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Rationale & Objective: The prevalence of community-acquired acute kidney injury (CA-AKI) in the United States and its clinical consequences are not well described. Our objective was to describe the epidemiology of CA-AKI and the associated clinical outcomes., Study Design: Retrospective cohort study., Setting & Participants: 178,927 encounters by 139,632 adults at 5 US emergency departments (EDs) between July 1, 2017, and December 31, 2022., Predictors: CA-AKI identified using KDIGO (Kidney Disease: Improving Global Outcomes) serum creatinine (Scr)-based criteria., Outcomes: For encounters resulting in hospitalization, the in-hospital trajectory of AKI severity, dialysis initiation, intensive care unit (ICU) admission, and death. For all encounters, occurrence over 180 days of hospitalization, ICU admission, new or progressive chronic kidney disease, dialysis initiation, and death., Analytical Approach: Multivariable logistic regression analysis to test the association between CA-AKI and measured outcomes., Results: For all encounters, 10.4% of patients met the criteria for any stage of AKI on arrival to the ED. 16.6% of patients admitted to the hospital from the ED had CA-AKI on arrival to the ED. The likelihood of AKI recovery was inversely related to CA-AKI stage on arrival to the ED. Among encounters for hospitalized patients, CA-AKI was associated with in-hospital dialysis initiation (OR, 6.2; 95% CI, 5.1-7.5), ICU admission (OR, 1.9; 95% CI, 1.7-2.0), and death (OR, 2.2; 95% CI, 2.0-2.5) compared with patients without CA-AKI. Among all encounters, CA-AKI was associated with new or progressive chronic kidney disease (OR, 6.0; 95% CI, 5.6-6.4), dialysis initiation (OR, 5.1; 95% CI, 4.5-5.7), subsequent hospitalization (OR, 1.1; 95% CI, 1.1-1.2) including ICU admission (OR, 1.2; 95% CI, 1.1-1.4), and death (OR, 1.6; 95% CI, 1.5-1.7) during the subsequent 180 days., Limitations: Residual confounding. Study implemented at a single university-based health system. Potential selection bias related to exclusion of patients without an available baseline Scr measurement. Potential ascertainment bias related to limited repeat Scr data during follow-up after an ED visit., Conclusions: CA-AKI is a common and important entity that is associated with serious adverse clinical consequences during the 6-month period after diagnosis., Plain-Language Summary: Acute kidney injury (AKI) is a condition characterized by a rapid decline in kidney function. There are many causes of AKI, but few studies have examined how often AKI is already present when patients first arrive to an emergency department seeking medical attention for any reason. We analyzed approximately 175,000 visits to Johns Hopkins emergency departments and found that AKI is common on presentation to the emergency department and that patients with AKI have increased risks of hospitalization, intensive care unit admission, development of chronic kidney disease, requirement of dialysis, and death in the first 6 months after diagnosis. AKI is an important condition for health care professionals to recognize and is associated with serious adverse outcomes., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Millions of Americans are infected by influenza annually. A minority seek care in the emergency department (ED) and, of those, only a limited number experience severe disease or death. ED clinicians must distinguish those at risk for deterioration from those who can be safely discharged., Methods: We developed random forest machine learning (ML) models to estimate needs for critical care within 24 h and inpatient care within 72 h in ED patients with influenza. Predictor data were limited to those recorded prior to ED disposition decision: demographics, ED complaint, medical problems, vital signs, supplemental oxygen use, and laboratory results. Our study population was comprised of adults diagnosed with influenza at one of five EDs in our university health system between January 1, 2017 and May 18, 2022; visits were divided into two cohorts to facilitate model development and validation. Prediction performance was assessed by the area under the receiver operating characteristic curve (AUC) and the Brier score., Results: Among 8032 patients with laboratory-confirmed influenza, incidence of critical care needs was 6.3% and incidence of inpatient care needs was 19.6%. The most common reasons for ED visit were symptoms of respiratory tract infection, fever, and shortness of breath. Model AUCs were 0.89 (95% CI 0.86-0.93) for prediction of critical care and 0.90 (95% CI 0.88-0.93) for inpatient care needs; Brier scores were 0.026 and 0.042, respectively. Importantpredictors included shortness of breath, increasing respiratory rate, and a high number of comorbid diseases., Conclusions: ML methods can be used to accurately predict clinical deterioration in ED patients with influenza and have potential to support ED disposition decision-making., Competing Interests: A. S., M. T., and S. L. participated in this work while employed by Johns Hopkins University but subsequently became employees of Beckman Coulter Diagnostics, where they contribute to the development of CDS tools. J. H. is a paid scientific consultant for Beckman Coulter Diagnostics. Beckman Coulter played no role in this study and no technology owned or licensed by Beckman Coulter was used. The remaining authors declare no competing financial or non‐financial interests., (© 2024 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Objective: Sepsis is a leading cause of mortality. Predicting outcomes is challenging and few biomarkers perform well. Defects in the renin-angiotensin system (RAS) can predict clinical outcomes in sepsis and may outperform traditional biomarkers. We postulated that RAS dysfunction (elevated active renin, angiotensin 1-7 [Ang-(1-7)], and angiotensin-converting enzyme 2 (ACE2) activity with depressed Ang-II and ACE activity) would be associated with mortality in a cohort of septic patients., Design: Post hoc analysis of patients enrolled in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized controlled trial., Setting: Forty-three hospitals across the United States., Patients: Biorepository samples of 103 patients., Interventions: We analyzed day 0 (within 24 hr of respiratory failure, septic shock, or both) and day 3 samples ( n = 103 and 95, respectively) for assessment of the RAS. The association of RAS values with 30-day mortality was determined using Cox proportional hazards regression with multivariable adjustments for age, sex, VICTAS treatment arm, systolic blood pressure, Sequential Organ Failure Assessment Score, and vasopressor use., Measurements and Main Results: High baseline active renin values were associated with higher 30-day mortality when dichotomized to the median of 188.7 pg/mL (hazard ratio [HR] = 2.84 [95% CI, 1.10-7.33], p = 0.031) or stratified into quartiles (Q1 = ref, HR Q2 = 2.01 [0.37-11.04], HR Q3 = 3.22 [0.64-16.28], HR Q4 = 5.58 [1.18-26.32], p for linear trend = 0.023). A 1- sd (593.6 pg/mL) increase in renin from day 0 to day 3 was associated with increased mortality (HR = 3.75 [95% CI, 1.94-7.22], p < 0.001), and patients whose renin decreased had improved survival compared with those whose renin increased (HR 0.22 [95% CI, 0.08-0.60], p = 0.003). Ang-(1-7), ACE2 activity, Ang-II and ACE activity did not show this association. Mortality was attenuated in patients with renin over the median on day 0 who received the VICTAS intervention, but not on day 3 ( p interaction 0.020 and 0.137, respectively). There were no additional consistent patterns of mortality on the RAS from the VICTAS intervention., Conclusions: Baseline serum active renin levels were strongly associated with mortality in critically ill patients with sepsis. Furthermore, a greater relative activation in circulating renin from day 0 to day 3 was associated with a higher risk of death., Competing Interests: Dr. Schaich received funding from the National Institute on Aging (K01AG073581) and an internal institutional pilot grant. Dr. Chappell’s institution received funding from the National Heart, Lung, and Blood Institute (R01HL146818); he received support for article research from the National Institutes of Health (NIH). Dr. McCurdy’s institution received funding from the Maryland Innovation Initiative; he disclosed he is chief medical officer for BOA Biomedical. Drs. Sevransky, Rothman, and Wright’s institutions received funding from the Marcus Foundation. Dr. Sevransky’s institution received funding from the Centers for Disease Control and Prevention and the Department of Health and Human Services; He disclosed he is an associate editor for Critical Care Medicine. Dr. Rothman disclosed use of Vit C, thiamine and steroid for treatment of sepsis. Dr. Wright’s institution received funding from the NIH; he received funding from the Neurotrauma Sciences Advisory Board and Astrocyte Pharma; he disclosed he was an expert witness for multiple different legal firms; he received support for article research from the Marcus Foundation. Dr. Khanna received grant funding from Hypertension and Vascular Research Center at the Wake Forest University School of Medicine (AG073581) to study mechanisms of renin dysregulation in shock. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: The use of large-scale data and artificial intelligence (AI) to support complex transplantation decisions is in its infancy. Transplant candidate decision-making, which relies heavily on subjective assessment (ie, high variability), provides a ripe opportunity for AI-based clinical decision support (CDS). However, AI-CDS for transplant applications must consider important concerns regarding fairness (ie, health equity). The objective of this study was to use human-centered design methods to elicit providers' perceptions of AI-CDS for liver transplant listing decisions., Methods: In this multicenter qualitative study conducted from December 2020 to July 2021, we performed semistructured interviews with 53 multidisciplinary liver transplant providers from 2 transplant centers. We used inductive coding and constant comparison analysis of interview data., Results: Analysis yielded 6 themes important for the design of fair AI-CDS for liver transplant listing decisions: (1) transparency in the creators behind the AI-CDS and their motivations; (2) understanding how the AI-CDS uses data to support recommendations (ie, interpretability); (3) acknowledgment that AI-CDS could mitigate emotions and biases; (4) AI-CDS as a member of the transplant team, not a replacement; (5) identifying patient resource needs; and (6) including the patient's role in the AI-CDS., Conclusions: Overall, providers interviewed were cautiously optimistic about the potential for AI-CDS to improve clinical and equitable outcomes for patients. These findings can guide multidisciplinary developers in the design and implementation of AI-CDS that deliberately considers health equity., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Introduction: In an effort to improve sepsis outcomes the Centers for Medicare and Medicaid Services (CMS) established a time sensitive sepsis management bundle as a core quality measure that includes blood culture collection, serum lactate collection, initiation of intravenous fluid administration, and initiation of broad-spectrum antibiotics. Few studies examine the effects of a prehospital sepsis alert protocol on decreasing time to complete CMS sepsis core measures., Methods: This study was a retrospective cohort study of patients transported via EMS from December 1, 2018 to December 1, 2019 who met the criteria of the Maryland Statewide EMS sepsis protocol and compared outcomes between patients who activated a prehospital sepsis alert and patients who did not activate a prehospital sepsis alert. The Maryland Institute for Emergency Medical Services Systems developed a sepsis protocol that instructs EMS providers to notify the nearest appropriate facility with a sepsis alert if a patient 18 years of age and older is suspected of having an infection and also presents with at least two of the following: temperature >38 °C or <35.5 °C, a heart rate >100 beats per minute, a respiratory rate >25 breaths per minute or end-tidal carbon dioxide less than or equal to 32 mmHg, a systolic blood pressure <90 mmHg, or a point of care lactate reading greater than or equal to 4 mmol/L., Results: Median time to achieve all four studied CMS sepsis core measures was 103 min [IQR 61-153] for patients who received a prehospital sepsis alert and 106.5 min [IQR 75-189] for patients who did not receive a prehospital sepsis alert (p-value 0.105). Median time to completion was shorter for serum lactate collection (28 min. vs 35 min., p-value 0.019), blood culture collection (28 min. vs 38 min., p-value <0.01), and intravenous fluid administration (54 min. vs 61 min., p-value 0.025) but was not significantly different for antibiotic administration (94 min. vs 103 min., p-value 0.12) among patients who triggered a sepsis alert., Conclusion: This study questions the effectiveness of prehospital sepsis alert protocols on decreasing time to complete CMS sepsis core measures. Future studies should address if these times can be impacted by having EMS providers independently administer antibiotics., Competing Interests: Declaration of Competing Interest The authors report there are no competing interests to declare. This study was approved by the Institutional Review Board (IRB00218034) and partially supported under grant number R18 HS026640–02 from the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services (HHS). The authors are solely responsible for this document's contents, findings, and conclusions, which do not necessarily represent the views of AHRQ. Readers should not interpret any statement in this report as an official position of AHRQ or of HHS., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Monocyte distribution width (MDW) is an emerging biomarker for infection. It is available easily and quickly as part of the CBC count, which is performed routinely on hospital admission. The increasing availability and promising results of MDW as a biomarker in sepsis has prompted an expansion of its use to other infectious diseases., Research Question: What is the diagnostic performance of MDW across multiple infectious disease outcomes and care settings?, Study Design and Methods: A systematic review of the diagnostic performance of MDW across multiple infectious disease outcomes was conducted by searching PubMed, Embase, Scopus, and Web of