Dysfunctional APPL1-Mediated Epigenetic Regulation in Diabetic Vascular Injury.

BACKGROUND: APN (adiponectin) and APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) are potent vasculoprotective molecules, and their deficiency (eg, hypoadiponectinemia) contributes to diabetic vascular complications. However, the molecular mechanisms that govern their vasculoprotective genes as well as their alteration by diabetes remain unknown. METHODS: Diabetic medium-cultured rat aortic endothelial cells, mouse aortic endothelial cells from high-fat-diet animals, and diabetic human aortic endothelial cells were used for molecular/cellular investigations. The in vivo concept-prove demonstration was conducted using diabetic vascular injury and diabetic hindlimb ischemia models. RESULTS: In vivo animal experiments showed that APN replenishment caused APPL1 nuclear translocation, resulting in an interaction with HDAC (histone deacetylase) 2, which inhibited HDAC2 activity and increased H3Kac27 levels. Based on transcriptionome pathway-specific real-time polymerase chain reaction profiling and bioinformatics analysis, Angpt1 (angiopoietin 1), Ocln (occludin), and Cav1 (caveolin 1) were found to be the top 3 vasculoprotective genes suppressed by diabetes and rescued by APN in an APPL1-dependent manner. APN reverses diabetes-induced inhibition of Cav1 interaction with APPL1. APN-induced Cav1 expression was not affected by Angpt1 or Ocln deficiency, whereas APN-induced APPL1 nuclear translocation or upregulation of Angpt1/Ocln expression was abolished in the absence of Cav1 both in vivo and in vitro, suggesting Cav1 is upstream molecule of Angpt1/Ocln in response to APN administration. Chromatin immunoprecipitation-qPCR (quantitative polymerase chain reaction) demonstrated that APN caused significant enrichment of H3K27ac in Angpt1 and Ocln promoter region, an effect blocked by APPL1/Cav1 knockdown or HDAC2 overexpression. The protective effects of APN on the vascular system were attenuated by overexpression of HDAC2 and abolished by knocking out APPL1 or Cav1. The double knockdown of ANGPT1/OCLN blunted APN vascular protection both in vitro and in vivo. Furthermore, in diabetic human endothelial cells, HDAC2 activity is increased, H3 acetylation is decreased, and ANGPT1/OCLN expression is reduced, suggesting that the findings have important translational implications. CONCLUSIONS: Hypoadiponectinemia and dysregulation of APPL1-mediated epigenetic regulation are novel mechanisms leading to diabetes-induced suppression of vasculoprotective gene expression. Diabetes-induced pathological vascular remodeling may be prevented by interventions promoting APPL1 nuclear translocation and inhibiting HDAC2.

Hypoadiponectinemia-induced upregulation of microRNA449b downregulating Nrf-1 aggravates cardiac ischemia-reperfusion injury in diabetic mice.

Diabetes enhances myocardial ischemic/reperfusion (MI/R) injury via an incompletely understood mechanism. Adiponectin (APN) is a cardioprotective adipokine suppressed by diabetes. However, how hypoadiponectinemia exacerbates cardiac injury remains incompletely understood. Dysregulation of miRNAs plays a significant role in disease development. However, whether hypoadiponectinemia alters cardiac miRNA profile, contributing to diabetic heart injury, remains unclear. Methods and Results: Wild-type (WT) and APN knockout (APN-KO) mice were subjected to MI/R. A cardiac microRNA profile was determined. Among 23 miRNAs increased in APN-KO mice following MI/R, miR-449b was most significantly upregulated (3.98-fold over WT mice). Administrating miR-449b mimic increased apoptosis, enlarged infarct size, and impaired cardiac function in WT mice. In contrast, anti-miR-449b decreased apoptosis, reduced infarct size, and improved cardiac function in APN-KO mice. Bioinformatic analysis predicted 73 miR-449b targeting genes, and GO analysis revealed oxidative stress as the top pathway regulated by these genes. Venn analysis followed by luciferase assay identified Nrf-1 and Ucp3 as the two most important miR-449b targets. In vivo administration of anti-miR-449b in APN-KO mice attenuated MI/R-stimulated superoxide overproduction. In vitro experiments demonstrated that high glucose/high lipid and simulated ischemia/reperfusion upregulated miR-449b and inhibited Nrf-1 and Ucp3 expression. These pathological effects were attenuated by anti-miR-449b or Nrf-1 overexpression. In a final attempt to validate our finding in a clinically relevant model, high-fat diet (HFD)-induced diabetic mice were subjected to MI/R and treated with anti-miR-449b or APN. Diabetes significantly increased miR-449b expression and downregulated Nrf-1 and Ucp3 expression. Administration of anti-miR-449b or APN preserved cardiac Nrf-1 expression, reduced cardiac oxidative stress, decreased apoptosis and infarct size, and improved cardiac function. Conclusion: We demonstrated for the first time that hypoadiponectinemia upregulates miR-449b and suppresses Nrf-1/Ucp3 expression, promoting oxidative stress and exacerbating MI/R injury in this population. Dysregulated APN/miR-449b/oxidative stress pathway is a potential therapeutic target against diabetic MI/R injury.

