Antibodies expand the scope of angiotensin receptor pharmacology.

G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue and cellular levels. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays and structural studies, we develop maternally selective heavy-chain-only antibody ('nanobody') antagonists against the angiotensin II type I receptor and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to angiotensin II type I receptor with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.

Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.

G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue, and cellular level. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays, and structural studies, we develop maternally selective heavy chain-only antibody ("nanobody") antagonists against the angiotensin II type I receptor (AT1R) and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to AT1R with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.

Practices for running a research-oriented shared cryo-EM facility.

The Harvard Cryo-Electron Microscopy Center for Structural Biology, which was formed as a consortium between Harvard Medical School, Boston Children's Hospital, Dana-Farber Cancer Institute, and Massachusetts General Hospital, serves both academic and commercial users in the greater Harvard community. The facility strives to optimize research productivity while training users to become expert electron microscopists. These two tasks may be at odds and require careful balance to keep research projects moving forward while still allowing trainees to develop independence and expertise. This article presents the model developed at Harvard Medical School for running a research-oriented cryo-EM facility. Being a research-oriented facility begins with training in cryo-sample preparation on a trainee's own sample, ideally producing grids that can be screened and optimized on the Talos Arctica via multiple established pipelines. The first option, staff assisted screening, requires no user experience and a staff member provides instant feedback about the suitability of the sample for cryo-EM investigation and discusses potential strategies for sample optimization. Another option, rapid access, allows users short sessions to screen samples and introductory training for basic microscope operation. Once a sample reaches the stage where data collection is warranted, new users are trained on setting up data collection for themselves on either the Talos Arctica or Titan Krios microscope until independence is established. By providing incremental training and screening pipelines, the bottleneck of sample preparation can be overcome in parallel with developing skills as an electron microscopist. This approach allows for the development of expertise without hindering breakthroughs in key research areas.

Troponin is unrelated to outcomes in heart failure patients discharged from the emergency department.

Background: Prior data has demonstrated increased mortality in hospitalized patients with acute heart failure (AHF) and troponin elevation. No data has specifically examined the prognostic significance of troponin elevation in patients with AHF discharged after emergency department (ED) management. Objective: Evaluate the relationship between troponin elevation and outcomes in patients with AHF who are treated and released from the ED. Methods: This was a secondary analysis of the Get with the Guidelines to Reduce Disparities in AHF Patients Discharged from the ED (GUIDED-HF) trial, a randomized, controlled trial of ED patients with AHF who were discharged. Patients with elevated conventional troponin not due to acute coronary syndrome (ACS) were included. Our primary outcome was a composite endpoint: time to 30-day cardiovascular death and/or heart failure-related events. Results: Of the 491 subjects included in the GUIDED-HF trial, 418 had troponin measured during the ED evaluation and 66 (16%) had troponin values above the 99th percentile. Median age was 63 years (interquartile range, 54-70), 62% (n = 261) were male, 63% (n = 265) were Black, and 16% (n = 67) experienced our primary outcome. There were no differences in our primary outcome between those with and without troponin elevation (12/66, 18.1% vs 55/352, 15.6%; P = 0.60). This effect was maintained regardless of assignment to usual care or the intervention arm. In multivariable regression analysis, there was no association between our primary outcome and elevated troponin (hazard ratio, 1.00; 95% confidence interval,  0.49-2.01, P = 0.994). Conclusion: If confirmed in a larger cohort, these findings may facilitate safe ED discharge for a group of patients with AHF without ACS when an elevated troponin is the primary reason for admission.

Improvement in Kansas City Cardiomyopathy Questionnaire Scores After a Self-Care Intervention in Patients With Acute Heart Failure Discharged From the Emergency Department.