Science through February 4, 2022. Meta-analysis was performed for outcomes with three or more reports identified (sepsis and COVID-19). Diagnostic performance measures were calculated for individual studies with pooled estimates created by linear mixed-effects models., Results: We identified 29 studies meeting inclusion criteria. Most examined sepsis (19 studies) and COVID-19 (six studies). Pooled estimates of diagnostic performance for sepsis differed by reference standard (Second vs Third International Consensus Definitions for Sepsis and Septic Shock criteria) and tube anticoagulant used and ranged from an area under the receiver operating characteristic curve (AUC) of 0.74 to 0.94, with mean sensitivity of 0.69 to 0.79 and mean specificity of 0.57 to 0.86. For COVID-19, the pooled AUC of MDW was 0.76, mean sensitivity was 0.79, and mean specificity was 0.59., Interpretation: MDW exhibited good diagnostic performance for sepsis and COVID-19. Diagnostic thresholds for sepsis should be chosen with consideration of reference standard and tube type used., Trial Registry: Prospero; No.: CRD42020210074; URL: https://www.crd.york.ac.uk/prospero/., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The objective was to evaluate the comparative effectiveness and safety of pharmacological and nonpharmacological management options for atrial fibrillation/atrial flutter with rapid ventricular response (AFRVR) in patients with acute decompensated heart failure (ADHF) in the acute care setting., Methods: This study was a systematic review of observational studies or randomized clinical trials (RCT) of adult patients with AFRVR and concomitant ADHF in the emergency department (ED), intensive care unit, or step-down unit. The primary effectiveness outcome was successful rate or rhythm control. Safety outcomes were adverse events, such as symptomatic hypotension and venous thromboembolism., Results: A total of 6577 unique articles were identified. Five studies met inclusion criteria: one RCT in the inpatient setting and four retrospective studies, two in the ED and the other three in the inpatient setting. In the RCT of diltiazem versus placebo, 22 patients (100%) in the treatment group had a therapeutic response compared to 0/15 (0%) in the placebo group, with no significant safety differences between the two groups. For three of the observational studies, data were limited. One observation study showed no difference between metoprolol and diltiazem for successful rate control, but worsening heart failure symptoms occurred more frequently in those receiving diltiazem compared to metoprolol (19 patients [33%] vs. 10 patients [15%], p = 0.019). A single study included electrical cardioversion (one patient exposed with failure to convert to sinus rhythm) as nonpharmacological management. The overall risk of bias for included studies ranged from serious to critical. Missing data and heterogeneity of definitions for effectiveness and safety outcomes precluded the combination of results for quantitative meta-analysis., Conclusions: High-level evidence to inform clinical decision making regarding effective and safe management of AFRVR in patients with ADHF in the acute care setting is lacking., (© 2022 by the Society for Academic Emergency Medicine.)

Purpose: Evidence of an association between intravenous contrast media (CM) and persistent renal dysfunction is lacking for patients with pre-existing acute kidney injury (AKI). This study was designed to determine the association between intravenous CM administration and persistent AKI in patients with pre-existing AKI., Methods: A retrospective propensity-weighted and entropy-balanced observational cohort analysis of consecutive hospitalized patients ≥ 18 years old meeting Kidney Disease Improving Global Outcomes (KDIGO) creatinine-based criteria for AKI at time of arrival to one of three emergency departments between 7/1/2017 and 6/30/2021 who did or did not receive intravenous CM. Outcomes included persistent AKI at hospital discharge and initiation of dialysis within 180 days of index encounter., Results: Our analysis included 14,449 patient encounters, with 12.8% admitted to the intensive care unit (ICU). CM was administered in 18.4% of all encounters. AKI resolved prior to hospital discharge for 69.1%. No association between intravenous CM administration and persistent AKI was observed after unadjusted multivariable logistic regression modeling (OR 1; 95% CI 0.89-1.11), propensity weighting (OR 0.93; 95% CI 0.83-1.05), and entropy balancing (OR 0.94; 95% CI 0.83-1.05). Sub-group analysis in those admitted to the ICU yielded similar results. Initiation of dialysis within 180 days was observed in 5.4% of the cohort. An association between CM administration and increased risk of dialysis within 180 days was not observed., Conclusion: Among patients with pre-existing AKI, contrast administration was not associated with either persistent AKI at hospital discharge or initiation of dialysis within 180 days. Current consensus recommendations for use of intravenous CM in patients with stable renal disease may also be applied to patients with pre-existing AKI., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Monocyte distribution width (MDW) is a novel marker of monocyte activation, which is known to occur in the immune response to viral pathogens. Our objective was to determine the performance of MDW and other leukocyte parameters as screening tests for SARS-CoV-2 and influenza infection. This was a prospective cohort analysis of adult patients who underwent complete blood count (CBC) and SARS-CoV-2 or influenza testing in an Emergency Department (ED) between January 2020 and July 2021. The primary outcome was SARS-CoV-2 or influenza infection. Secondary outcomes were measures of severity of illness including inpatient hospitalization, critical care admission, hospital lengths of stay and mortality. Descriptive statistics and test performance measures were evaluated for monocyte percentage, MDW, white blood cell (WBC) count, and neutrophil to lymphocyte ratio (NLR). 3,425 ED patient visits were included. SARS-CoV-2 testing was performed during 1,922 visits with a positivity rate of 5.4%; influenza testing was performed during 2,090 with a positivity rate of 2.3%. MDW was elevated in patients with SARS-Cov-2 (median 23.0U; IQR 20.5-25.1) or influenza (median 24.1U; IQR 22.0-26.9) infection, as compared to those without (18.9U; IQR 17.4-20.7 and 19.1U; 17.4-21, respectively, P < 0.001). Monocyte percentage, WBC and NLR values were within normal range in patients testing positive for either virus. MDW identified SARS-CoV-2 and influenza positive patients with an area under the curve (AUC) of 0.83 (95% CI 0.79-0.86) and 0.83 (95% CI 0.77-0.88), respectively. At the accepted cut-off value of 20U for MDW, sensitivities were 83.7% (95% CI 76.5-90.8%) for SARS-CoV-2 and 89.6% (95% CI 80.9-98.2%) for influenza, compared to sensitivities below 45% for monocyte percentage, WBC and NLR. MDW negative predictive values were 98.6% (95% CI 98.0-99.3%) and 99.6% (95% CI 99.3-100.0%) respectively for SARS-CoV-2 and influenza. Monocyte Distribution Width (MDW), available as part of a routine complete blood count (CBC) with differential, may be a useful indicator of SARS-CoV-2 or influenza infection., (© 2022. The Author(s).)