Structural competency in emergency medical education: A scoping review and operational framework.

Objectives: Existing curricula and recommendations on the incorporation of structural competency and vulnerability into medical education have not provided clear guidance on how best to do so within emergency medicine (EM). The goal of this scoping review and consensus building process was to provide a comprehensive overview of structural competency, link structural competency to educational and patient care outcomes, and identify existing gaps in the literature to inform curricular implementation and future research in EM. Methods: A scoping review focused on structural competency and vulnerability following Arksey and O'Malley's six-step framework was performed in concurrence with a multistep consensus process culminating in the 2021 SAEM Consensus Conference. Feedback was incorporated in developing a framework for a national structural competency curriculum in EM. Results: A literature search identified 291 articles that underwent initial screening. Of these, 51 were determined to be relevant to EM education. The papers consistently conceptualized structural competency as an interdisciplinary framework that requires learners and educators to consider historical power and privilege to develop a professional commitment to justice. However, the papers varied in their operationalization, and no consensus existed on how to observe or measure the effects of structural competency on learners or patients. None of the studies examined the structural constraints of the learners studied. Conclusions: Findings emphasize the need for training structurally competent physicians via national structural competency curricula focusing on standardized core competency proficiencies. Moreover, the findings highlight the need to assess the impact of such curricula on patient outcomes and learners' knowledge, attitudes, and clinical care delivery. The framework aims to standardize EM education while highlighting the need for further research in how structural competency interventions would translate to an ED setting and affect patient outcomes and experiences.

Targeting Adiponectin Receptor 1 Phosphorylation Against Ischemic Heart Failure.

BACKGROUND: Despite significantly reduced acute myocardial infarction (MI) mortality in recent years, ischemic heart failure continues to escalate. Therapeutic interventions effectively reversing pathological remodeling are an urgent unmet medical need. We recently demonstrated that AdipoR1 (APN [adiponectin] receptor 1) phosphorylation by GRK2 (G-protein-coupled receptor kinase 2) contributes to maladaptive remodeling in the ischemic heart. The current study clarified the underlying mechanisms leading to AdipoR1 phosphorylative desensitization and investigated whether blocking AdipoR1 phosphorylation may restore its protective signaling, reversing post-MI remodeling. METHODS: Specific sites and underlying molecular mechanisms responsible for AdipoR1 phosphorylative desensitization were investigated in vitro (neonatal and adult cardiomyocytes). The effects of AdipoR1 phosphorylation inhibition upon APN post-MI remodeling and heart failure progression were investigated in vivo. RESULTS: Among 4 previously identified sites sensitive to GRK2 phosphorylation, alanine substitution of Ser205 (AdipoR1S205A), but not other 3 sites, rescued GRK2-suppressed AdipoR1 functions, restoring APN-induced cell salvage kinase activation and reducing oxidative cell death. The molecular investigation followed by functional determination demonstrated that AdipoR1 phosphorylation promoted clathrin-dependent (not caveolae) endocytosis and lysosomal-mediated (not proteasome) degradation, reducing AdipoR1 protein level and suppressing AdipoR1-mediated cytoprotective action. GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1S205A overexpression. Moreover, AdipoR1S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function. Most importantly, AdipoR1 function was preserved during heart failure development in AdipoR1-KO (AdipoR1 knockout) mice reexpressing hAdipoR1S205A. APN administration in the failing heart reversed post-MI remodeling and improved cardiac function. However, reexpressing hAdipoR1WT in AdipoR1-KO mice failed to restore APN cardioprotection. CONCLUSIONS: Ser205 is responsible for AdipoR1 phosphorylative desensitization in the failing heart. Blockade of AdipoR1 phosphorylation followed by pharmacological APN administration is a novel therapy effective in reversing post-MI remodeling and mitigating heart failure progression.