BACKGROUND: We conducted a secondary analysis of changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 over 30 days in a randomized trial of self-care coaching versus structured usual care in patients with acute heart failure who were discharged from the emergency department. METHODS: Patients in 15 emergency departments completed the KCCQ-12 at emergency department discharge and at 30 days. We compared change in KCCQ-12 scores between the intervention and usual care arms, adjusted for enrollment KCCQ-12 and demographic characteristics. We used linear regression to describe changes in KCCQ-12 summary scores and logistic regression to characterize clinically meaningful KCCQ-12 subdomain changes at 30 days. RESULTS: There were 350 patients with both enrollment and 30-day KCCQ summary scores available; 166 allocated to usual care and 184 to the intervention arm. Median age was 64 years (interquartile range, 55-70), 37% were female participants, 63% were Black, median KCCQ-12 summary score at enrollment was 47 (interquartile range, 33-64). Self-care coaching resulted in significantly greater improvement in health status compared with structured usual care (5.4-point greater improvement, 95% CI, 1.12-9.68; P=0.01). Improvements in health status in the intervention arm were driven by improvements within the symptom frequency (adjusted odds ratio, 1.62 [95% CI, 1.01-2.59]) and quality of life (adjusted odds ratio, 2.39 [95% CI, 1.46-3.90]) subdomains. CONCLUSIONS: In this secondary analysis, patients with acute heart failure who received a tailored, self-care intervention after emergency department discharge had clinically significant improvements in health status at 30 days compared with structured usual care largely due to improvements within the symptom frequency and quality of life subdomains of the KCCQ-12. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02519283.

Structural basis for enhanced infectivity and immune evasion of SARS-CoV-2 variants.

Several fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the dominant circulating strains in the COVID-19 pandemic. We report here cryo-electron microscopy structures of the full-length spike (S) trimers of the B.1.1.7 and B.1.351 variants, as well as their biochemical and antigenic properties. Amino acid substitutions in the B.1.1.7 protein increase both the accessibility of its receptor binding domain and the binding affinity for receptor angiotensin-converting enzyme 2 (ACE2). The enhanced receptor engagement may account for the increased transmissibility. The B.1.351 variant has evolved to reshape antigenic surfaces of the major neutralizing sites on the S protein, making it resistant to some potent neutralizing antibodies. These findings provide structural details on how SARS-CoV-2 has evolved to enhance viral fitness and immune evasion.

Structural basis for enhanced infectivity and immune evasion of SARS-CoV-2 variants.

Several fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the dominant circulating strains that continue to fuel the COVID-19 pandemic despite intensive vaccination efforts throughout the world. We report here cryo-EM structures of the full-length spike (S) trimers of the B.1.1.7 and B.1.351 variants, as well as their biochemical and antigenic properties. Mutations in the B.1.1.7 protein increase the accessibility of its receptor binding domain and also the binding affinity for receptor angiotensin-converting enzyme 2 (ACE2). The enhanced receptor engagement can account for the increased transmissibility and risk of mortality as the variant may begin to infect efficiently infect additional cell types expressing low levels of ACE2. The B.1.351 variant has evolved to reshape antigenic surfaces of the major neutralizing sites on the S protein, rendering complete resistance to some potent neutralizing antibodies. These findings provide structural details on how the wide spread of SARS-CoV-2 enables rapid evolution to enhance viral fitness and immune evasion. They may guide intervention strategies to control the pandemic.

Structural impact on SARS-CoV-2 spike protein by D614G substitution.

Substitution for aspartic acid (D) by glycine (G) at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. Here, we report cryo-electron microscopy structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations that differ primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer-effectively increasing the number of functional spikes and enhancing infectivity-and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

Effect of a Self-care Intervention on 90-Day Outcomes in Patients With Acute Heart Failure Discharged From the Emergency Department: A Randomized Clinical Trial.

