DHCR7 Expression Predicts Poor Outcomes and Mortality From Sepsis.

This is a study of lipid metabolic gene expression patterns to discover precision medicine for sepsis. OBJECTIVES: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 d). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. DESIGN SETTING AND PARTICITPANTS: Secondary analysis of samples from prospectively enrolled sepsis patients (first 24 hr) and a zebrafish endotoxemia model for drug discovery. Patients were enrolled from the emergency department or ICU at an urban teaching hospital. Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing and reverse transcriptase polymerase chain reaction. A lipopolysaccharide zebrafish endotoxemia model was used for confirmation of human transcriptomic findings and drug discovery. MAIN OUTCOMES AND MEASURES: The derivation cohort included 96 patients and controls (12 early death, 13 CCI, 51 rapid recovery, and 20 controls) and the validation cohort had 52 patients (6 early death, 8 CCI, and 38 rapid recovery). RESULTS: The cholesterol metabolism gene 7-dehydrocholesterol reductase (DHCR7) was significantly up-regulated in both derivation and validation cohorts in poor outcome sepsis compared with rapid recovery patients and in 90-day nonsurvivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed up-regulation of dhcr7 and several of the same lipid genes up-regulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1, and ldlra) compared with controls. We then tested six lipid-based drugs in the zebrafish endotoxemia model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from lipopolysaccharide death in a model with 100% lethality. CONCLUSIONS: DHCR7, an important cholesterol metabolism gene, was up-regulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis.

Objective: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 days). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. Design: Secondary analysis of samples from prospectively enrolled sepsis patients and a zebrafish sepsis model for drug discovery. Setting: Emergency department or ICU at an urban teaching hospital. Patients: Sepsis patients presenting within 24 hours. Methods: Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing (RNA-seq) and reverse transcriptase polymerase chain reaction (RT-qPCR). A lipopolysaccharide (LPS) zebrafish sepsis model was used for confirmation of human transcriptomic findings and drug discovery. Measurements and Main Results: There were 96 samples in the derivation (76 sepsis, 20 controls) and 52 in the validation cohort (sepsis only). The cholesterol metabolism gene 7-Dehydrocholesterol Reductase ( DHCR7) was significantly upregulated in both derivation and validation cohorts in poor outcome sepsis compared to rapid recovery patients and in 90-day non-survivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed upregulation of dhcr7 and several of the same lipid genes upregulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1 , ldlra) compared to controls. We then tested six lipid-based drugs in the zebrafish sepsis model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from LPS death in a model with 100% lethality. Conclusions: DHCR7, an important cholesterol metabolism gene, was upregulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

Emergency Medicine Around the World: Analysis of the 2019 American College of Emergency Physicians International Ambassador Country Reports.

OBJECTIVE: The specialty of emergency medicine and recognition of the need for emergency care continue to grow globally. The specialty and emergency care systems vary according to context. This study characterizes the specialty of emergency medicine around the world, trends according to region and income level, and challenges for the specialty. METHODS: We distributed a 56-question electronic survey to all members of the American College of Emergency Physicians International Ambassador Program between March 2019 and January 2020. The Ambassador Program leadership designed the survey covering specialty recognition, workforce, system components, and emergency medicine training. We analyzed results by country and in aggregate using SAS software (SAS Institute Inc). We tested the associations between World Bank income group and number of emergency medicine residency-trained physicians (RTPs) and emergency medicine specialty recognition using non-parametric Fisher's exact testing. We performed inductive coding of qualitative data for themes. RESULTS: Sixty-three out of 78 countries' teams (80%) responded to the survey. Response countries represented roughly 67% of the world's population and included countries in all World Bank income groups. Fifty-four countries (86%) recognized emergency medicine as a specialty. Ten (16%) had no emergency medicine residency programs, and 19 (30%) had only one. Eight (11%) reported having no emergency medicine RTPs and 30 (48%) had <100. Fifty-seven (90%) had an emergency medical services (EMS) system, and 52 (83%) had an emergency access number. Higher country income was associated with a higher number of emergency medicine RTPs per capita (P = 0.02). Only 6 countries (8%) had >5 emergency medicine RTPs per 100,000 population, all high income. All 5 low-income countries in the sample had <2 emergency medicine RTPs per 100,000 population. Challenges in emergency medicine development included lack of resources (38%), burnout and poor working conditions (31%), and low salaries (23%). CONCLUSIONS: Most surveyed countries recognized emergency medicine as a specialty. However, numbers of emergency medicine RTPs were small, particularly in lower income countries. Most surveyed countries reported an EMS system and emergency access number. Lack of resources, burnout, and poor pay were major threats to emergency medicine growth.

A hypolipoprotein sepsis phenotype indicates reduced lipoprotein antioxidant capacity, increased endothelial dysfunction and organ failure, and worse clinical outcomes.