C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood-Retinal Barrier Tight Junctions.

Background The impairment of the inner blood-retinal barrier (iBRB) increases the pathological development of diabetic retinopathy (DR), a severe complication in diabetic patients. Identifying approaches to preserving iBRB integrity and function is a significant challenge in DR. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly discovered adipokine and a vital biomarker, predicting DR severity. We sought to determine whether and how CTRP3 affects the pathological development of non-proliferative diabetic retinopathy (NPDR). Methods To clarify the pathophysiologic progress of the blood-retinal barrier in NPDR and explore its potential mechanism, a mouse Type 2 diabetic model of diabetic retinopathy was used. The capillary leakage was assessed by confocal microscope with fluorescent-labeled protein in vivo. Furthermore, the effect of CTRP3 on the inner blood-retinal barrier (iBRB) and its molecular mechanism was clarified. Results The results demonstrated that CTRP3 protects iBRB integrity and resists the vascular permeability induced by DR. Mechanistically, the administration of CTRP3 activates the AMPK signaling pathway and enhances the expression of Occludin and Claudin-5 (tight junction protein) in vivo and in vitro. Meanwhile, CTRP3 improves the injury of human retinal endothelial cells (HRMECs) induced by high glucose/high lipids (HG/HL), and its protective effects are AMPK-dependent. Conclusions In summary, we report, for the first time, that CTRP3 prevents diabetes-induced retinal vascular permeability via stabilizing the tight junctions of the iBRB and through the AMPK-dependent Occludin/Claudin-5 signaling pathway, thus critically affecting the development of NPDR.

C1q/TNF-related protein 5 contributes to diabetic vascular endothelium dysfunction through promoting Nox-1 signaling.

OBJECTIVE: Dysregulated adipokine profiles contribute to the pathogenesis of diabetic cardiovascular complications. Endothelial cell (EC) dysfunction, a common pathological alteration in cardiovascular disorders, is exaggerated in diabetes. However, it is unclear whether and how dysregulated adipokines may contribute to diabetic EC dysfunction. METHODS AND RESULTS: Serum C1q/TNF-Related Protein 5 (CTRP5) were determined in control/diabetes patients, and control/diabetic mice (high-fat diet, HFD). We observed for the first time that serum total CTRP5 was increased, high molecular weight (HMW) form was decreased, but the globular form (gCTRP5) was significantly increased in diabetic patients. These pathological alterations were reproduced in diabetic mice. To determine the pathological significance of increased gCTRP5 in diabetes, in vivo, ex vivo and in vitro experiments were performed. Diabetic atherosclerosis and EC dysfunction were significantly attenuated by the in vivo administration of CTRP5 neutralization antibody (CTRP5Ab). EC apoptosis was significantly increased in diabetic EC (isolated from HFD animal aorta) or high glucose high lipid (HGHL) cultured HUVECs. These pathological alterations were further potentiated by gCTRP5 and attenuated by CTRP5Ab. Pathway specific discovery-driven approach revealed that Nox1 expression was one of the signaling molecules commonly activated by HFD, HGHL, and gCTRP5. Treatment with CTRP5Ab reversed HFD-induced Nox1 upregulation. Finally, Nox1siRNA was used to determine the causative role of Nox1 in gCTRP5 induced EC apoptosis in diabetes. Results showed that gCTRP5 activated the mitochondrial apoptotic signal of EC in diabetes, which was blocked by the silencing Nox1 gene. CONCLUSION: We demonstrated for the first time that gCTRP5 is a novel molecule contributing to diabetic vascular EC dysfunction through Nox1-mediated mitochondrial apoptosis, suggesting that interventions blocking gCTRP5 may protect diabetic EC function, ultimately attenuate diabetic cardiovascular complications.

