives and anticipating ELSI issues will help inform policies for hospitals and public health departments to evaluate and perhaps adopt host genomic technologies in an ethically and socially responsible manner during future infectious disease outbreaks., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Healthcare workers (HCWs) at community hospitals, also known as frontline hospitals (FLHs), may encounter patients with possible infectious diseases, including those caused by high-consequence pathogens such as Zaire ebolavirus. We created and piloted a 1-day, in-person, didactic and skills training program to determine the feasibility and acceptability of implementing an educational program to enhance the knowledge and skills needed to respond when a patient with a potential high-consequence pathogen presents to an FLH. The Maryland Department of Health queried all 104 state FLHs to identify their interest in participating in the pilot training program. HCWs from 12 (75%) of the 16 interested FLHs participated in the program before it was interrupted by the COVID-19 pandemic. In addition to pathogen-specific training based on the Identify, Isolate, and Inform framework, we provided skills training in the proper use of personal protective equipment, spill cleanup, and removal of an incapacitated HCW from an isolation area. We conducted a paired pretraining and posttraining knowledge assessment and measured a significant learning gain among 135 participants (2-tailed t test, P <.05). Over 95% of the participants reported that the training was relevant to their daily work and the clinical simulations and reference material were useful and appropriate for their learning level. Findings from this pilot program demonstrated the feasibility and acceptability of a 1-day combined didactic and skills training program focused on high-consequence pathogens. We plan to reengage the original FLHs and add regional FLHs in an updated training effort based on our findings.

Study Objective: To estimate the prevalence of potential moderate to severe drug-drug interactions (DDIs) involving nirmatrelvir/ritonavir, identify interacting medications, and evaluate risk factors associated with potential DDIs., Design: Cross-sectional study., Data Source: Electronic health records from the National COVID Cohort Collaborative Enclave, one of the largest COVID-19 data resources in the United States., Patients: Outpatients aged ≥18 years and started nirmatrelvir/ritonavir between December 23, 2021 and March 31, 2022., Intervention: Nirmatrelvir/ritonavir., Measurements: The outcome is potential moderate to severe DDIs, defined as starting interacting medications reported by National Institutes of Health 30 days before or 10 days after starting nirmatrelvir/ritonavir., Main Results: Of 3214 outpatients who started nirmatrelvir/ritonavir, the mean age was 56.8 ± 17.1 years, 39.5% were male, and 65.8% were non-Hispanic white. Overall, 521 (16.2%) were potentially exposed to at least one moderate to severe DDI, most commonly to atorvastatin (19.2% of all DDIs), hydrocodone (14.0%), or oxycodone (14.0%). After adjustment for covariates, potential DDIs were more likely among individuals who were older (odds ratio [OR] 1.16 per 10-year increase, 95% confidence interval [CI] 1.08-1.25), male (OR 1.36, CI 1.09-1.71), smokers (OR 1.38, CI 1.10-1.73), on more co-medications (OR 1.35, CI 1.31-1.39), and with a history of solid organ transplant (OR 3.63, CI 2.05-6.45)., Conclusions: One in six of individuals receiving nirmatrelvir/ritonavir were at risk of a potential moderate or severe DDI, underscoring the importance of clinical and pharmacy systems to mitigate such risks., (© 2023 Pharmacotherapy Publications, Inc.)

As disasters increase in frequency and severity, so too does the health impact on affected populations. Disasters exacerbate the already challenging health information-sharing landscape. A reduced capacity to access and share patient information may have negative impacts on providers' ability to care for patients individually and to address disaster health outcomes at the population level. Between October 2018 and July 2019, we conducted 21 semistructured interviews with physicians experienced in providing healthcare during disasters to understand the challenges related to patient information sharing in disaster responses. Key informants noted challenges with patient information management-including accessing, sharing, and transferring information-and that it was a barrier to providing effective clinical care in disasters. Three major areas were identified as challenges: (1) lack of systematic mechanisms for patient information sharing during disaster handoffs, (2) lack of access to a patient's past medical history, and (3) population-level impacts of patient information-sharing breakdowns in disasters. Reducing barriers to effective patient information sharing is a critical need during disasters. Requirements generally fall to overburdened clinicians, and novel solutions that ease this responsibility and leverage existing infrastructure should be explored. Work conducted during the COVID-19 pandemic may inform new solutions. Integrated approaches that support information sharing in real time will improve patient care at the individual level and can support operational improvements to current and future disaster responses.

Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2345.

Rationale & Objective: Patients hospitalized with COVID-19 are at increased risk for major adverse kidney events (MAKE). We sought to identify plasma biomarkers predictive of MAKE in patients hospitalized with COVID-19., Study Design: Prospective cohort study., Setting & Participants: A total of 576 patients hospitalized with COVID-19 between March 2020 and January 2021 across 3 academic medical centers., Exposure: Twenty-six plasma biomarkers of injury, inflammation, and repair from first available blood samples collected during hospitalization., Outcome: MAKE, defined as KDIGO stage 3 acute kidney injury (AKI), dialysis-requiring AKI, or mortality up to 60 days., Analytical Approach: Cox proportional hazards regression to associate biomarker level with MAKE. We additionally applied the least absolute shrinkage and selection operator (LASSO) and random forest regression for prediction modeling and estimated model discrimination with time-varying C index., Results: The median length of stay for COVID-19 hospitalization was 9 (IQR, 5-16) days. In total, 95 patients (16%) experienced MAKE. Each 1 SD increase in soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 was significantly associated with an increased risk of MAKE (adjusted HR [AHR], 2.30 [95% CI, 1.86-2.85], and AHR, 2.26 [95% CI, 1.73-2.95], respectively). The C index of sTNFR1 alone was 0.80 (95% CI, 0.78-0.84), and the C index of sTNFR2 was 0.81 (95% CI, 0.77-0.84). LASSO and random forest regression modeling using all biomarkers yielded C indexes of 0.86 (95% CI, 0.83-0.89) and 0.84 (95% CI, 0.78-0.91), respectively., Limitations: No control group of hospitalized patients without COVID-19., Conclusions: We found that sTNFR1 and sTNFR2 are independently associated with MAKE in patients hospitalized with COVID-19 and can both also serve as predictors for adverse kidney outcomes., Plain-Language Summary: Patients hospitalized with COVID-19 are at increased risk for long-term adverse health outcomes, but not all patients suffer long-term kidney dysfunction. Identification of patients with COVID-19 who are at high risk for adverse kidney events may have important implications in terms of nephrology follow-up and patient counseling. In this study, we found that the plasma biomarkers soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 measured in hospitalized patients with COVID-19 were associated with a greater risk of adverse kidney outcomes. Along with clinical variables previously shown to predict adverse kidney events in patients with COVID-19, both sTNFR1 and sTNFR2 are also strong predictors of adverse kidney outcomes., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Many pulse oximeters have been shown to overestimate oxygen saturation in persons of color, and this phenomenon has potential clinical implications. The relationship between overestimation of oxygen saturation with timing of COVID-19 medication delivery and clinical outcomes remains unknown., Objective: To investigate the association between overestimation of oxygen saturation by pulse oximetry and delay in administration of COVID-19 therapy, hospital length of stay, risk of hospital readmission, and in-hospital mortality., Design, Setting, and Participants: This cohort study included patients hospitalized for COVID-19 at 186 acute care facilities in the US with at least 1 functional arterial oxygen saturation (SaO2) measurement between March 2020 and October 2021. A subset of patients were admitted after July 1, 2020, without immediate need for COVID-19 therapy based on pulse oximeter saturation (SpO2 levels of 94% or higher without supplemental oxygen)., Exposures: Self-reported race and ethnicity, difference between concurrent SaO2 and pulse oximeter saturation (SpO2) within 10 minutes, and initially unrecognized need for COVID-19 therapy (first SaO2 reading below 94% despite SpO2 levels of 94% or above)., Main Outcome and Measures: The association of race and ethnicity with degree of pulse oximeter measurement error (SpO2 - SaO2) and odds of unrecognized need for COVID-19 therapy were determined using linear mixed-effects models. Associations of initially unrecognized need for treatment with time to receipt of therapy (remdesivir or dexamethasone), in-hospital mortality, 30-day hospital readmission, and length of stay were evaluated using mixed-effects models. All models accounted for demographics, clinical characteristics, and hospital site. Effect modification by race and ethnicity was evaluated using interaction terms., Results: Among 24 504 patients with concurrent SpO2 and SaO2 measurements (mean [SD] age, 63.9 [15.8] years; 10 263 female [41.9%]; 3922 Black [16.0%], 7895 Hispanic [32.2%], 2554 Asian, Native American or Alaskan Native, Hawaiian or Pacific Islander, or another race or ethnicity [10.4%], and 10 133 White [41.4%]), pulse oximetry overestimated SaO2 for Black (adjusted mean difference, 0.93 [95% CI, 0.74-1.12] percentage points), Hispanic (0.49 [95% CI, 0.34-0.63] percentage points), and other (0.53 [95% CI, 0.35-0.72] percentage points) patients compared with White patients. In a subset of 8635 patients with a concurrent SpO2 - SaO2 pair without immediate need for COVID-19 therapy, Black patients were significantly more likely to have pulse oximetry values that masked an indication for COVID-19 therapy compared with White patients (adjusted odds ratio [aOR], 1.65; 95% CI, 1.33-2.03). Patients with an unrecognized need for COVID-19 therapy were 10% less likely to receive COVID-19 therapy (adjusted hazard ratio, 0.90; 95% CI, 0.83-0.97) and higher odds of readmission (aOR, 2.41; 95% CI, 1.39-4.18) regardless of race (P for interaction = .45 and P = .14, respectively). There was no association of unrecognized need for COVID-19 therapy with in-hospital mortality (aOR, 0.84; 95% CI, 0.71-1.01) or length of stay (mean difference, -1.4 days; 95% CI, -3.1 to 0.2 days)., Conclusions and Relevance: In this cohort study, overestimation of oxygen saturation by pulse oximetry led to delayed delivery of COVID-19 therapy and higher probability of readmission regardless of race. Black patients were more likely to have unrecognized need for therapy with potential implications for population-level health disparities.