Importance: Up to 20% of patients who present to the emergency department (ED) with acute heart failure (AHF) are discharged without hospitalization. Compared with rates in hospitalized patients, readmission and mortality are worse for ED patients. Objective: To assess the impact of a self-care intervention on 90-day outcomes in patients with AHF who are discharged from the ED. Design, Setting, and Participants: Get With the Guidelines in Emergency Department Patients With Heart Failure was an unblinded, parallel-group, multicenter randomized trial. Patients were randomized 1:1 to usual care vs a tailored self-care intervention. Patients with AHF discharged after ED-based management at 15 geographically diverse EDs were included. The trial was conducted from October 28, 2015, to September 5, 2019. Interventions: Home visit within 7 days of discharge and twice-monthly telephone-based self-care coaching for 3 months. Main Outcomes and Measures: The primary outcome was a global rank of cardiovascular death, HF-related events (unscheduled clinic visit due to HF, ED revisit, or hospitalization), and changes in the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) summary score (SS) at 90 days. Key secondary outcomes included the global rank outcome at 30 days and changes in the KCCQ-12 SS score at 30 and 90 days. Intention-to-treat analysis was performed for the primary, secondary, and safety outcomes. Per-protocol analysis was conducted including patients who completed a home visit and had scheduled outpatient follow-up in the intervention arm. Results: Owing to slow enrollment, 479 of a planned 700 patients were randomized: 235 to the intervention arm and 244 to the usual care arm. The median age was 63.0 years (interquartile range, 54.7-70.2), 302 patients (63%) were African American, 305 patients (64%) were men, and 178 patients (37%) had a previous ejection fraction greater than 50%. There was no significant difference in the primary outcome between patients in the intervention vs usual care arm (hazard ratio [HR], 0.89; 95% CI, 0.73-1.10; P = .28). At day 30, patients in the intervention arm had significantly better global rank (HR, 0.80; 95% CI, 0.64-0.99; P = .04) and a 5.5-point higher KCCQ-12 SS (95% CI, 1.3-9.7; P = .01), while at day 90, the KCCQ-12 SS was 2.7 points higher (95% CI, -1.9 to 7.2; P = .25). Conclusions and Relevance: The self-care intervention did not improve the primary global rank outcome at 90 days in this trial. However, benefit was observed in the global rank and KCCQ-12 SS at 30 days, suggesting that an early benefit of a tailored self-care program initiated at an ED visit for AHF was not sustained through 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02519283.

Do Hospitals Providing Telehealth in Emergency Departments Have Lower Emergency Department Costs?

Background: Since 2003, the University of Mississippi Medical Center has operated a robust telehealth emergency department (ED) network, TelEmergency, which enhances access to emergency medicine-trained physicians at participating rural hospitals. TelEmergency was developed as a cost-control measure for financially constrained rural hospitals to improve access to quality, emergency care. However, the literature remains unclear as to whether ED telehealth services can be provided at lower costs compared with traditional in-person ED services. Introduction: Our objective was to empirically determine whether TelEmergency was associated with lower ED costs at rural hospitals when compared with similar hospitals without TelEmergency between 2010 and 2017. Materials and Methods: A panel of data for 2010-2017 was constructed at the hospital level. Hospitals with TelEmergency (n = 14 hospitals; 112 hospital-years) were compared with similar hospitals that did not use TelEmergency from Arkansas, Georgia, Mississippi, and South Carolina (n = 102; 766 hospital-years), matched using Coarsened Exact Matching. The relationship between total ED costs and treatment (e.g., participation in TelEmergency) was predicted using generalized estimating equations with a Poisson distribution, a log link, an exchangeable error term, and robust standard errors. Results: After controlling for ownership type, critical access hospital status, year, and size, TelEmergency was associated with an estimated 31.4% lower total annual ED costs compared with similar matched hospitals that did not provide TelEmergency. Conclusions: TelEmergency utilization was associated with significantly lower total annual ED costs compared with similarly matched hospitals that did not utilize TelEmergency. These findings suggest that access to quality ED care in rural communities can occur at lower costs.

Structural impact on SARS-CoV-2 spike protein by D614G substitution.

Substitution for aspartic acid by glycine at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing pandemic, appears to facilitate rapid viral spread. The G614 variant has now replaced the D614-carrying virus as the dominant circulating strain. We report here cryo-EM structures of a full-length S trimer carrying G614, which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain (RBD). A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer, effectively increasing the number of functional spikes and enhancing infectivity. The loop transition may also modulate structural rearrangements of S protein required for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

Distinct conformational states of SARS-CoV-2 spike protein.