Objective: We analyzed the efficacy, cost, and cost-effectiveness of predictive decision-support systems based on surveillance interventions to reduce the spread of carbapenem-resistant Enterobacteriaceae (CRE)., Design: We developed a computational model that included patient movement between acute-care hospitals (ACHs), long-term care facilities (LTCFs), and communities to simulate the transmission and epidemiology of CRE. A comparative cost-effectiveness analysis was conducted on several surveillance strategies to detect asymptomatic CRE colonization, which included screening in ICUs at select or all hospitals, a statewide registry, or a combination of hospital screening and a statewide registry., Setting: We investigated 51 ACHs, 222 LTCFs, and skilled nursing facilities, and 464 ZIP codes in the state of Maryland., Patients or Participants: The model was informed using 2013-2016 patient-mix data from the Maryland Health Services Cost Review Commission. This model included all patients that were admitted to an ACH., Results: On average, the implementation of a statewide CRE registry reduced annual CRE infections by 6.3% (18.8 cases). Policies of screening in select or all ICUs without a statewide registry had no significant impact on the incidence of CRE infections. Predictive algorithms, which identified any high-risk patient, reduced colonization incidence by an average of 1.2% (3.7 cases) without a registry and 7.0% (20.9 cases) with a registry. Implementation of the registry was estimated to save $572,000 statewide in averted infections per year., Conclusions: Although hospital-level surveillance provided minimal reductions in CRE infections, regional coordination with a statewide registry of CRE patients reduced infections and was cost-effective.

Demand has outstripped healthcare supply during the coronavirus disease 2019 (COVID-19) pandemic. Emergency departments (EDs) are tasked with distinguishing patients who require hospital resources from those who may be safely discharged to the community. The novelty and high variability of COVID-19 have made these determinations challenging. In this study, we developed, implemented and evaluated an electronic health record (EHR) embedded clinical decision support (CDS) system that leverages machine learning (ML) to estimate short-term risk for clinical deterioration in patients with or under investigation for COVID-19. The system translates model-generated risk for critical care needs within 24 h and inpatient care needs within 72 h into rapidly interpretable COVID-19 Deterioration Risk Levels made viewable within ED clinician workflow. ML models were derived in a retrospective cohort of 21,452 ED patients who visited one of five ED study sites and were prospectively validated in 15,670 ED visits that occurred before (n = 4322) or after (n = 11,348) CDS implementation; model performance and numerous patient-oriented outcomes including in-hospital mortality were measured across study periods. Incidence of critical care needs within 24 h and inpatient care needs within 72 h were 10.7% and 22.5%, respectively and were similar across study periods. ML model performance was excellent under all conditions, with AUC ranging from 0.85 to 0.91 for prediction of critical care needs and 0.80-0.90 for inpatient care needs. Total mortality was unchanged across study periods but was reduced among high-risk patients after CDS implementation., (© 2022. The Author(s).)

Study Objective: Enhancement of a routine complete blood count (CBC) for detection of sepsis in the emergency department (ED) has pragmatic utility for early management. This study evaluated the performance of monocyte distribution width (MDW) alone and in combination with other routine CBC parameters as a screen for sepsis and septic shock in ED patients., Methods: A prospective cohort analysis of adult patients with a CBC collected at an urban ED from January 2020 through July 2021. The performance of MDW, white blood count (WBC) count, and neutrophil-to-lymphocyte-ratio (NLR) to detect sepsis and septic shock (Sepsis-3 Criteria) was evaluated using diagnostic performance measures., Results: The cohort included 7952 ED patients, with 180 meeting criteria for sepsis; 43 with septic shock and 137 without shock. MDW was highest for patients with septic shock (median 24.8 U, interquartile range [IQR] 22.0-28.1) and trended downward for patients with sepsis without shock (23.9 U, IQR 20.2-26.8), infection (20.4 U, IQR 18.2-23.3), then controls (18.6 U, IQR 17.1-20.4). In isolation, MDW detected sepsis and septic shock with an area under the receiver operator characteristic curve (AUC) of 0.80 (95% confidence interval [CI] 0.77-0.84) and 0.85 (95% CI 0.80-0 .91), respectively. Optimal performance was achieved in combination with WBC count and NLR for detection of sepsis (AUC 0.86, 95% CI 0.83-0.89) and septic shock (0.86, 95% CI 0.80-0.92)., Conclusion: A CBC differential panel that includes MDW demonstrated strong performance characteristics in a broad ED population suggesting pragmatic value as a rapid screen for sepsis and septic shock., Competing Interests: Stocastic (Jeremiah S. Hinson, Arnaud Debraine, Matthew Toerper, and Scott Levin) is collaborating with Beckman Coulter on integrating data‐driven clinical decision support (CDS) with biomarkers measured by Beckman Coulter devices, including MDW. Jeremiah S. Hinson, Matthew Toerper, and Scott Levin and Johns Hopkins University have equity ownership in Stocastic. Although no CDS was directly studied, this research could underpin development of CDS in the future. These authors and the university are entitled to royalty distributions related to CDS technology that may be created. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with conflict of interest policies., (© 2022 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Artificial intelligence (AI) refers to the performance of tasks by machines ordinarily associated with human intelligence. Machine learning (ML) is a subtype of AI; it refers to the ability of computers to draw conclusions (ie, learn) from data without being directly programmed. ML builds from traditional statistical methods and has drawn significant interest in healthcare epidemiology due to its potential for improving disease prediction and patient care. This review provides an overview of ML in healthcare epidemiology and practical examples of ML tools used to support healthcare decision making at 4 stages of hospital-based care: triage, diagnosis, treatment, and discharge. Examples include model-building efforts to assist emergency department triage, predicting time before septic shock onset, detecting community-acquired pneumonia, and classifying COVID-19 disposition risk level. Increasing availability and quality of electronic health record (EHR) data as well as computing power provides opportunities for ML to increase patient safety, improve the efficiency of clinical management, and reduce healthcare costs., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2021.)

Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis., Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis., Design, Setting, and Participants: Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020., Interventions: Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone., Main Outcomes and Measures: The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality., Results: Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group., Conclusions and Relevance: Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference., Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

Opportunity exists to decrease healthcare-related exposure to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), preserve infection control resources, and increase care capacity by reducing the time to diagnosis of coronavirus disease 2019 (COVID-19). A retrospective cohort analysis was undertaken to measure the effect of targeted rapid molecular testing for SARS-CoV-2 on these outcomes. In comparison with standard platform testing, rapid testing was associated with a 65.6% reduction (12.6 h) in the median time to removal from the isolation cohort for patients with negative diagnostic results. This translated to an increase in COVID-19 treatment capacity of 3028 bed-hours and 7500 fewer patient interactions that required the use of personal protective equipment per week., (Copyright © 2020 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Study Objective: Acute kidney injury occurs commonly and is a leading cause of prolonged hospitalization, development and progression of chronic kidney disease, and death. Early acute kidney injury treatment can improve outcomes. However, current decision support is not able to detect patients at the highest risk of developing acute kidney injury. We analyzed routinely collected emergency department (ED) data and developed prediction models with capacity for early identification of ED patients at high risk for acute kidney injury., Methods: A multisite, retrospective, cross-sectional study was performed at 3 EDs between January 2014 and July 2017. All adult ED visits in which patients were hospitalized and serum creatinine level was measured both on arrival and again with 72 hours were included. We built machine-learning-based classifiers that rely on vital signs, chief complaints, medical history and active medical visits, and laboratory results to predict the development of acute kidney injury stage 1 and 2 in the next 24 to 72 hours, according to creatinine-based international consensus criteria. Predictive performance was evaluated out of sample by Monte Carlo cross validation., Results: The final cohort included 91,258 visits by 59,792 unique patients. Seventy-two-hour incidence of acute kidney injury was 7.9% for stages greater than or equal to 1 and 1.0% for stages greater than or equal to 2. The area under the receiver operating characteristic curve for acute kidney injury prediction ranged from 0.81 (95% confidence interval 0.80 to 0.82) to 0.74 (95% confidence interval 0.74 to 0.75), with a median time from ED arrival to prediction of 1.7 hours (interquartile range 1.3 to 2.5 hours)., Conclusion: Machine learning applied to routinely collected ED data identified ED patients at high risk for acute kidney injury up to 72 hours before they met diagnostic criteria. Further prospective evaluation is necessary., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Patients who develop acute kidney injury (AKI) have a 2-fold increased risk for major adverse events within 1 year. An estimated 19-26% of all cases of hospital-acquired AKI may be attributable to drug-induced kidney disease (DIKD). Patients evaluated in the emergency department (ED) are often prescribed potentially nephrotoxic drugs, yet the role of ED prescribing in DIKD is unknown., Objective: We sought to measure the association between ED medication administration and development of AKI., Methods: This was a retrospective 5-year cohort analysis at a single center. Patients with a serum creatinine measurement at presentation in the ED and 24-168 h later were included. Outcome was incidence of AKI as defined by Kidney Disease Improving Global Outcomes criteria in the 7 days after ED evaluation. Medication administration risk was estimated using Cox proportional hazards model., Results: There were 46,965 ED encounters by 30,407 patients included in the study, of which 6461 (13.8%) patients met the criteria for AKI. For hospitalized patients, administration of a potentially nephrotoxic medication was associated with increased risk of AKI (hazard ratio [HR] 1.30 [95% confidence interval {CI} 1.20-1.41]). Diuretics were associated with the largest risk of AKI (HR 1.64 [95% CI 1.52-1.78]), followed by angiotensin-converting enzyme inhibitors (HR 1.39 [95% CI 1.26-1.54]) and antibiotics (HR 1.13 [95% CI 1.05-1.22]). For discharged patients, administration of antibiotics was strongly associated with increased risk of AKI (HR 3.19 [95% CI 1.08-9.43])., Conclusion: ED administration of potentially nephrotoxic medications was associated with an increased risk of AKI in the following 7 days. Diuretics, angiotensin-converting enzyme inhibitors, and antibiotics were independently associated with increased risk of AKI. Nephroprotective practices in the ED may mitigate kidney injury and long-term adverse outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Study Objective: Rapid growth in emergency department (ED) triage literature has been accompanied by diversity in study design, methodology, and outcome assessment. We aim to synthesize existing ED triage literature by using a framework that enables performance comparisons and benchmarking across triage systems, with respect to clinical outcomes and reliability., Methods: PubMed, EMBASE, Scopus, and Web of Science were systematically searched for studies of adult ED triage systems through 2016. Studies evaluating triage systems with evidence of widespread adoption (Australian Triage Scale, Canadian Triage and Acuity Scale, Emergency Severity Index, Manchester Triage Scale, and South African Triage Scale) were cataloged and compared for performance in identifying patients at risk for mortality, critical illness and hospitalization, and interrater reliability. This study was performed and reported in adherence to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines., Results: A total of 6,160 publications were identified, with 182 meeting eligibility criteria and 50 with sufficient data for inclusion in comparative analysis. The Canadian Triage and Acuity Scale (32 studies), Emergency Severity Index (43), and Manchester Triage Scale (38) were the most frequently studied triage scales, and all demonstrated similar performance. Most studies (6 of 8) reported high sensitivity (>90%) of triage scales for identifying patients with ED mortality as high acuity at triage. However, sensitivity was low (<80%) for identification of patients who had critical illness outcomes and those who died within days of the ED visit or during the index hospitalization. Sensitivity varied by critical illness and was lower for severe sepsis (36% to 74%), pulmonary embolism (54%), and non-ST-segment elevation myocardial infarction (44% to 85%) compared with ST-segment elevation myocardial infarction (56% to 92%) and general outcomes of ICU admission (58% to 100%) and lifesaving intervention (77% to 98%). Some proportion of hospitalized patients (3% to 45%) were triaged to low acuity (level 4 to 5) in all studies. Reliability measures (κ) were variable across evaluations, with only a minority (11 of 42) reporting κ above 0.8., Conclusion: We found that a substantial proportion of ED patients who die postencounter or are critically ill are not designated as high acuity at triage. Opportunity to improve interrater reliability and triage performance in identifying patients at risk of adverse outcome exists., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the risk for acute kidney injury (AKI) attributable to intravenous contrast media (CM) administration in septic patients., Materials and Methods: This was a single-center retrospective propensity matched cohort analysis performed in the emergency department (ED) of an academic medical center. All visits for patients ≥18 years who met sepsis diagnostic criteria and had serum creatinine (SCr) measured both on arrival to the ED and again 48 to 72 h later were included. Of 4171 visits, 1464 patients underwent contrast-enhanced CT (CECT), 976 underwent unenhanced CT and 1731 underwent no CT at all., Results: The primary outcome was incidence of AKI. Logistic regression and between-groups odds ratios with and without propensity-score matching were used to test for an independent association between CM administration and AKI. Incidence of AKI was 7.2%, 9.4% and 9.7% in those who underwent CECT, unenhanced CT and no CT. CM administration was not associated with increased incidence of AKI., Conclusions: Sepsis is a medical emergency proven to benefit from early diagnosis and rapid initiation of treatment, which is often aided by CECT. Our findings argue against withholding CM for fear of precipitating AKI in potentially septic patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed., Methods: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30 days following randomization. The key secondary outcome is mortality at 30 days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed., Discussion: VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide., Trial Registration: ClinicalTrials.gov Identifier: NCT03509350 . First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019.