Advancing Diversity and Inclusion: An Organized Approach Through a Medical Specialty Academy.

BACKGROUND: The benefits of a diverse workforce in medicine have been previously described. While the population of the United States has become increasingly diverse, this has not occurred in the physician workforce. In academic medicine, underrepresented in medicine (URiM) faculty are less likely to be promoted or retained in academic institutions. Studies suggest that mentorship and engagement increase the likelihood of development, retention, and promotion. However, it is not clear what form of mentorship creates these changes. The Academy for Diversity and Inclusion in Emergency Medicine (ADIEM), an academy within the Society for Academic Emergency Medicine, is a group focused on advancing diversity and inclusion as well as promoting the development of its URiM students, residents, and faculty. The Academy serves many of the functions of a mentoring program. We assessed whether active involvement in ADIEM led to increased publications, promotion, or leadership advancement in the areas of diversity, equity, and inclusion. METHODS: We performed a survey of ADIEM members to determine if career development and productivity, defined as written scholarly products, presentations, and mentorship in the area of diversity, equity, and inclusion was enhanced by the establishment of the academy. To determine whether there were significant changes in academic accomplishments after the formation of ADIEM, two groups, ADIEM leaders and ADIEM nonleader members, were examined. RESULTS: Thirteen ADIEM leaders and 14 ADIEM nonleader members completed the survey. Academic productivity in the area of diversity, equity, and inclusion increased significantly among ADIEM leaders when compared to ADIEM nonleader members after the founding of ADIEM. In particular, in the ADIEM leader group, there were significant increases in manuscript publications (1.31 ± 1.6 to 5.5 ± 7.96, p = 0.12), didactic presentations (3.85 ± 7.36 to 23.46 ± 44.52, p < 0.01), grand rounds presentations (0.83 ± 1.75 to 8.6 ± 10.71, p < 0.05), and student/resident mentees (6.46 ± 9.36 to 25 ± 30.41, p = 0.02). CONCLUSION: The formation of a specialized academy within a national medical society has advanced academic accomplishments in diversity, equity, and inclusion in emergency medicine among ADIEM leadership. Involvement of URiM and lesbian, gay, bisexual, and transgender faculty in the academy fostered faculty development, mentoring, and educational scholarship.

Toward Structural Competency in Emergency Medical Education.

As the emergency department (ED) is the "front door" of the hospital and the primary site by which most patients access the health care system, issues of inequity are especially salient for emergency medicine (EM) practice. Improving the health of ED patients, especially those who are stigmatized and disenfranchised, depends on having emergency physicians that are cognizant and attentive to their needs in and out of the medical encounter. EM resident education has traditionally incorporated a "cultural competency" model to equip residents with tools to combat individual bias and stigma. Although this framework has been influential in drawing attention to health inequities, it has also been criticized for its potential to efface differences within groups (such as socioeconomic differences), overstate cultural or racial differences, and unintentionally reinforce stereotypes or blaming of patients for their ill health or difficult circumstances. In contrast, emerging frameworks of structural competency call for physicians to recognize the ways in which health outcomes are influenced by complex, interrelated structural forces (e.g., poverty, racism, gender discrimination, immigration policy) and to attend to these causes of poor health. We present here the framework of structural competency, extending it to the unique ED setting. We provide tangible illustrations of the ways in which this framework is relevant to the ED setting and can be incorporated in EM education.

Overemphasis of Step 1 Scores May Affect Application Pool Diversity in Radiation Oncology.