Intervention strategies are urgently needed to control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The trimeric viral spike (S) protein catalyzes fusion between viral and target cell membranes to initiate infection. Here, we report two cryo-electron microscopy structures derived from a preparation of the full-length S protein, representing its prefusion (2.9-angstrom resolution) and postfusion (3.0-angstrom resolution) conformations, respectively. The spontaneous transition to the postfusion state is independent of target cells. The prefusion trimer has three receptor-binding domains clamped down by a segment adjacent to the fusion peptide. The postfusion structure is strategically decorated by N-linked glycans, suggesting possible protective roles against host immune responses and harsh external conditions. These findings advance our understanding of SARS-CoV-2 entry and may guide the development of vaccines and therapeutics.

Distinct conformational states of SARS-CoV-2 spike protein.

The ongoing SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic has created urgent needs for intervention strategies to control the crisis. The spike (S) protein of the virus forms a trimer and catalyzes fusion between viral and target cell membranes - the first key step of viral infection. Here we report two cryo-EM structures, both derived from a single preparation of the full-length S protein, representing the prefusion (3.1Å resolution) and postfusion (3.3Å resolution) conformations, respectively. The spontaneous structural transition to the postfusion state under mild conditions is independent of target cells. The prefusion trimer forms a tightly packed structure with three receptor-binding domains clamped down by a segment adjacent to the fusion peptide, significantly different from recently published structures of a stabilized S ectodomain trimer. The postfusion conformation is a rigid tower-like trimer, but decorated by N-linked glycans along its long axis with almost even spacing, suggesting possible involvement in a mechanism protecting the virus from host immune responses and harsh external conditions. These findings advance our understanding of how SARS-CoV-2 enters a host cell and may guide development of vaccines and therapeutics.

Sequential Organ Failure Assessment Component Score Prediction of In-hospital Mortality From Sepsis.

OBJECTIVES: Early organ dysfunction in sepsis confers a high risk of in-hospital mortality, but the relative contribution of specific types of organ failure to overall mortality is unclear. The objective of this study was to assess the predictive ability of individual types of organ failure to in-hospital mortality or prolonged intensive care. METHODS: Retrospective cohort study of adult emergency department patients with sepsis from October 1, 2013, to November 10, 2015. Multivariable regression was used to assess the odds ratios of individual organ failure types for the outcomes of in-hospital death (primary) and in-hospital death or ICU stay ≥ 3 days (secondary). RESULTS: Of 2796 patients, 283 (10%) experienced in-hospital mortality, and 748 (27%) experienced in-hospital mortality or an ICU stay ≥ 3 days. The following components of Sequential Organ Failure Assessment (SOFA) score were most predictive of in-hospital mortality (descending order): coagulation (odds ratio [OR]: 1.60, 95% confidence interval [CI]: 1.32-1.93), hepatic (1.58, 95% CI: 1.32-1.90), respiratory (OR: 1.33, 95% CI: 1.21-1.47), neurologic (OR: 1.20, 95% CI: 1.07-1.35), renal (OR: 1.14, 95% CI: 1.02-1.27), and cardiovascular (OR: 1.13, 95% CI: 1.01-1.25). For mortality or ICU stay ≥3 days, the most predictive SOFA components were respiratory (OR: 1.97, 95% CI: 1.79-2.16), neurologic (OR: 1.72, 95% CI: 1.54-1.92), cardiovascular (OR: 1.38, 95% CI: 1.23-1.54), coagulation (OR: 1.31, 95% CI: 1.10-1.55), and renal (OR: 1.19, 95% CI: 1.08-1.30) while hepatic SOFA (OR: 1.16, 95% CI: 0.98-1.37) did not reach statistical significance (P = .092). CONCLUSION: In this retrospective study, SOFA score components demonstrated varying predictive abilities for mortality in sepsis. Elevated coagulation or hepatic SOFA scores were most predictive of in-hospital death, while an elevated respiratory SOFA was most predictive of death or ICU stay >3 days.