Objectives: The gastrointestinal (GI) physical exam provides critical information about underlying disease states. However, since assessment of physical examination skills is rarely conducted as part of internal medicine residency training, little is known about resident performance on the GI physical exam., Methods: During a clinical skills assessment that took place between November 2019 and February 2020, internal medicine interns examined the same patient with chronic liver disease while being observed by faculty preceptors. We compared the exam maneuvers performed with those expected by the faculty evaluators. We noted which maneuvers were performed incorrectly, whether physical exam technique correlated with identification of physical exam findings, and if performance on the physical exam was associated with building an appropriate differential diagnosis. This four-hour assessment was required for internal medicine interns within two different residency programs in the Baltimore area., Results: More than half of the 29 participating interns (n=17, 58.6 %) received a "needs improvement" score on their physical exam technique. Technique was highly correlated with identifying the correct physical signs (r=0.88, p<0.0001). The most commonly excluded maneuvers were assessing for splenomegaly and hepatomegaly. The most commonly missed findings were splenomegaly and hepatomegaly. Most interns included chronic liver disease as part of their differential diagnosis even if they received "needs improvement" scores on physical exam technique or identifying physical signs., Conclusions: Internal medicine interns would benefit from learning an organized approach to the gastrointestinal exam. This would likely lead to increased identification of important gastrointestinal findings., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Prior observation has shown differences in COVID-19 hospitalization risk between SARS-CoV-2 variants, but limited information describes hospitalization outcomes., Methods: Inpatients with COVID-19 at 5 hospitals in the eastern United States were included if they had hypoxia, tachypnea, tachycardia, or fever, and SARS-CoV-2 variant data, determined from whole-genome sequencing or local surveillance inference. Analyses were stratified by history of SARS-CoV-2 vaccination or infection. The average effect of SARS-CoV-2 variant on 28-day risk of severe disease, defined by advanced respiratory support needs, or death was evaluated using models weighted on propensity scores derived from baseline clinical features., Results: Severe disease or death within 28 days occurred for 977 (29%) of 3369 unvaccinated patients and 269 (22%) of 1230 patients with history of vaccination or prior SARS-CoV-2 infection. Among unvaccinated patients, the relative risk of severe disease or death for Delta variant compared with ancestral lineages was 1.30 (95% confidence interval [CI]: 1.11-1.49). Compared with Delta, the risk for Omicron patients was .72 (95% CI: .59-.88) and compared with ancestral lineages was .94 (.78-1.1). Among Omicron and Delta infections, patients with history of vaccination or prior SARS-CoV-2 infection had half the risk of severe disease or death (adjusted hazard ratio: .40; 95% CI: .30-.54), but no significant outcome difference by variant., Conclusions: Although risk of severe disease or death for unvaccinated inpatients with Omicron was lower than with Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients, with no difference between Delta and Omicron infections., Competing Interests: Potential conflicts of interest. The Maryland Department of Health collaborates for research with BioRad, Hologic, and DiaSorin. J. B. has equity/entitlement to future royalties in miDiagnostics. B. T. G. is a member of the Food and Drug Administration (FDA) Pulmonary-Asthma Drug Advisory Committee and a board member of the Society of Bedside Medicine and has received consulting fees from Janssen Research and Development, LLC (related to vaccine trial case adjudication); Gilead Sciences, Inc (related to COVID therapeutics); and Atea Pharmaceuticals, Inc (related to COVID therapeutics). R. B. is a consultant for Merck & Co and Hologic. R. B. also reports royalties or licenses from emocha Health, support for attending meetings and/or travel from Hologic, and participation on a Data Safety Monitoring Board or Advisory Board for Merck. H. H. M. reports the following grants or contracts unrelated to this work: National Institutes of Health (NIH) UM1AI0686, NIH UM1 AI068613-14, NIH R01 DA045556-04S1, NIH 3U54HL143541-02S2, NIH 4UH3CA211396-03, and NIH R01 CA243393 and receipt of equipment, materials, drugs, medical writing, gifts, or other services related to research contract from BioRad, DiaSorin, and Hologic. D. C. G. reports grants or contracts unrelated to this work from Illumina, Inc; IDbyNDA, Inc; and Fisher Center Discovery Program, Johns Hopkins; consulting fees from bioMerieux, Inc; and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from the American Association of Clinical Chemistry and Pan American Society of Clinical Virology. A. G. reports unrelated grants or contracts from NIH and Unitaid and the Centers for Disease Control and Prevention (CDC); participation on an NIH/NIAID Advisory Council and Indo US Science Technology Governing Board; and roles on the IMPAACT Network TB Scientific Committee and World Health Organization (WHO) MDR TB Guidelines Committee. M. L. R. reports grants or contracts unrelated to this work from Critical Path Institute/FDA, paid to their institution. S. L. Z. reports the following grants or contracts unrelated to this work: 1R01AR073208-01 (Shah) (1 April 2018–31 March 2023), NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Autoantibodies Define Scleroderma Subgroups with Distinct Relationships to Cancer; UL1TR003098 (Ford) (1 June 2019–30 April 2024), NIH/National Center for Advancing Translational Sciences (NCATS), Johns Hopkins Institutional Clinical and Translational Science Award. S. L. Z. also reports a role as Co-Director for Data Science, JHM inHealth Precision Medicine (paid to their institution). These conflicts of interest are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies. 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) 2022. 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: People with disabilities might experience worse clinical outcomes of SARS-CoV-2 infection, but evidence is limited., Objective: To investigate if people with disabilities requiring assistance are more likely to experience severe COVID-19 or death., Methods: Data from the Johns Hopkins COVID-19 Precision Medicine Analytics Platform Registry (JH-CROWN) included 6494 adult patients diagnosed with COVID-19 and admitted between March 4, 2020-October 29, 2021. Severe COVID-19 and death were defined using the occurrence and timing of clinical events. Assistive needs due to disabilities were reported by patients or their proxies upon admission. Multivariable-adjusted Cox proportional hazards models were used to examine the associations between disability status and severe COVID-19 or death. Primary models adjusted for demographics and secondary models additionally adjusted for clinical covariates., Results: In this clinical cohort (47-73 years, 49% female, 39% Black), patients with disabilities requiring assistance had 1.35 times (95% confidence interval [CI]:1.01, 1.81) the hazard of severe COVID-19 among patients <65 years, but not among those ≥65 years, equating to an additional 17.5 severe COVID-19 cases (95% CI:7.7, 28.2) per 100 patients. A lower risk of mortality was found among patients <65 years, but this finding was not robust due to the small number of deaths., Conclusions: People with disabilities requiring assistance aged <65 years are more likely to develop severe COVID-19. Although our study is limited by using a medical model of disability, these analyses intend to further our understanding of COVID-19 outcomes among people with disabilities. Also, standardized disability data collection within electronic health records is needed., Competing Interests: Conflicts of interest Mr. Betz reported equity and entitlement to future royalties from miDiagnostics. Dr. Reed reported membership on the advisory board of Neosensory. Dr. Garibaldi reported consulting fees from Janssen Research and Development, LLC, Gilead Sciences Inc, and Atea Pharmaceuticals Inc, and is also a member of the FDA Pulmonary-Asthma Drug Advisory Committee. Dr. Swenor is an advisor to the Innovation and Value Initiative. No other disclosures were reported., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