PURPOSE: Many radiation oncology programs use Step 1 score metrics as a surrogate for intelligence and success to screen applicants. The impact of this practice on radiation oncology applicant pool diversity is unknown. METHODS AND MATERIALS: Electronic Residency Application Service applications submitted to our institution between 2015 and 2018 match cycles were reviewed. Sex, age, race/ethnicity, and Step 1 scores were collected. Groupings by characteristics were sex (female vs male), age ≤30 versus >30 years, and race/ethnicity by underrepresented minority (URM) versus non-URM status. URMs were defined as Black/African American, Hispanic, Native American/Alaskan Native, and Hawaiian/Pacific Islander. Step 1 scores were divided based on scores of 220 and 240. The association between applicant demographics and Step 1 scores was assessed using proportional odds logistic regression for ordinal outcomes. RESULTS: Eight hundred ten applicants with Step 1 scores ranging from 188 to 275 were collected, representing nearly 90% of all applicants during the 2015 to 2018 Electronic Residency Application Service cycles. Twenty-nine percent were female, 29% were >30 years of age, and 10% were URMs. Increasing Step 1 score requirements disproportionately decreased representation of applicants who were female versus male at 240 (-51% vs -31%), >30 versus ≤30 years old at 220 (-28% vs -6%) and 240 (-55% vs -26%), and URMs versus non-URMs at 220 (-34% vs -9%) and 240 (-61% vs -34%). On analysis, Step 1 score requirements had a statistically significantly impact on applicant distributions based on sex, age, and URM status (P < .001). CONCLUSIONS: Overemphasis of Step 1 scores may reduce the diversity of the radiation oncology applicant pool. Further evaluation of practices that counter the stated American Society of Clinical Oncology, American Society of Radiation Oncology, and American College of Radiology diversity missions should be pursued to improve understanding of barriers and biases.

miRNA-Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post-MI Remodeling by Sleep Breathing Disorders.

RATIONALE: Obstructive sleep apnea-hypopnea syndrome, a sleep breathing disorder in which chronic intermittent hypoxia (CIH) is the primary pathology, is associated with multiple cardiovascular diseases. However, whether and how CIH may affect cardiac remodeling following myocardial infarction (MI) remains unknown. OBJECTIVE: To determine whether CIH exposure at different periods of MI may exacerbate post-MI heart failure and to identify the mechanisms underlying CIH-exacerbated post-MI remodeling. METHODS AND RESULTS: Adult male mice were subjected to MI (4 weeks) with and without CIH (4 or 8 weeks). CIH before MI (CIH+MI) had no significant effect on post-MI remodeling. However, double CIH exposure (CIH+MI+CIH) or CIH only during the MI period (MI+CIH) significantly exacerbated pathological remodeling and reduced survival rate. Mechanistically, CIH activated TGF-ß (tumor growth factor-ß)/Smad (homologs of both the Drosophila protein MAD and the C. elegans protein SMA) signaling and enhanced cardiac epithelial to mesenchymal transition, markedly increasing post-MI cardiac fibrosis. Transcriptome analysis revealed that, among 15 genes significantly downregulated (MI+CIH versus MI), Ctrp9 (a novel cardioprotective cardiokine) was one of the most significantly inhibited genes. Real-time polymerase chain reaction/Western analysis confirmed that cardiomyocyte CTRP9 expression was significantly reduced in MI+CIH mice. RNA-sequencing, real-time polymerase chain reaction, and dual-luciferase reporter assays identified that microRNA-214-3p is a novel Ctrp9 targeting miRNA. Its upregulation is responsible for Ctrp9 gene suppression in MI+CIH. Finally, AAV9 (adeno-associated virus 9)-mediated cardiac-specific CTRP9 overexpression or rCTRP9 (recombinated CTRP9) administration inhibited TGF-ß/Smad and Wnt/ß-catenin pathways, attenuated interstitial fibrosis, improved cardiac function, and enhanced survival rate in MI+CIH animals. CONCLUSIONS: This study provides the first evidence that MI+CIH upregulates miR-214-3p, suppresses cardiac CTRP9 (C1q tumor necrosis factor-related protein-9) expression, and exacerbates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathological remodeling in MI patients with obstructive sleep apnea-hypopnea syndrome.