Development of a Simple Sequential Organ Failure Assessment Score for Risk Assessment of Emergency Department Patients With Sepsis.

OBJECTIVES: Sepsis-3 recommends using the quick Sequential Organ Failure Assessment (qSOFA) score followed by SOFA score for sepsis evaluation. The SOFA is complex and unfamiliar to most emergency physicians, while qSOFA is insensitive for sepsis screening and may result in missed cases of sepsis. The objective of this study was to devise an easy-to-use simple SOFA score for use in the emergency department (ED). METHODS: Retrospective study of ED patients with sepsis with in-hospital mortality as the primary outcome. A simple SOFA score was derived and validated and compared with SOFA and qSOFA. RESULTS: A total of 3297 patients with sepsis were included, and in-hospital mortality was 10.1%. Simple SOFA had a sensitivity and specificity of 88% and 44% in the derivation set and 93% and 44% in the validation set for in-hospital mortality, respectively. The sensitivity and specificity of qSOFA was 38% and 86% and for SOFA was 90% and 50%, respectively. There were 2760 (84%) of 3297 qSOFA-negative (<2) patients. In this group, simple SOFA had a sensitivity and specificity of 86% and 48% in the derivation set and 91% and 48% in the validation set, respectively. Sequential Organ Failure Assessment was 86% sensitive and 57% specific in qSOFA-negative patients. For all encounters, the areas under the receiver-operator characteristic curves (AUROC) were 0.82 for SOFA, 0.78 (derivation) and 0.82 (validation) for simple SOFA, and 0.68 for qSOFA. In qSOFA-negative patients, the AUROCs were 0.80 for SOFA and 0.76 (derivation) and 0.82 (validation) for simple SOFA. CONCLUSIONS: Simple SOFA demonstrates similar predictive ability for in-hospital mortality from sepsis compared to SOFA. External validation of these findings is indicated.

Effect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock: The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trial.

Importance: Sepsis induces profound metabolic derangements, while exogenous levocarnitine mitigates metabolic dysfunction by enhancing glucose and lactate oxidation and increasing fatty acid shuttling. Previous trials in sepsis suggest beneficial effects of levocarnitine on patient-centered outcomes. Objectives: To test the hypothesis that levocarnitine reduces cumulative organ failure in patients with septic shock at 48 hours and, if present, to estimate the probability that the most efficacious dose will decrease 28-day mortality in a pivotal phase 3 clinical trial. Design, Setting, and Participants: Multicenter adaptive, randomized, blinded, dose-finding, phase 2 clinical trial (Rapid Administration of Carnitine in Sepsis [RACE]). The setting was 16 urban US medical centers. Participants were patients aged 18 years or older admitted from March 5, 2013, to February 5, 2018, with septic shock and moderate organ dysfunction. Interventions: Within 24 hours of identification, patients were assigned to 1 of the following 4 treatments: low (6 g), medium (12 g), or high (18 g) doses of levocarnitine or an equivalent volume of saline placebo administered as a 12-hour infusion. Main Outcomes and Measures: The primary outcome required, first, a greater than 90% posterior probability that the most promising levocarnitine dose decreases the Sequential Organ Failure Assessment (SOFA) score at 48 hours and, second (given having met the first condition), at least a 30% predictive probability of success in reducing 28-day mortality in a subsequent traditional superiority trial to test efficacy. Results: Of the 250 enrolled participants (mean [SD] age, 61.7 [14.8] years; 56.8% male), 35, 34, and 106 patients were adaptively randomized to the low, medium, and high levocarnitine doses, respectively, while 75 patients were randomized to placebo. In the intent-to-treat analysis, the fitted mean (SD) changes in the SOFA score for the low, medium, and high levocarnitine groups were -1.27 (0.49), -1.66 (0.38), and -1.97 (0.32), respectively, vs -1.63 (0.35) in the placebo group. The posterior probability that the 18-g dose is superior to placebo was 0.78, which did not meet the a priori threshold of 0.90. Mortality at 28 days was 45.9% (34 of 74) in the placebo group compared with 43.3% (45 of 104) for the most promising levocarnitine dose (18 g). Similar findings were noted in the per-protocol analysis. Conclusions and Relevance: In this dose-finding, phase 2 adaptive randomized trial, the most efficacious dose of levocarnitine (18 g) did not meaningfully reduce cumulative organ failure at 48 hours. Trial Registration: ClinicalTrials.gov Identifier: NCT01665092.