As clinicians are faced with a deluge of clinical data, data science can play an important role in highlighting key features driving patient outcomes, aiding in the development of new clinical hypotheses. Insight derived from machine learning can serve as a clinical support tool by connecting care providers with reliable results from big data analysis that identify previously undetected clinical patterns. In this work, we show an example of collaboration between clinicians and data scientists during the COVID-19 pandemic, identifying sub-groups of COVID-19 patients with unanticipated outcomes or who are high-risk for severe disease or death. We apply a random forest classifier model to predict adverse patient outcomes early in the disease course, and we connect our classification results to unsupervised clustering of patient features that may underpin patient risk. The paradigm for using data science for hypothesis generation and clinical decision support, as well as our triaged classification approach and unsupervised clustering methods to determine patient cohorts, are applicable to driving rapid hypothesis generation and iteration in a variety of clinical challenges, including future public health crises., (© 2023. The Author(s).)

COVID-19 continues to be a major source of global morbidity and mortality. It abruptly stressed healthcare systems early in 2020 and the pressures continue. Devastating hardships have been endured by individuals, families and communities; the losses will be felt for years to come. As healthcare professionals and organisations stepped up to respond to the overwhelming number of cases, it is understandable that the focus has been primarily on coping with the quantity of the demand. During a pandemic, it is not surprising that few papers have drawn attention to the quality of the care delivered to those afflicted with illness. Despite the challenges, clinicians caring for patients with COVID-19 have risen to the occasion. This manuscript highlights aspirational examples from the published literature of thoughtful and superb care of patients with COVID-19 using an established framework for clinical excellence (formulated by the Miller-Coulson Academy of Clinical Excellence)., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is an urgent need to understand the real-world effectiveness of remdesivir in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Methods: This was a retrospective comparative effectiveness study. Individuals hospitalized in a large private healthcare network in the United States from 23 February 2020 through 11 February 2021 with a positive test for SARS-CoV-2 and ICD-10 diagnosis codes consistent with symptomatic coronavirus disease 2019 (COVID-19) were included. Remdesivir recipients were matched to controls using time-dependent propensity scores. The primary outcome was time to improvement with a secondary outcome of time to death., Results: Of 96 859 COVID-19 patients, 42 473 (43.9%) received at least 1 remdesivir dose. The median age of remdesivir recipients was 65 years, 23 701 (55.8%) were male, and 22 819 (53.7%) were non-White. Matches were found for 18 328 patients (43.2%). Remdesivir recipients were significantly more likely to achieve clinical improvement by 28 days (adjusted hazard ratio [aHR] 1.19, 95% confidence interval [CI], 1.16-1.22). Remdesivir patients on no oxygen (aHR 1.30, 95% CI, 1.22-1.38) or low-flow oxygen (aHR 1.23, 95% CI, 1.19-1.27) were significantly more likely to achieve clinical improvement by 28 days. There was no significant impact on the likelihood of mortality overall (aHR 1.02, 95% CI, .97-1.08). Remdesivir recipients on low-flow oxygen were significantly less likely to die than controls (aHR 0.85, 95% CI, .77-.92; 28-day mortality 8.4% [865 deaths] for remdesivir patients, 12.5% [1334 deaths] for controls)., Conclusions: These results support the use of remdesivir for hospitalized COVID-19 patients on no or low-flow oxygen. Routine initiation of remdesivir in more severely ill patients is unlikely to be beneficial., (© 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.)