Withaferin A Prevents Myocardial Ischemia/Reperfusion Injury by Upregulating AMP-Activated Protein Kinase-Dependent B-Cell Lymphoma2 Signaling.

BACKGROUND: Withaferin A (WFA), an anticancer constituent of the plant Withania somnifera, inhibits tumor growth in association with apoptosis induction. However, the potential role of WFA in the cardiovascular system is little-studied and controversial.Methods and Results:Two different doses of WFA were tested to determine their cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury through evaluation of cardiofunction in wild-type and AMP-activated protein kinase domain negative (AMPK-DN) gentransgenic mice. Surprisingly, cardioprotective effects (improved cardiac function and reduced infarct size) were observed with low-dose WFA (1 mg/kg) delivery but not high-dose (5 mg/kg). Mechanistically, low-dose WFA attenuated myocardial apoptosis. It decreased MI/R-induced activation of caspase 9, the indicator of the intrinsic mitochondrial pathway, but not caspase 8. It also upregulated the level of AMP-activated protein kinase (AMPK) phosphorylation and increased the MI/R inhibited ratio of Bcl2/Bax. In AMPK-deficient mice, WFA did not ameliorate MI/R-induced cardiac dysfunction, attenuate infarct size, or restore the Bcl2/Bax (B-cell lymphoma2/Mcl-2-like protein 4) ratio. CONCLUSIONS: These results demonstrated for the first time that low-dose WFA is cardioprotective via upregulation of the anti-apoptotic mitochondrial pathway in an AMPK-dependent manner.

Implicit Bias Education and Emergency Medicine Training: Step One? Awareness.

OBJECTIVE: Prior research suggests that health care providers are susceptible to implicit biases, specifically prowhite biases, and that these may contribute to health care disparities by influencing physician behavior. Despite these findings, implicit bias training is not currently embedded into emergency medicine (EM) residency training and few studies exist that evaluate the effectiveness of implicit bias training on awareness during residency conference. We sought to conduct a mixed-methods program evaluation of a formalized educational intervention targeted on the topic of implicit bias. METHODS: We used a design thinking framework to develop a curricular intervention. The intervention consisted of taking the Harvard Implicit Association Test (IAT) on race to introduce the concept of implicit bias, followed by a facilitated discussion to explore participant's perceptions on whether implicit bias may lead to variations in care. The facilitated discussion was audio recorded, transcribed, and coded for emerging themes. An online survey assessed participant awareness of these topics before and after the intervention and was analyzed using paired t-tests. RESULTS: After the intervention, participant's awareness of their individual implicit biases increased by 33.3% (p = 0.003) and their awareness of how their IAT results influences how they deliver care to patients increased by 9.1% (p = 0.03). Emerging themes included skepticism of the implicit bias test results with the desire to have "neutral" results, acknowledgment that pattern recognition may lead to "blind spots" in care, recognition that bias exists on a personal and systemic level, and interest in regular educational interventions to address implicit bias. CONCLUSIONS: This novel educational intervention on implicit bias resulted in improvement in participants' awareness of their implicit biases and how it may affect their patient care. Our intervention can serve as a model for other residency programs to develop and implement an intervention to create awareness of implicit bias and its potential impact on patient care.

Withaferin A inhibits apoptosis via activated Akt-mediated inhibition of oxidative stress.

Withaferin A (WFA), a withanolide derived from medicinal plant Withania somnifera, possesses anti-tumorigenic and immunomodulatory activities against various cancer cells. However, the role of WFA in myocardial ischemia reperfusion (MI/R) injury remains unclear. In the present study, we determined whether WFA may regulate cardiac ischemia reperfusion injury and elucidate the underlying mechanisms. We demonstrated that WFA enhanced H9c2 cells survival ability against simulated ischemia/reperfusion (SI/R) or hydrogen peroxide (H2O2)-induced cell apoptosis. In addition, the enhanced oxidative stress induced by SI/R was inhibited by WFA. Among the multiple antioxidant molecules determined, antioxidants SOD2, SOD3, Prdx-1 was obviously upregulated by WFA. When Akt inhibitor IV was administrated, WFA's suppression effect on oxidative stress was obviously abolished. Additional experiments demonstrated that WFA successfully inhibited H2O2 induced upregulation of SOD2, SOD3, and Prdx-1, ameliorated cardiomyocyte caspase-3 activity via an Akt dependent manner. Collectively, these results support the therapeutic potential of WFA against cardiac ischemia reperfusion injury and highlight the application of WFA in cardiovascular diseases holding great promise for the future.