Clinical predictors of early death from sepsis.

PURPOSE: Patients with severe sepsis who experience rapid, early deterioration and death are of particular concern. Our objective was to identify predictors of early death in Emergency Department (ED) patients with severe sepsis. METHODS: Secondary analysis of two prospective studies of adult ED patients with severe sepsis. The primary outcome was early death, defined as death within 24h of triage. RESULTS: Out of 410 severe sepsis admissions, 20 patients experienced early death. These patients demonstrated significantly higher initial lactate (7.3 versus 3.3mmol/L, p<0.001) and modified SOFA (mSOFA) scores (10 vs 6, p<0.001), were less likely to normalize their lactate (p<0.001), had lower initial pH (p<0.001), and more frequently had early positive blood cultures (p=0.021). Multivariable logistic regression identified initial serum lactate level (OR 1.19, 95% CI 1.06-1.35) and mSOFA score (OR 1.17, 95% CI 1.00-1.36) as independent predictors of early death. A repeat lactate≥5mmol/L had a sensitivity of 55% and specificity of 89% for early death. There were no significant treatment differences between groups. CONCLUSION: Initial serum lactate and mSOFA score were independent predictors of mortality within 24h of ED admission in patients with severe sepsis.

A Systematic Review of the Impact of Physician Implicit Racial Bias on Clinical Decision Making.

OBJECTIVES: Disparities in diagnosis and treatment of racial minorities exist in the emergency department (ED). A better understanding of how physician implicit (unconscious) bias contributes to these disparities may help identify ways to eliminate such racial disparities. The objective of this systematic review was to examine and summarize the evidence on the association between physician implicit racial bias and clinical decision making. METHODS: Based on PRISMA guidelines, a structured electronic literature search of PubMed, CINAHL, Scopus, and PsycINFO databases was conducted. Eligible studies were those that: 1) included physicians, 2) included the Implicit Association Test as a measure of implicit bias, 3) included an assessment of physician clinical decision making, and 4) were published in peer-reviewed journals between 1998 and 2016. Articles were reviewed for inclusion by two independent investigators. Data extraction was performed by one investigator and checked for accuracy by a second investigator. Two investigators independently scored the quality of articles using a modified version of the Downs and Black checklist. RESULTS: Of the 1,154 unique articles identified in the initial search, nine studies (n = 1,910) met inclusion criteria. Three of the nine studies involved emergency providers including residents, attending physicians, and advanced practice providers. The majority of studies used clinical vignettes to examine clinical decision making. Studies that included emergency medicine (EM) providers had vignettes relating to treatment of acute myocardial infarction, pain, and pediatric asthma. An implicit preference favoring white people was common across providers, regardless of specialty. Two of the nine studies found evidence of a relationship between implicit bias and clinical decision making; one of these studies included EM providers. This one study found that EM and internal medicine residents who demonstrated an implicit preference for white individuals were more likely to treat white patients and not black patients with thrombolysis for myocardial infarction. Evidence from the two studies reporting a relationship between physician implicit racial bias and decision making was low in quality. CONCLUSIONS: The current literature indicates that although many physicians, regardless of specialty, demonstrate an implicit preference for white people, this bias does not appear to impact their clinical decision making. Further studies on the impact of implicit racial bias on racial disparities in ED treatment are needed.