Background and Objectives: Current clinical guidelines recommend thromboprophylaxis for adults hospitalized with coronavirus disease 2019 (COVID-19), yet it is unknown whether higher doses of thromboprophylaxis offer benefits beyond standard doses., Methods: We studied electronic health records from 50 091 adults hospitalized with COVID-19 in the United States between February 2020 and February 2021. We compared standard (enoxaparin 30 or 40 mg/day, fondaparinux 2.5 mg, or heparin 5000 units twice or thrice per day) versus intermediate (enoxaparin 30 or 40 mg twice daily, or up to 1.2 mg/kg of body weight daily, heparin 7500 units thrice per day or heparin 10 000 units twice or thrice per day) thromboprophylaxis. We separately examined risk of escalation to therapeutic anticoagulation, severe disease (first occurrence of high-flow nasal cannula, noninvasive positive pressure ventilation or invasive mechanical ventilation), and death. To summarize risk, we present hazard ratios (HRs) with 95% confidence intervals (CIs) using adjusted time-dependent Cox proportional hazards regression models., Results: People whose first dose was high intensity were younger, more often obese, and had greater oxygen support requirements. Intermediate dose thromboprophylaxis was associated with increased risk of therapeutic anticoagulation (HR, 3.39; 95% CI, 3.22-3.57), severe disease (HR, 1.22; 95% CI, 1.17-1.28), and death (HR, 1.37; 95% CI, 1.21-1.55). Increased risks associated with intermediate-dose thromboprophylaxis persisted in subgroup and sensitivity analyses varying populations and definitions of exposures, outcomes, and covariates., Conclusions: Our findings do not support routine use of intermediate-dose thromboprophylaxis to prevent clinical worsening, severe disease, or death among adults hospitalized with COVID-19., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Importance: Pulse oximetry guides triage and therapy decisions for COVID-19. Whether reported racial inaccuracies in oxygen saturation measured by pulse oximetry are present in patients with COVID-19 and associated with treatment decisions is unknown., Objective: To determine whether there is differential inaccuracy of pulse oximetry by race or ethnicity among patients with COVID-19 and estimate the association of such inaccuracies with time to recognition of eligibility for oxygen threshold-specific COVID-19 therapies., Design, Setting, and Participants: This retrospective cohort study of clinical data from 5 referral centers and community hospitals in the Johns Hopkins Health System included patients with COVID-19 who self-identified as Asian, Black, Hispanic, or White., Exposures: Concurrent measurements (within 10 minutes) of oxygen saturation levels in arterial blood (SaO2) and by pulse oximetry (SpO2)., Main Outcomes and Measures: For patients with concurrent SpO2 and SaO2 measurements, the proportion with occult hypoxemia (SaO2<88% with concurrent SpO2 of 92%-96%) was compared by race and ethnicity, and a covariate-adjusted linear mixed-effects model was produced to estimate the association of race and ethnicity with SpO2 and SaO2 difference. This model was applied to identify a separate sample of patients with predicted SaO2 levels of 94% or less before an SpO2 level of 94% or less or oxygen treatment initiation. Cox proportional hazards models were used to estimate differences by race and ethnicity in time to recognition of eligibility for guideline-recommended COVID-19 therapies, defined as an SpO2 level of 94% or less or oxygen treatment initiation. The median delay among individuals who ultimately had recognition of eligibility was then compared., Results: Of 7126 patients with COVID-19, 1216 patients (63 Asian [5.2%], 478 Black [39.3%], 215 Hispanic [17.7%], and 460 White [37.8%] individuals; 507 women [41.7%]) had 32 282 concurrently measured SpO2 and SaO2. Occult hypoxemia occurred in 19 Asian (30.2%), 136 Black (28.5%), and 64 non-Black Hispanic (29.8%) patients compared with 79 White patients (17.2%). Compared with White patients, SpO2 overestimated SaO2 by an average of 1.7% among Asian (95% CI, 0.5%-3.0%), 1.2% among Black (95% CI, 0.6%-1.9%), and 1.1% among non-Black Hispanic patients (95% CI, 0.3%-1.9%). Separately, among 1903 patients with predicted SaO2 levels of 94% or less before an SpO2 level of 94% or less or oxygen treatment initiation, compared with White patients, Black patients had a 29% lower hazard (hazard ratio, 0.71; 95% CI, 0.63-0.80), and non-Black Hispanic patients had a 23% lower hazard (hazard ratio, 0.77; 95% CI, 0.66-0.89) of treatment eligibility recognition. A total of 451 patients (23.7%) never had their treatment eligibility recognized, most of whom (247 [54.8%]) were Black. Among the remaining 1452 (76.3%) who had eventual recognition of treatment eligibility, Black patients had a median delay of 1.0 hour (95% CI, 0.23-1.9 hours; P = .01) longer than White patients. There was no significant median difference in delay between individuals of other racial and ethnic minority groups and White patients., Conclusions and Relevance: The results of this cohort study suggest that racial and ethnic biases in pulse oximetry accuracy were associated with greater occult hypoxemia in Asian, Black, and non-Black Hispanic patients with COVID-19, which was associated with significantly delayed or unrecognized eligibility for COVID-19 therapies among Black and Hispanic patients. This disparity may contribute to worse outcomes among Black and Hispanic patients with COVID-19.

Importance: The patient-physician clinical encounter is the cornerstone of medical training, yet residents spend as little as 12% of their time in direct patient contact., Objectives: To use a real-time locating system (RTLS) to characterize intern work experiences in the hospital, understand factors associated with time spent at patients' bedsides, and inform future interventions to increase time spent with patients., Design, Setting, and Participants: This cross-sectional study was conducted from July 1, 2018, to June 30, 2019 (ie, the academic year 2018-2019). Internal medicine residents from postgraduate year 1 (interns) at an academic medical center wore an infrared badge that recorded location and duration (eg, patient room, ward hall, physician workroom). Data were analyzed from September 1, 2020, to August 30, 2021., Main Outcomes and Measures: Main outcome was time (in minutes) at the bedside; the unit of analysis was a 24-hour intern day or interval of time within the day (eg, rounding period). Descriptive statistics are reported overall, by intern, and for 5 clinical service categories. Multilevel modeling assessed the association of intern, service, and calendar time with time spent at the bedside., Results: Data from 43 of 52 interns (82.7%) encompassing 95 275 hours of observations were included for analyses. Twenty-six interns (60.5%) were women. Interns were detected for a mean (SD) of 722.8 (194.4) minutes per 24-hour period; 13.4% of this time was spent in patient rooms (mean [SD] time, 96.8 [57.2] minutes) and 33.3% in physician workrooms (mean [SD] time, 240.9 [228.8] minutes). Mean percentage of time at the bedside during a 24-hour period varied among interns from 8.8% to 18.3%. Mean (SD) percentage of time at the bedside varied by service for the 24-hour period from 11.7% (6.6%) for nononcology subspecialties to 15.4% (6.0%) for oncology, and during rounds from 8.0% (12.4%) for nononcology subspecialties to 26.5% (12.1%) for oncology. In multilevel modeling, the individual intern accounted for 8.1% of overall variance in time spent at the bedside during a 24-hour period, and service accounted for 18.0% of variance during rounds., Conclusions and Relevance: The findings of this cross-sectional study support previous evidence suggesting that interns spend only a small proportion of time with hospitalized patients. The differences in time spent in patients' rooms among interns and during rounds constitute an opportunity to design interventions that bring trainees back to the bedside.

Background: The purpose of this research was to use direct observation of the physical examination to elucidate the role physical examination technique plays in diagnostic accuracy. Physical examination is important for quality clinical care and requires multiple interrelated skills. The relationship of physical examination technique to related skills is poorly understood. Current methods of teaching and assessing physical examination skills provide few opportunities to evaluate physical examination technique and accuracy., Methods: The authors developed a clinical examination assessment using volunteer patients and direct observation. Trained faculty preceptors rated resident performance in 7 domains: 1) physical examination technique, 2) identification of physical signs, 3) clinical communication, 4) differential diagnosis, 5) clinical judgment, 6) managing patient concerns, and 7) maintaining patient welfare. The Pearson correlation coefficient was used to determine relationships between performance in each of these domains. Data on residents' self-assessed competency in the physical examination and perceptions of feedback received during the assessment were collected., Results: From December 2018 to February 2020, 113 interns from 2 internal medicine residency programs participated in the assessment. Physical examination technique was significantly correlated with accurate identification of physical signs, differential diagnosis and clinical judgment. Time spent in graduate medical education was negatively correlated with performance. Interns more highly rated the feedback received from this assessment than traditional clinical skills feedback., Conclusions: Our findings emphasize the necessity of multi-dimensional physical examination assessment. Observed deterioration of physical examination skill during internship may reflect contemporary practice patterns, which deprioritize the physical examination. Future research on physical examination education should focus on the interface between physical examination technique and related clinical skills., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The National Emerging Special Pathogens Training and Education Center (NETEC) was established in 2015 to improve the capabilities of healthcare facilities to provide safe and effective care to patients with Ebola and other special pathogens in the United States. Through NETEC, a collaborative network of 10 Regional Emerging Special Pathogen Treatment Centers (RESPTCs) undertook readiness activities that included potential respiratory pathogens. These preparations, which took place before the COVID-19 pandemic, established a foundation of readiness that enabled RESPTCs to play a pivotal role in the US COVID-19 pandemic response. As initial COVID-19 cases were detected in the United States, RESPTCs provided essential isolation capacity, supplies, and subject matter expertise that allowed for additional time for healthcare systems to prepare. Through the Special Pathogen Research Network, RESPTCs rapidly enrolled patients into early clinical trials. During periods of high community transmission, RESPTCs provided educational, clinical, and logistical support to a wide range of healthcare and nonhealthcare settings. In this article, we describe how NETEC and the RESPTC network leveraged this foundation of special pathogen readiness to strengthen the national healthcare system's response to the COVID-19 pandemic. NETEC and the RESPTC network have proven to be an effective model that can support the national response to future emerging special pathogens.