Introduction: With emergency department crowding becoming an increasing problem across the globe, nursing triage to prioritize patients receiving care is ever more important. ESI is the most common triage system used in the United States and is increasingly used worldwide. This qualitative study that explores emergency nursing perceptions of the ESI identifies strengths, weaknesses, and barriers to implementation of the ESI internationally., Methods: We conducted a cross-sectional qualitative analysis using semistructured interviews of 27 emergency triage nurses. Content analysis was performed by 2 independent coders, using NVivo software to identify and analyze important themes., Results: Interview coding revealed 7 core themes related to use of the ESI (frequencies indicated in parentheses): ease of use (90), speed and efficiency (135), patient safety (12), accuracy and reliability (30), challenging patient characteristics (123), subjectivity and variability (173), and effect of triage system on team dynamics (100). Intercoder agreement was excellent (Cohen's unweighted kappa = 0.84). Subjectivity and variability in ESI score assignment consistently emerged in all interviews and included variability in number and use of resources, definition of "high risk," nursing experience, and subjectivity in pain assessment., Discussion: Although emergency nurses perceive the ESI as easy to use, there are concerns about the subjectivity and variability inherent in the ESI that can lead to a functional lack of triage and a burden of undifferentiated ESI level 3 patients. These limitations in separating critically ill patients and in stratifying patients based on anticipated required resources points to the need for improvement in the ESI algorithm or a more objective triage system that can predict patient outcomes., (Copyright © 2018 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Study Objective: Standards for emergency department (ED) triage in the United States rely heavily on subjective assessment and are limited in their ability to risk-stratify patients. This study seeks to evaluate an electronic triage system (e-triage) based on machine learning that predicts likelihood of acute outcomes enabling improved patient differentiation., Methods: A multisite, retrospective, cross-sectional study of 172,726 ED visits from urban and community EDs was conducted. E-triage is composed of a random forest model applied to triage data (vital signs, chief complaint, and active medical history) that predicts the need for critical care, an emergency procedure, and inpatient hospitalization in parallel and translates risk to triage level designations. Predicted outcomes and secondary outcomes of elevated troponin and lactate levels were evaluated and compared with the Emergency Severity Index (ESI)., Results: E-triage predictions had an area under the curve ranging from 0.73 to 0.92 and demonstrated equivalent or improved identification of clinical patient outcomes compared with ESI at both EDs. E-triage provided rationale for risk-based differentiation of the more than 65% of ED visits triaged to ESI level 3. Matching the ESI patient distribution for comparisons, e-triage identified more than 10% (14,326 patients) of ESI level 3 patients requiring up triage who had substantially increased risk of critical care or emergency procedure (1.7% ESI level 3 versus 6.2% up triaged) and hospitalization (18.9% versus 45.4%) across EDs., Conclusion: E-triage more accurately classifies ESI level 3 patients and highlights opportunities to use predictive analytics to support triage decisionmaking. Further prospective validation is needed., (Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Study Objective: We assess accuracy and variability of triage score assignment by emergency department (ED) nurses using the Emergency Severity Index (ESI) in 3 countries. In accordance with previous reports and clinical observation, we hypothesize low accuracy and high variability across all sites., Methods: This cross-sectional multicenter study enrolled 87 ESI-trained nurses from EDs in Brazil, the United Arab Emirates, and the United States. Standardized triage scenarios published by the Agency for Healthcare Research and Quality (AHRQ) were used. Accuracy was defined by concordance with the AHRQ key and calculated as percentages. Accuracy comparisons were made with one-way ANOVA and paired t test. Interrater reliability was measured with Krippendorff's α. Subanalyses based on nursing experience and triage scenario type were also performed., Results: Mean accuracy pooled across all sites and scenarios was 59.2% (95% confidence interval [CI] 56.4% to 62.0%) and interrater reliability was modest (α=.730; 95% CI .692 to .767). There was no difference in overall accuracy between sites or according to nurse experience. Medium-acuity scenarios were scored with greater accuracy (76.4%; 95% CI 72.6% to 80.3%) than high- or low-acuity cases (44.1%, 95% CI 39.3% to 49.0% and 54%, 95% CI 49.9% to 58.2%), and adult scenarios were scored with greater accuracy than pediatric ones (66.2%, 95% CI 62.9% to 69.7% versus 46.9%, 95% CI 43.4% to 50.3%)., Conclusion: In this multinational study, concordance of nurse-assigned ESI score with reference standard was universally poor and variability was high. Although the ESI is the most popular ED triage tool in the United States and is increasingly used worldwide, our findings point to a need for more reliable ED triage tools., (Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Emergency departments (ED) are sites of prevalent imaging overuse; however, determinants that drive imaging in this setting are not well-characterized. We systematically reviewed the literature to summarize the determinants of imaging overuse in the ED., Methods: We searched MEDLINE® and Embase® from January 1998 to March 2017. Studies were included if they were written in English, contained original data, pertained to a U.S. population, and identified a determinant associated with overuse of imaging in the ED., Results: Twenty relevant studies were included. Fourteen evaluated computerized tomography (CT) scanning in patents presenting to a regional ED who were then transferred to a level 1 trauma center; incomplete transfer of data and poor image quality were the most frequently described reasons for repeat scanning. Unnecessary pre-transfer scanning or repeated scanning after transfer, in multiple studies, was highest among older patients, those with higher Injury Severity Scores (ISS) and those being transferred further. Six studies explored determinants of overused imaging in the ED in varied conditions, with overuse greater in older patients and those having more comorbid diseases. Defensive imaging reportedly influenced physician behavior. Less integration of services across the health system also predisposed to overuse of imaging., Conclusions: The literature is heterogeneous with surprisingly few studies of determinants of imaging in minor head injury or of spine imaging. Older patient age and higher ISS were the most consistently associated with ED imaging overuse. This review highlights the need for precise definitions of overuse of imaging in the ED., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Emergency department (ED) triage is performed to prioritize care for patients with critical and time-sensitive illness. Triage errors create opportunity for increased morbidity and mortality. Here, we sought to measure the frequency of under- and over-triage