Sickle Cell Disease in the Emergency Department.

Acute painful episodes are the most common reason for emergency department visits among patients with sickle cell disease (SCD). Early and aggressive pain management is a priority. Emergency providers (EPs) must also diagnose other emergent diagnoses in patients with SCD and differentiate them from vaso-occlusive crisis. EPs should be aware of cognitive biases that may misdirect the diagnostic process. Administration of intravenous fluids should be used judiciously. Blood transfusion may be considered. Coordination of care with hematology is an important part of the effective emergency department and long-term management of patients with SCD.

Acquired Bleeding Disorders.

Emergency medicine practitioners treat bleeding patients on a regular basis. Disorders of hemostasis are an additional challenge in these patients but can be assessed and managed in a systematic fashion. Of particular importance to the emergency clinician are the iatrogenic causes of abnormal hemostasis. Other acquired causes of abnormal hemostasis include renal disease, immune thrombocytopenia, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, acquired coagulation factor inhibitors, acute traumatic coagulopathy, liver disease, and disseminated intravascular coagulopathy.

Current Status of Gender and Racial/Ethnic Disparities Among Academic Emergency Medicine Physicians.

OBJECTIVE: A 2010 survey identified disparities in salaries by gender and underrepresented minorities (URM). With an increase in the emergency medicine (EM) workforce since, we aimed to 1) describe the current status of academic EM workforce by gender, race, and rank and 2) evaluate if disparities still exist in salary or rank by gender. METHODS: Information on demographics, rank, clinical commitment, and base and total annual salary for full-time faculty members in U.S. academic emergency departments were collected in 2015 via the Academy of Administrators in Academic Emergency Medicine (AAAEM) Salary Survey. Multiple linear regression was used to compare salary by gender while controlling for confounders. RESULTS: Response rate was 47% (47/101), yielding data on 1,371 full-time faculty: 33% women, 78% white, 4% black, 5% Asian, 3% Asian Indian, 4% other, and 7% unknown race. Comparing white race to nonwhite, 62% versus 69% were instructor/assistant, 23% versus 20% were associate, and 15% versus 10% were full professors. Comparing women to men, 74% versus 59% were instructor/assistant, 19% versus 24% were associate, and 7% versus 17% were full professors. Of 113 chair/vice-chair positions, only 15% were women, and 18% were nonwhite. Women were more often fellowship trained (37% vs. 31%), less often core faculty (59% vs. 64%), with fewer administrative roles (47% vs. 57%; all p < 0.05) but worked similar clinical hours (mean ± SD = 1,069 ± 371 hours vs. 1,051 ± 393 hours). Mean overall salary was $278,631 (SD ± $68,003). The mean (±SD) salary of women was $19,418 (±$3,736) less than men (p < 0.001), even after adjusting for race, region, rank, years of experience, clinical hours, core faculty status, administrative roles, board certification, and fellowship training. CONCLUSIONS: In 2015, disparities in salary and rank persist among full-time U.S. academic EM faculty. There were gender and URM disparities in rank and leadership positions. Women earned less than men regardless of rank, clinical hours, or training. Future efforts should focus on evaluating salary data by race and developing systemwide practices to eliminate disparities.

High glucose/High Lipids impair vascular adiponectin function via inhibition of caveolin-1/AdipoR1 signalsome formation.