Introduction: Over the past decade, there have been outbreaks associated with high consequence infectious diseases such as Ebola virus disease, Lassa fever, and Monkeypox. The proper handling of clinical waste from patients infected with such pathogens is critical to ensure healthcare personnel and community safety., Methods: Mock clinical waste bags were created to simulate four distinct waste streams: personal protective equipment (PPE), dry linens, wet linens, and solidified liquids. Pressure and temperature data loggers were buried in the middle of simulated waste loads to record time at a sterilization temperature of 132°C (270°F) to reduce sterilization time. We also validated super rapid biological indicators (BIs) by embedding standard BIs (48 h), rapid BIs (3 h), and super rapid BIs (24 min) within each load. Cycles were validated over a 2-day period, using a total of 36 simulated waste bags (6 bags each for PPE, dry linen, and wet linen, and 18 bags for solidified liquids)., Results: All waste bags achieved the target sterilization temperature, all BIs passed and cycle times were substantially decreased. For PPE waste processing, an estimated 15 h was saved for a 24-h period., Discussion: Default factory settings are inadequate to disinfect Category A clinical waste. Reliance on autoclave temperature readings may overestimate time at goal sterilization temperature for actual waste loads., Conclusions: The data provided by within bag data loggers and BIs allow for the optimization of autoclave parameters to increase throughput and enhance staff safety., Competing Interests: The authors have no conflicts of interest to report., (Copyright 2022, ABSA International 2022.)

Staff safety is paramount when managing an infectious disease event. However, early data from the COVID-19 pandemic suggested that staff compliance with personal protective equipment and other safety protocols was poor. In response to patient surges, many hospitals created dedicated "biomode" units to provide care for patients infected with SARS-CoV-2, the virus that causes COVID-19. To enhance staff safety on biomode units and during patient transports, our hospital created a safety officer/transport safety officer (SO/TSO) program. The first SOs/TSOs were nurses, clinical technicians, and other support staff who were redeployed from their home units when the units closed during the initial surge. During subsequent COVID-19 surges, dedicated SOs/TSOs were hired to maintain the program. SOs/TSOs provided just-in-time personal protective equipment training and helped staff safely enter and exit COVID-19 clinical units. SOs/TSOs participated in the transport of over 1,000 COVID-19 patients with no safety incidents reported. SOs/TSOs conducted safety audits throughout the hospital and observed 86% compliance with COVID-19 precautions across 32,500 activities. During contact tracing of frontline staff who became infected with SARS-CoV-2, potential deviations from COVID-19 precautions were identified in only 7.7% of cases. The SO/TSO program contributed to a culture of safety in the biomode units and helped to enhance infection prevention throughout the hospital. This program can serve as a model for other health systems during the response to the current pandemic and during future infectious disease threats.

BackgroundSome clinical features of severe COVID-19 represent blood vessel damage induced by activation of host immune responses initiated by the coronavirus SARS-CoV-2. We hypothesized autoantibodies against angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor expressed on vascular endothelium, are generated during COVID-19 and are of mechanistic importance.MethodsIn an opportunity sample of 118 COVID-19 inpatients, autoantibodies recognizing ACE2 were detected by ELISA. Binding properties of anti-ACE2 IgM were analyzed via biolayer interferometry. Effects of anti-ACE2 IgM on complement activation and endothelial function were demonstrated in a tissue-engineered pulmonary microvessel model.ResultsAnti-ACE2 IgM (not IgG) autoantibodies were associated with severe COVID-19 and found in 18/66 (27.2%) patients with severe disease compared with 2/52 (3.8%) of patients with moderate disease (OR 9.38, 95% CI 2.38-42.0; P = 0.0009). Anti-ACE2 IgM autoantibodies were rare (2/50) in non-COVID-19 ventilated patients with acute respiratory distress syndrome. Unexpectedly, ACE2-reactive IgM autoantibodies in COVID-19 did not undergo class-switching to IgG and had apparent KD values of 5.6-21.7 nM, indicating they are T cell independent. Anti-ACE2 IgMs activated complement and initiated complement-binding and functional changes in endothelial cells in microvessels, suggesting they contribute to the angiocentric pathology of COVID-19.ConclusionWe identify anti-ACE2 IgM as a mechanism-based biomarker strongly associated with severe clinical outcomes in SARS-CoV-2 infection, which has therapeutic implications.FUNDINGBill & Melinda Gates Foundation, Gates Philanthropy Partners, Donald B. and Dorothy L. Stabler Foundation, and Jerome L. Greene Foundation; NIH R01 AR073208, R01 AR069569, Institutional Research and Academic Career Development Award (5K12GM123914-03), National Heart, Lung, and Blood Institute R21HL145216, and Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Science Foundation Graduate Research Fellowship (DGE1746891).