of patients by nurses using the Emergency Severity Index (ESI) in Brazil and to identify factors independently associated with each., Methods: This was a single-center retrospective cohort study. The accuracy of initial ESI score assignment was determined by comparison with a score entered at the close of each ED encounter by treating physicians with full knowledge of actual resource utilization, disposition, and acute outcomes. Chi-square analysis was used to validate this surrogate gold standard, via comparison of associations with disposition and clinical outcomes. Independent predictors of under- and over-triage were identified by multivariate logistic regression., Results: Initial ESI-determined triage score was classified as inaccurate for 16,426 of 96,071 patient encounters. Under-triage was associated with a significantly higher rate of admission and critical outcome, while over-triage was associated with a lower rate of both. A number of factors identifiable at time of presentation including advanced age, bradycardia, tachycardia, hypoxia, hyperthermia, and several specific chief complaints (i.e., neurologic complaints, chest pain, shortness of breath) were identified as independent predictors of under-triage, while other chief complaints (i.e., hypertension and allergic complaints) were independent predictors of over-triage., Conclusions: Despite rigorous and ongoing training of ESI users, a large number of patients in this cohort were under- or over-triaged. Advanced age, vital sign derangements, and specific chief complaints-all subject to limited guidance by the ESI algorithm-were particularly under-appreciated.

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare that DENT was supported by the Armstrong Institute Center for Diagnostic Excellence at Johns Hopkins University School of Medicine. SK is supported by an NIH Medical Scientist Training Program grant.

Background: Esophageal foreign body (EFB) and impaction are common gastrointestinal emergencies. Detection with standard imaging can be challenging. Computed tomography is a commonly used non-invasive imaging modality, but is not 100% sensitive and not always feasible. Sensitivity of plain film x-ray varies widely and the addition of a barium swallow can obscure evaluation by subsequent esophagogastroduodenoscopy (EGD). Use of emergency ultrasound (EUS) for detection of EFB in adults has not been previously studied., Objective: To evaluate the role of EUS in detection of EFB and to characterize sonographic findings., Methods: A case control series of five patients with clinical suspicion of EFB underwent EUS, and findings were compared to five healthy controls. Patients were evaluated for persistent air-fluid levels after swallowing, esophageal dilatation, and visualization of EFB., Results: All patients with suspected EFB had esophageal dilatation (17.5mm vs 9.3mm in healthy controls; p=0.0011) and persistent air-fluid levels after swallowing. EFB was visualized on EUS in 60% of patients. All patients had EFB confirmed on EGD except one, who vomited a significant food bolus during EUS and prior to EGD., Conclusion: In patients with suspected EFB, point-of-care ultrasound may identify those with impaction. Suggestive findings include cervical esophageal dilatation and persistent intraluminal air-fluid levels after swallowing. EUS is a rapid, convenient test with the potential to expedite definitive management while decreasing cost and radiation exposure in this patient population., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Study Objective: The study objective was to determine whether intravenous contrast administration for computed tomography (CT) is independently associated with increased risk for acute kidney injury and adverse clinical outcomes., Methods: This single-center retrospective cohort analysis was performed in a large, urban, academic emergency department with an average census of 62,179 visits per year; 17,934 ED visits for patients who underwent contrast-enhanced, unenhanced, or no CT during a 5-year period (2009 to 2014) were included. The intervention was CT scan with or without intravenous contrast administration. The primary outcome was incidence of acute kidney injury. Secondary outcomes included new chronic kidney disease, dialysis, and renal transplantation at 6 months. Logistic regression modeling and between-groups odds ratios with and without propensity-score matching were used to test for an independent association between contrast administration and primary and secondary outcomes. Treatment decisions, including administration of contrast and intravenous fluids, were examined., Results: Rates of acute kidney injury were similar among all groups. Contrast administration was not associated with increased incidence of acute kidney injury (contrast-induced nephropathy criteria odds ratio=0.96, 95% confidence interval 0.85 to 1.08; and Acute Kidney Injury Network/Kidney Disease Improving Global Outcomes criteria odds ratio=1.00, 95% confidence interval 0.87 to 1.16). This was true in all subgroup analyses regardless of baseline renal function and whether comparisons were made directly or after propensity matching. Contrast administration was not associated with increased incidence of chronic kidney disease, dialysis, or renal transplant at 6 months. Clinicians were less likely to prescribe contrast to patients with decreased renal function and more likely to prescribe intravenous fluids if contrast was administered., Conclusion: In the largest well-controlled study of acute kidney injury following contrast administration in the ED to date, intravenous contrast was not associated with an increased frequency of acute kidney injury., (Copyright © 2016 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Our goal was to reduce ordering of coagulation studies in the emergency department (ED) that have no added value for patients presenting with chest pain. We hypothesized this could be achieved via implementation of a stopgap measure in the electronic medical record (EMR)., Methods: We used a pre and post quasi-experimental study design to evaluate the impact of an EMR-based intervention on coagulation study ordering for patients with chest pain. A simple interactive prompt was incorporated into the EMR of our ED that required clinicians to indicate whether patients were on anticoagulation therapy prior to completion of orders for coagulation studies. Coagulation order frequency was measured via detailed review of randomly sampled encounters during two-month periods before and after intervention. We classified existing orders as clinically indicated or non-value added. Order frequencies were calculated as percentages, and we assessed differences between groups by chi-square analysis., Results: Pre-intervention, 73.8% (76/103) of patients with chest pain had coagulation studies ordered, of which 67.1% (51/76) were non-value added. Post-intervention, 38.5% (40/104) of patients with chest pain had coagulation studies ordered, of which 60% (24/40) were non-value added. There was an absolute reduction of 35.3% (95% confidence interval [CI]: 22.7%, 48.0%) in the total ordering of coagulation studies and 26.4% (95% CI: 13.8%, 39.0%) in non-value added order placement., Conclusion: Simple EMR-based interactive prompts can serve as effective deterrents to indiscriminate ordering of diagnostic studies., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. This work was funded via institutional support; there were no additional funding sources.