Reduced levels of adiponectin (APN) contribute to cardiovascular injury in the diabetic population. Recent studies demonstrate elevated circulating APN levels are associated with endothelial dysfunction during pre-diabetes, suggesting the development of APN resistance. However, mechanisms leading to, and the role of, vascular APN resistance in endothelial dysfunction remain unidentified. The current study determined whether diabetes cause endothelial APN resistance, and by what mechanisms. Under high glucose/high lipids (HG/HL), APN-stimulated nitric oxide production by HUVEC was decreased, phosphorylation of eNOS, AMPK, and Akt was attenuated (P<0.01), and APN's anti-TNFα effect was blunted (P<0.01). APN receptor expression remained normal, whereas Cav1 expression was reduced in HG/HL cells (P<0.01). The AdipoR1/Cav1 signaling complex was dissociated in HG/HL cells. Knock-down of Cav1 inhibited APN's anti-oxidative and anti-inflammatory actions. Conversely, preventing HG/HL-induced Cav1 downregulation by Cav1 overexpression preserved APN signaling in HG/HL cells. Knock-in of a wild type Cav1 in Cav1 knock-down cells restored caveolae structure and rescued APN signaling. In contrast, knock-in of a mutated Cav1 scaffolding domain restored caveolae structure, but failed to rescue APN signaling in Cav1 knock-down cells. Finally, AdipoR1/Cav1 interaction was significantly reduced in diabetic vascular tissue, and the vasorelaxative response to APN was impaired in diabetic animals. The current study demonstrates for the first time the interaction between AdipoR1 and Cav1 is critical for adiponectin-mediated vascular signaling. The AdipoR1/Cav1 interaction is adversely affected by HG/HL, due largely to reduced Cav1 expression, supporting a potential mechanism for the development of APN resistance, contributing to diabetic endothelial dysfunction.

Body mass index and risk of hospitalization among adults presenting with asthma exacerbation to the emergency department.

RATIONALE: Studies have linked obesity to incident asthma and worse chronic severity/control. However, the relationship between obesity and acute asthma morbidity remains unclear. OBJECTIVES: To determine whether obese adults presenting to the emergency department (ED) with asthma exacerbation are at higher risk of hospitalization compared with normal-weight adults. METHODS: Multicenter chart review study of 48 EDs across 23 U.S. states. We identified ED patients aged 18 to 54 years with asthma exacerbation during 2011 to 2012. Primary outcome was hospitalization. MEASUREMENTS AND MAIN RESULTS: The analytic cohort comprised 1,227 patients. Of these, 323 patients (27%) were overweight (body mass index [BMI], 25-29.9 kg/m(2)), and 607 (50%) were obese (BMI ≥ 30 kg/m(2)). Among the 607 obese patients, 364 patients (60%) were severely obese (BMI ≥ 35 kg/m(2)). Several markers of chronic severity/control of asthma and acute severity did not differ across BMI groups. By contrast, compared with normal-weight patients, the risk of hospitalization was higher in patients who were overweight (11 vs. 18%; odds ratio [OR], 1.68; 95% confidence interval [CI], 1.05-2.68; P = 0.03) or obese (11 vs. 23%; OR, 2.30; 95% CI, 1.53-3.49; P < 0.001). In the adjusted analysis with multiple imputation, the association lost statistical significance in overweight patients (OR, 1.56; 95% CI, 0.90-2.71; P = 0.11) but persisted in obese patients (OR, 1.69; 95% CI, 1.02-2.81; P = 0.04). The latter finding was driven by an even higher risk of hospitalization in severely obese patients (OR, 1.95; 95% CI, 1.13-3.34; P = 0.02). CONCLUSIONS: In this multicenter study of ED patients with asthma exacerbation, we found that obese adults were at a higher risk of hospitalization compared with normal-weight adults.

Sickle cell disease in the emergency department.

Acute painful episodes are the most common reason for emergency department visits among patients with sickle cell disease (SCD). Early and aggressive pain management is a priority. Emergency providers (EPs) must also diagnose other emergent diagnoses in patients with SCD and differentiate them from vaso-occlusive crisis. EPs should be aware of cognitive biases that may misdirect the diagnostic process. Administration of intravenous fluids should be used judiciously. Blood transfusion may be considered. Coordination of care with hematology is an important part of the effective emergency department and long-term management of patients with SCD.