Objectives: High-flow nasal cannula is widely used in acute hypoxemic respiratory failure due to coronavirus disease 2019, yet data regarding its effectiveness is lacking. More evidence is needed to guide patient selection, timing of high-flow nasal cannula initiation, and resource allocation. We aimed to assess time to discharge and time to death in severe coronavirus disease 2019 in patients treated with high-flow nasal cannula compared with matched controls. We also evaluated the ability of the respiratory rate-oxygenation ratio to predict progression to invasive mechanical ventilation., Design: Time-dependent propensity score matching was used to create pairs of individuals who were then analyzed in a Cox proportional-hazards regression model to estimate high-flow nasal cannula's effect on time to discharge and time to death. A secondary analysis excluded high-flow nasal cannula patients intubated within 6 hours of admission. A Cox proportional-hazards regression model was used to assess risk of invasive mechanical ventilation among high-flow nasal cannula patients stratified by respiratory rate-oxygenation., Setting: The five hospitals of the Johns Hopkins Health System., Patients: All patients who were admitted with a laboratory-confirmed diagnosis of coronavirus disease 2019 were eligible for inclusion., Interventions: None., Measurements and Main Results: High-flow nasal cannula was associated with longer median time to discharge: 10.6 days (interquartile range, 7.1-15.8 d) versus 7.8 days (interquartile range, 4.9-12.1 d). Respiratory rate-oxygenation index performed poorly in predicting ventilation or death. In the primary analysis, there was no significant association between high-flow nasal cannula and hazard of death (adjusted hazard ratio, 0.79; 95% CI, 0.57-1.09). Excluding patients intubated within 6 hours of admission, high-flow nasal cannula was associated with reduced hazard of death (adjusted hazard ratio, 0.67; 95% CI, 0.45-0.99)., Conclusions: Among unselected patients with severe coronavirus disease 2019 pneumonia, high-flow nasal cannula was not associated with a statistically significant reduction in hazard of death. However, in patients not mechanically ventilated within 6 hours of admission, high-flow nasal cannula was associated with a significantly reduced hazard of death., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Rationale & Objective: Acute kidney injury (AKI) is common in patients with coronavirus disease 2019 (COVID-19) and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. We investigated the association between urinary biomarkers and adverse kidney outcomes among patients hospitalized with COVID-19., Study Design: Prospective cohort study., Setting & Participants: Patients hospitalized with COVID-19 (n=153) at 2 academic medical centers between April and June 2020., Exposure: 19 urinary biomarkers of injury, inflammation, and repair., Outcome: Composite of KDIGO (Kidney Disease: Improving Global Outcomes) stage 3 AKI, requirement for dialysis, or death within 60 days of hospital admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings., Analytical Approach: Time-varying Cox proportional hazards regression to associate biomarker level with composite outcome., Results: Out of 153 patients, 24 (15.7%) experienced the primary outcome. Twofold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR, 1.34 [95% CI, 1.14-1.57]), monocyte chemoattractant protein (MCP-1) (HR, 1.42 [95% CI, 1.09-1.84]), and kidney injury molecule 1 (KIM-1) (HR, 2.03 [95% CI, 1.38-2.99]) were associated with highest risk of sustaining primary composite outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR, 0.61 [95% CI, 0.47-0.79]). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. The degree of kidney injury by biomarker level in COVID-19 was comparable to other settings of clinical AKI. There was evidence of subclinical AKI in COVID-19 patients based on elevated injury biomarker level in patients without clinical AKI defined by serum creatinine., Limitations: Small sample size with low number of composite outcome events., Conclusions: Urinary biomarkers are associated with adverse kidney outcomes in patients hospitalized with COVID-19 and may provide valuable information to monitor kidney disease progression and recovery., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Many individuals take long-term immunosuppressive medications. We evaluated whether these individuals have worse outcomes when hospitalised with COVID-19 compared with non-immunosuppressed individuals., Methods: We conducted a retrospective cohort study using data from the National COVID Cohort Collaborative (N3C), the largest longitudinal electronic health record repository of patients in hospital with confirmed or suspected COVID-19 in the USA, between Jan 1, 2020, and June 11, 2021, within 42 health systems. We compared adults with immunosuppressive medications used before admission to adults without long-term immunosuppression. We considered immunosuppression overall, as well as by 15 classes of medication and three broad indications for immunosuppressive medicines. We used Fine and Gray's proportional subdistribution hazards models to estimate the hazard ratio (HR) for the risk of invasive mechanical ventilation, with the competing risk of death. We used Cox proportional hazards models to estimate HRs for in-hospital death. Models were adjusted using doubly robust propensity score methodology., Findings: Among 231 830 potentially eligible adults in the N3C repository who were admitted to hospital with confirmed or suspected COVID-19 during the study period, 222 575 met the inclusion criteria (mean age 59 years [SD 19]; 111 269 [50%] male). The most common comorbidities were diabetes (23%), pulmonary disease (17%), and renal disease (13%). 16 494 (7%) patients had long-term immunosuppression with medications for diverse conditions, including rheumatological disease (33%), solid organ transplant (26%), or cancer (22%). In the propensity score matched cohort (including 12 841 immunosuppressed patients and 29 386 non-immunosuppressed patients), immunosuppression was associated with a reduced risk of invasive ventilation (HR 0·89, 95% CI 0·83-0·96) and there was no overall association between long-term immunosuppression and the risk of in-hospital death. None of the 15 medication classes examined were associated with an increased risk of invasive mechanical ventilation. Although there was no statistically significant association between most drugs and in-hospital death, increases were found with rituximab for rheumatological disease (1·72, 1·10-2·69) and for cancer (2·57, 1·86-3·56). Results were generally consistent across subgroup analyses that considered race and ethnicity or sex, as well as across sensitivity analyses that varied exposure, covariate, and outcome definitions., Interpretation: Among this cohort, with the exception of rituximab, there was no increased risk of mechanical ventilation or in-hospital death for the rheumatological, antineoplastic, or antimetabolite therapies examined., Funding: None., Competing Interests: RBM reports grants and other fees from Vitaeris/CSL Behring; other fees from the American Journal of Transplantation; and grants from Mallinckrodt, CSL Behring, Transplant Genomics, and Quark Phamaceuticals, outside the submitted work. RCP reports grants from Trasher Foundation and investigator-sponsored studies from Merck, outside the submitted work. JSi reports consulting fees from Crealta/Horizon, Medisys, Fidia, PK Med, Two Labs, Adept Field Solutions, Clinical Care Options, Clearview Healthcare Partners, Putnam Associates, Focus Forward, Navigant Consulting, Spherix, MedIQ, Jupiter Life Science, UBM, Trio Health, Medscape, WebMD, and Practice Point Communications, the National Institutes of Health, and the American College of Rheumatology; is on the speaker's bureau of Simply Speaking; receives support from OMERACT to attend their biennial meeting; serves as a member of the US Food and Drug Administration (FDA) Arthritis Advisory Committee; serves as the Chair of the Veterans Affairs Rheumatology Field Advisory Committee, is the editor and director of the UAB Cochrane; owns stock options in TPT Global Tech, Vaxart Pharmaceuticals, and Charlotte's Web Holdings, and previously owned stock options in Amarin, Viking, and Moderna Pharmaceuticals, outside the submitted work. PGA reports consulting fees from EMD Serono; has participated on a data safety monitoring board or advisory board for Humanigen; and has personal stock or stock options with Johnson and Johnson. HBM reports investigator initiated research grants from Bristol Myers Squibb. GCA is a current member and past chair of the FDA Peripheral and Central Nervous System Advisory Committee, is a co-founding principal and equity holder in Monument Analytics, a health care consultancy with clients in the life sciences industry as well as plaintiffs in opioid litigation, and is a past member of OptumRx's National Pharmacy and Therapeutics Committee. BTG is a member of the FDA Pulmonary and Asthma Drug Advisory Committee, has received speaking fees from Gilead Sciences, and consulting fees from Janssen Research and Development. All other authors declare no competing interests., (© 2021 Elsevier Ltd. All rights reserved.)

Background: It is unclear whether chronic use of immunosuppressive drugs worsens or improves the severity of coronavirus disease 2019 (COVID-19), with plausible mechanisms for both., Methods: Retrospective cohort study in 2121 consecutive adults with acute inpatient hospital admission between 4 March and 29 August 2020 with confirmed or suspected COVID-19 in a large academic health system, with adjustment for confounding with propensity score-derived stabilized inverse probability of treatment weights. Chronic immunosuppression was defined as prescriptions for immunosuppressive drugs current at the time of admission. Outcomes included mechanical ventilation, in-hospital mortality, and length of stay., Results: There were 2121 patients admitted with laboratory-confirmed (1967, 93%) or suspected (154, 7%) COVID-19 during the study period, with a median age of 55 years (interquartile range, 40-67). Of these, 108 (5%) were classified as immunosuppressed before COVID-19, primarily with prednisone (>7.5 mg/day), tacrolimus, or mycophenolate mofetil. Among the entire cohort, 311 (15%) received mechanical ventilation; the median (interquartile range) length of stay was 5.2 (2.5-10.6) days, and 1927 (91%) survived to discharge. After adjustment, there were no significant differences in the risk of mechanical ventilation (hazard ratio [HR], .79; 95% confidence interval [CI], .46-1.35), in-hospital mortality (HR, .66; 95% CI, .28-1.55), or length of stay (HR, 1.16; 95% CI, .92-1.47) among individuals with immunosuppression and counterparts., Conclusions: Chronic use of immunosuppressive drugs was neither associated with worse nor better clinical outcomes among adults hospitalized with COVID-19 in one US health system., (© 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.)