Extensive evidence indicates that serum response factor (SRF) regulates muscle-specific gene expression and that myocardin family SRF cofactors are critical for smooth muscle cell differentiation. In a yeast two hybrid screen for novel SRF binding partners expressed in aortic SMC, we identified four and a half LIM domain protein 2 (FHL2) and confirmed this interaction by GST pull-down and coimmunoprecipitation assays. FHL2 also interacted with all three myocardin factors and enhanced myocardin and myocardin-related transcription factor (MRTF)-A-dependent transactivation of smooth muscle alpha-actin, SM22, and cardiac atrial natriuretic factor promoters in 10T1/2 cells. The expression of FHL2 increased myocardin and MRTF-A protein levels, and, importantly, this effect was due to an increase in protein stability not due to an increase in myocardin factor mRNA expression. Treatment of cells with proteasome inhibitors MG-132 and lactacystin strongly upregulated endogenous MRTF-A protein levels and resulted in a substantial increase in ubiquitin immunoreactivity in MRTF-A immunoprecipitants. Interestingly, the expression of FHL2 attenuated the effects of RhoA and MRTF-B on promoter activity, perhaps through decreased MRTF-B nuclear localization or decreased SRF-CArG binding. Taken together, these data indicate that myocardin factors are regulated by proteasome-mediated degradation and that FHL2 regulates SRF-dependent transcription by multiple mechanisms, including stabilization of myocardin and MRTF-A.

On the basis of our previous studies on RhoA signaling in smooth muscle cells (SMC), we hypothesized that RhoA-mediated nuclear translocalization of the myocardin-related transcription factors (MRTFs) was important for regulating SMC phenotype. MRTF-A protein and MRTF-B message were detected in aortic SMC and in many adult mouse organs that contain a large SMC component. Both MRTFs upregulated SMC-specific promoter activity as well as endogenous SM22alpha expression in multipotential 10T1/2 cells, although to a lesser extent than myocardin. We used enhanced green fluorescent protein (EGFP) fusion proteins to demonstrate that the myocardin factors have dramatically different localization patterns and that the stimulation of SMC-specific transcription by certain RhoA-dependent agonists was likely mediated by increased nuclear translocation of the MRTFs. Importantly, a dominant-negative form of MRTF-A (DeltaB1/B2) that traps endogenous MRTFs in the cytoplasm inhibited the SM alpha-actin, SM22alpha, and SM myosin heavy chain promoters in SMC and attenuated the effects of sphingosine 1-phosphate and transforming growth factor (TGF)-beta on SMC-specific transcription. Our data confirmed the importance of the NH(2)-terminal RPEL domains for regulating MRTF localization, but our analysis of MRTF-A/myocardin chimeras and myocardin RPEL2 mutations indicated that the myocardin B1/B2 region can override this signal. Gel shift assays demonstrated that myocardin factor activity correlated well with ternary complex formation at the SM alpha-actin CArGs and that MRTF-serum response factor interactions were partially dependent on CArG sequence. Taken together, our results indicate that the MRTFs regulate SMC-specific gene expression in at least some SMC subtypes and that regulation of MRTF nuclear localization may be important for the effects of selected agonists on SMC phenotype.

Sphingosine 1-phosphate (S1P) is a lipid agonist that regulates smooth muscle cell (SMC) and endothelial cell functions by activating several members of the S1P subfamily of G-protein-coupled Edg receptors. We have shown previously that SMC differentiation is regulated by RhoA-dependent activation of serum response factor (SRF). Because S1P is a strong activator of RhoA, we hypothesized that S1P would stimulate SMC differentiation. Treatment of primary rat aortic SMC cells with S1P activated RhoA as measured by precipitation with a glutathione S-transferase-rhotekin fusion protein. In SMC and 10T1/2 cells, S1P treatment up-regulated the activities of several transiently transfected SMC-specific promoters, and these effects were inhibited by the Rho-kinase inhibitor, Y-27632. S1P also increased smooth muscle alpha-actin protein levels in SMC but had no effect on SRF binding to the smooth muscle alpha-actin CArG B element. Quantitative reverse transcriptase-PCR showed that S1P treatment of SMC or 10T1/2 cells did not increase the mRNA level of either of the recently identified SRF co-factors, myocardin or myocardin-related transcription factor-A (MRTF-A). MRTF-A protein was expressed highly in SMC and 10T1/2 cultures, and importantly the effects of S1P were inhibited by a dominant negative form of MRTF-A indicating that S1P may regulate the transcriptional activity of MRTF-A. Indeed, S1P treatment increased the nuclear localization of FLAG-MRTF-A, and the effect of MRTF-A overexpression on smooth muscle alpha-actin promoter activity was inhibited by dominant negative RhoA. S1P also stimulated SMC growth by activating the early growth response gene, c-fos. This effect was not attenuated by Y-27632 but could be inhibited by the MEK inhibitor, UO126. S1P enhanced SMC growth through ERK-mediated phosphorylation of the SRF co-factor, Elk-1, as measured by gel shift and Elk-1 activation assays. Taken together these results demonstrate that S1P activates multiple signaling pathways in SMC and regulates proliferation by ERK-dependent activation of Elk-1 and differentiation by RhoA-dependent activation of MRTF-A.