The bedside encounter between a patient and physician remains the cornerstone of the practice of medicine. However, physicians and trainees spend less time in direct contact with patients and families in the modern health care system. The current pandemic has further threatened time spent with patients. This lack of time has led to a decline in clinical skills and a decrease in the number of faculty members who are confident in teaching at the bedside. We offer several strategies to get physicians and trainees back to the bedside to engage in clinical skills teaching and assessment. We recommend that providers pause before bedside encounters to be present with patients and learners and to develop clear goals for a bedside teaching session. We suggest that clinical teachers practice an evidence-based approach, which includes an hypothesis-driven physical examination. We encourage the use of point-of-care technology to assist in diagnosis and to allow learners to calibrate traditional physical examination skills with real-time visualization of disease. Tools like point-of-care ultrasound can be powerful levers to get learners excited about bedside teaching and to engage patients in their clinical care. We value telemedicine visits as unique opportunities to engage with patients in their home environment and to participate in patient-directed physical examination maneuvers. Finally, we recommend that educators provide feedback to learners on specific clinical examination skills, whether in the clinic, the wards, or during dedicated clinical skills assessments., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no competing interest.

Background: Relatively little is known about the use patterns of potential pharmacologic treatments of COVID-19 in the United States., Objective: To use the National COVID Cohort Collaborative (N3C), a large, multicenter, longitudinal cohort, to characterize the use of hydroxychloroquine, remdesivir, and dexamethasone, overall as well as across individuals, health systems, and time., Design: Retrospective cohort study., Setting: 43 health systems in the United States., Participants: 137 870 adults hospitalized with COVID-19 between 1 February 2020 and 28 February 2021., Measurements: Inpatient use of hydroxychloroquine, remdesivir, or dexamethasone., Results: Among 137 870 persons hospitalized with confirmed or suspected COVID-19, 8754 (6.3%) received hydroxychloroquine, 29 272 (21.2%) remdesivir, and 53 909 (39.1%) dexamethasone during the study period. Since the release of results from the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial in mid-June, approximately 78% to 84% of people who have had invasive mechanical ventilation have received dexamethasone or other glucocorticoids. The use of hydroxychloroquine increased during March 2020, peaking at 42%, and started declining by April 2020. By contrast, remdesivir and dexamethasone use gradually increased over the study period. Dexamethasone and remdesivir use varied substantially across health centers (intraclass correlation coefficient, 14.2% for dexamethasone and 84.6% for remdesivir)., Limitation: Because most N3C data contributors are academic medical centers, findings may not reflect the experience of community hospitals., Conclusion: Dexamethasone, an evidence-based treatment of COVID-19, may be underused among persons who are mechanically ventilated. The use of remdesivir and dexamethasone varied across health systems, suggesting variation in patient case mix, drug access, treatment protocols, and quality of care., Primary Funding Source: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute; and National Institute on Aging.

Longitudinal trajectories of vital signs and biomarkers during hospital admission of patients with COVID-19 remain poorly characterized despite their potential to provide critical insights about disease progression. We studied 1884 patients with severe acute respiratory syndrome coronavirus 2 infection from April 3, 2020, to June 25, 2020, within 1 Maryland hospital system and used a retrospective longitudinal framework with linear mixed-effects models to investigate relevant biomarker trajectories leading up to 3 critical outcomes: mechanical ventilation, discharge, and death. Trajectories of 4 vital signs (respiratory rate, ratio of oxygen saturation (Spo2) to fraction of inspired oxygen (Fio2), pulse, and temperature) and 4 laboratory values (C-reactive protein (CRP), absolute lymphocyte count (ALC), estimated glomerular filtration rate, and D-dimer) clearly distinguished the trajectories of patients with COVID-19. Before any ventilation, log(CRP), log(ALC), respiratory rate, and Spo2-to-Fio2 ratio trajectories diverge approximately 8-10 days before discharge or death. After ventilation, log(CRP), log(ALC), respiratory rate, Spo2-to-Fio2 ratio, and estimated glomerular filtration rate trajectories again diverge 10-20 days before death or discharge. Trajectories improved until discharge and remained unchanged or worsened until death. Our approach characterizes the distribution of biomarker trajectories leading up to competing outcomes of discharge versus death. Moving forward, this model can contribute to quantifying the joint probability of biomarkers and outcomes when provided clinical data up to a given moment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Males experience increased severity of illness and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with females, but the mechanisms of male susceptibility are unclear., Methods: We performed a retrospective cohort analysis of SARS-CoV-2 testing and admission data at 5 hospitals in the Maryland/Washington DC area. Using age-stratified logistic regression models, we quantified the impact of male sex on the risk of the composite outcome of severe disease or death (World Health Organization score 5-8) and tested the impact of demographics, comorbidities, health behaviors, and laboratory inflammatory markers on the sex effect., Results: Among 213 175 SARS-CoV-2 tests, despite similar positivity rates, males in age strata between 18 and 74 years were more frequently hospitalized. For the 2626 hospitalized individuals, clinical inflammatory markers (interleukin-6, C-reactive protein, ferritin, absolute lymphocyte count, and neutrophil:lymphocyte ratio) were more favorable for females than males ( P < .001). Among 18-49-year-olds, male sex carried a higher risk of severe outcomes, both early (odds ratio [OR], 3.01; 95% CI, 1.75 to 5.18) and at peak illness during hospitalization (OR, 2.58; 95% CI, 1.78 to 3.74). Despite multiple differences in demographics, presentation features, comorbidities, and health behaviors, these variables did not change the association of male sex with severe disease. Only clinical inflammatory marker values modified the sex effect, reducing the OR for severe outcomes in males aged 18-49 years to 1.81 (95% CI, 1.00 to 3.26) early and 1.39 (95% CI, 0.93 to 2.08) at peak illness., Conclusions: Higher inflammatory laboratory test values were associated with increased risk of severe coronavirus disease 2019 for males. A sex-specific inflammatory response to SARS-CoV-2 infection may underlie the sex differences in outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Cytokines seen in severe coronavirus disease 2019 (COVID-19) are associated with proliferation, differentiation, and survival of plasma cells. Plasma cells are not routinely found in peripheral blood, though may produce virus-neutralizing antibodies in COVID-19 later in the course of an infection., Methods: Using the Johns Hopkins COVID-19 Precision Medicine Analytics Platform Registry, we identified hospitalized adult patients with confirmed severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and stratified by presence of plasma cells and World Health Organization (WHO) disease severity. To identify plasma cells, we employed a sensitive flow cytometric screening method for highly fluorescent lymphocytes and confirmed these microscopically. Cox regression models were used to evaluate time to death and time to clinical improvement by the presence of plasma cells in patients with severe disease., Results: Of 2301 hospitalized patients with confirmed infection, 371 had plasma cells identified. Patients with plasma cells were more likely to have severe disease, though 86.6% developed plasma cells after onset of severe disease. In patients with severe disease, after adjusting for age, sex, body mass index, race, and other covariates associated with disease severity, patients with plasma cells had a reduced hazard of death (adjusted hazard ratio: 0.57; 95% confidence interval: 0.38-0.87; P value: .008). There was no significant association with the presence of plasma cells and time to clinical improvement., Conclusions: Patients with severe disease who have detectable plasma cells in the peripheral blood have improved mortality despite adjusting for known covariates associated with disease severity in COVID-19. Further investigation is warranted to understand the role of plasma cells in the immune response to COVID-19., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Immunosuppression and comorbidities might place solid organ transplant (SOT) recipients at higher risk from COVID-19, as suggested by recent case series. We compared 45 SOT vs. 2427 non-SOT patients who were admitted with COVID-19 to our health-care system (March 1, 2020 - August 21, 2020), evaluating hospital length-of-stay and inpatient mortality using competing-risks regression. We compared trajectories of WHO COVID-19 severity scale using mixed-effects ordinal logistic regression, adjusting for severity score at admission. SOT and non-SOT patients had comparable age, sex, and race, but SOT recipients were more likely to have diabetes (60% vs. 34%, p < .001), hypertension (69% vs. 44%, p = .001), HIV (7% vs. 1.4%, p = .024), and peripheral vascular disorders (19% vs. 8%, p = .018). There were no statistically significant differences between SOT and non-SOT in maximum illness severity score (p = .13), length-of-stay (sHR: 0.9 1.1 1.4 , p = .5), or mortality (sHR: 0.1 0.4 1.6 , p = .19), although the severity score on admission was slightly lower for SOT (median [IQR] 3 [3, 4]) than for non-SOT (median [IQR] 4 [3-4]) (p = .042) Despite a higher risk profile, SOT recipients had a faster decline in disease severity over time (OR = 0.76 0.81 0.86 , p < .001) compared with non-SOT patients. These findings have implications for transplant decision-making during the COVID-19 pandemic, and insights about the impact of SARS-CoV-2 on immunosuppressed patients., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Although troponin elevation is common in COVID-19, the extent of myocardial dysfunction and its contributors to dysfunction are less well-characterized. We aimed to determine the prevalence of subclinical myocardial dysfunction and its association with mortality using speckle tracking echocardiography (STE), specifically global longitudinal strain (GLS) and myocardial work efficiency (MWE). We also tested the hypothesis that reduced myocardial function was associated with increased systemic inflammation in COVID-19. Methods and Results: We conducted a retrospective study of hospitalized COVID-19 patients undergoing echocardiography ( n = 136), of whom 83 and 75 had GLS (abnormal >-16%) and MWE (abnormal <95%) assessed, respectively. We performed adjusted logistic regression to examine associations of GLS and MWE with in-hospital mortality. Patients were mean 62 ± 14 years old (58% men). While 81% had normal left ventricular ejection fraction (LVEF), prevalence of myocardial dysfunction was high by STE; [39/83 (47%) had abnormal GLS; 59/75 (79%) had abnormal MWE]. Higher MWE was associated with lower in-hospital mortality in unadjusted [OR 0.92 (95% CI 0.85-0.99); p = 0.048] and adjusted models [aOR 0.87 (95% CI 0.78-0.97); p = 0.009]. In addition, increased systemic inflammation measured by interleukin-6 level was associated with reduced MWE. Conclusions: Subclinical myocardial dysfunction is common in COVID-19 patients with clinical echocardiograms, even in those with normal LVEF. Reduced MWE is associated with higher interleukin-6 levels and increased in-hospital mortality. Non-invasive STE represents a readily available method to rapidly evaluate myocardial dysfunction in COVID-19 patients and can play an important role in risk stratification., 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 © 2021 Minhas, Gilotra, Goerlich, Metkus, Garibaldi, Sharma, Bavaro, Phillip, Michos and Hays.)

Background: Predicting the clinical trajectory of individual patients hospitalized with coronavirus disease 2019 (COVID-19) is challenging but necessary to inform clinical care. The majority of COVID-19 prognostic tools use only data present upon admission and do not incorporate changes occurring after admission., Objective: To develop the Severe COVID-19 Adaptive Risk Predictor (SCARP) (https://rsconnect.biostat.jhsph.edu/covid&#95;trajectory/), a novel tool that can provide dynamic risk predictions for progression from moderate disease to severe illness or death in patients with COVID-19 at any time within the first 14 days of their hospitalization., Design: Retrospective observational cohort study., Settings: Five hospitals in Maryland and Washington, D.C., Patients: Patients who were hospitalized between 5 March and 4 December 2020 with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed by nucleic acid test and symptomatic disease., Measurements: A clinical registry for patients hospitalized with COVID-19 was the primary data source; data included demographic characteristics, admission source, comorbid conditions, time-varying vital signs, laboratory measurements, and clinical severity. Random forest for survival, longitudinal, and multivariate (RF-SLAM) data analysis was applied to predict the 1-day and 7-day risks for progression to severe disease or death for any given day during the first 14 days of hospitalization., Results: Among 3163 patients admitted with moderate COVID-19, 228 (7%) became severely ill or died in the next 24 hours; an additional 355 (11%) became severely ill or died in the next 7 days. The area under the receiver-operating characteristic curve (AUC) for 1-day risk predictions for progression to severe disease or death was 0.89 (95% CI, 0.88 to 0.90) and 0.89 (CI, 0.87 to 0.91) during the first and second weeks of hospitalization, respectively. The AUC for 7-day risk predictions for progression to severe disease or death was 0.83 (CI, 0.83 to 0.84) and 0.87 (CI, 0.86 to 0.89) during the first and second weeks of hospitalization, respectively., Limitation: The SCARP tool was developed by using data from a single health system., Conclusion: Using the predictive power of RF-SLAM and longitudinal data from more than 3000 patients hospitalized with COVID-19, an interactive tool was developed that rapidly and accurately provides the probability of an individual patient's progression to severe illness or death on the basis of readily available clinical information., Primary Funding Source: Hopkins inHealth and COVID-19 Administrative Supplement for the HHS Region 3 Treatment Center from the Office of the Assistant Secretary for Preparedness and Response.

The impact of host genomics on an individual's susceptibility, immune response, and risk of severe outcomes for a given infectious pathogen is increasingly recognized. As we uncover the links between host genomics and infectious disease, a number of ethical, legal, and social issues need to be considered when using that information in clinical practice or workforce decisions. We conducted a survey of the clinical staff at 10 federally funded Regional Ebola and Other Special Pathogen Treatment Centers to understand their views regarding the ethical, legal, and social issues related to host genomics and the administrative and clinical functions of high-level isolation units. Respondents overwhelmingly agreed that genomics could provide valuable information to identify patients and employees at higher risk for poor outcomes from highly infectious diseases. However, there was considerable disagreement about whether such data should inform the allocation of scarce resources or determine treatment decisions. While most respondents supported a confidential employer-based genomic testing system to inform individual employees about risk, respondents disagreed about whether such information should be used in staffing models. Respondents who thought genomic information would be valuable for patient treatment were more willing to undergo genetic testing for staffing purposes. Most respondents felt they would benefit from additional training to better interpret results from genetic testing. Although this study was completed before the COVID-19 pandemic, the responses provide a baseline assessment of provider attitudes that can inform policy during the current pandemic and in future infectious disease outbreaks.

Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19)., Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival., Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used., Setting: 67 hospitals in the United States., Participants: Adults with COVID-19 admitted to a participating ICU., Measurements: Time to death, censored at hospital discharge, or date of last follow-up., Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35])., Limitation: Observational design., Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation., Primary Funding Source: None.