OBJECTIVE: Approximately one-third of sepsis patients experience poor outcomes including chronic critical illness (CCI, intensive care unit (ICU) stay > 14 days) or early death (in-hospital death within 14 days). We sought to characterize lipoprotein predictive ability for poor outcomes and contribution to sepsis heterogeneity. DESIGN: Prospective cohort study with independent replication cohort. SETTING: Emergency department and surgical ICU at two hospitals. PATIENTS: Sepsis patients presenting within 24 h. METHODS: Measures included cholesterol levels (total cholesterol, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C]), triglycerides, paraoxonase-1 (PON-1), and apolipoprotein A-I (Apo A-I) in the first 24 h. Inflammatory and endothelial markers, and sequential organ failure assessment (SOFA) scores were also measured. LASSO selection assessed predictive ability for outcomes. Unsupervised clustering was used to investigate the contribution of lipid variation to sepsis heterogeneity. MEASUREMENTS AND MAIN RESULTS: 172 patients were enrolled. Most (~ 67%, 114/172) rapidly recovered, while ~ 23% (41/172) developed CCI, and ~ 10% (17/172) had early death. ApoA-I, LDL-C, mechanical ventilation, vasopressor use, and Charlson Comorbidity Score were significant predictors of CCI/early death in LASSO models. Unsupervised clustering yielded two discernible phenotypes. The Hypolipoprotein phenotype was characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1), higher SOFA scores, and worse clinical outcomes (45% rapid recovery, 40% CCI, 16% early death; 28-day mortality, 21%). The Normolipoprotein cluster patients had higher cholesterol levels, less endothelial dysfunction, lower SOFA scores and better outcomes (79% rapid recovery, 15% CCI, 6% early death; 28-day mortality, 15%). Phenotypes were validated in an independent replication cohort (N = 86) with greater sepsis severity, which similarly demonstrated lower HDL-C, ApoA-I, and higher ICAM-1 in the Hypolipoprotein cluster and worse outcomes (46% rapid recovery, 23% CCI, 31% early death; 28-day mortality, 42%). Normolipoprotein patients in the replication cohort had better outcomes (55% rapid recovery, 32% CCI, 13% early death; 28-day mortality, 28%) Top features for cluster discrimination were HDL-C, ApoA-I, total SOFA score, total cholesterol level, and ICAM-1. CONCLUSIONS: Lipoproteins predicted poor sepsis outcomes. A Hypolipoprotein sepsis phenotype was identified and characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1) and organ failure, and worse clinical outcomes.

Updates and controversies in the early management of sepsis and septic shock.

Sepsis is a common and life-threatening condition that requires early recognition and swift initial management. Diagnosis and treatment of sepsis and septic shock are fundamental for emergency clinicians, and include knowledge of clinical and laboratory indicators of subtle and overt organ dysfunction, infection source control, and protocols for prompt identification of the early signs of septic shock. This issue is a structured review of the literature on the management of sepsis, focusing on the current evidence, guidelines, and protocols.

Building a virtual community of practice for medical students: The Global Emergency Medicine Student Leadership Program.

Virtual communities of practice (VCoPs) facilitate distance learning and mentorship by engaging members around shared knowledge and experiences related to a central interest. The American College of Emergency Physicians and Emergency Medicine Residents' Association's Global Emergency Medicine Student Leadership Program (GEM-SLP) provides a valuable model for building a VCoP for GEM and other niche areas of interest. This VCoP facilitates opportunities for experts and mentees affiliated with these national organizations to convene regularly despite barriers attributed to physical distance. The GEM-SLP VCoP is built around multiple forms of mentorship, monthly mentee-driven didactics, academic projects, and continued engagement of program graduates in VCoP leadership. GEM-SLP fosters relationships through (1) themed mentoring calls (career paths, work/life balance, etc); (2) functional mentorship through didactics and academic projects; and (3) near-peer mentoring, provided by mentors near the mentees' stage of education and experience. Monthly mentee-driven didactics focus on introducing essential GEM principles while (1) critically analyzing literature based on a journal article; (2) building a core knowledge base from a foundational textbook; (3) applying knowledge and research to a project proposal; and (4) gaining exposure to training and career opportunities via mentor career presentations. Group academic projects provide a true GEM apprenticeship as mentees and mentors work collaboratively. GEM-SLP mentees found the VCoP beneficial in building fundamental GEM skills and knowledge and forming relationships with mentors and like-minded peers. GEM-SLP provides a framework for developing mentorship programs and VCoPs in emergency medicine, especially when niche interests or geographic distance necessitate a virtual format.

Points & Pearls: Updates and controversies in the early management of sepsis and septic shock

Sepsis is a common and life-threatening condition that requires early recognition and swift initial management. Diagnosis and treatment of sepsis and septic shock are fundamental for emergency clinicians, and include knowledge of clinical and laboratory indicators of subtle and overt organ dysfunction, infection source control, and protocols for prompt identification of the early signs of septic shock. [Points & Pearls is a digest of Emergency Medicine Practice.]

Updates and controversies in the early management of sepsis and septic shock.

Sepsis is a common and life-threatening condition that requires early recognition and swift initial management. Diagnosis and treatment of sepsis and septic shock are fundamental for emergency clinicians, and include knowledge of clinical and laboratory indicators of subtle and overt organ dysfunction, infection source control, and protocols for prompt identification of the early signs of septic shock. This issue is a structured review of the literature on the management of sepsis, focusing on the current evidence, guidelines, and protocols.

Poisoning cases and their management in emergency centres of government hospitals in northwest Ethiopia.

INTRODUCTION: With the widespread availability of a vast number of chemicals and drugs, acute poisoning is a common medical emergency worldwide. In spite of the success of interventions to prevent toxic ingestions, acute poisoning continues to be an important public health problem. Because of weak regulations and limited health care services in developing countries, adverse outcomes from poisoning are more prevalent than in the developed world. Due to the limited Ethiopian literature on this topic, the primary objective of this study was to evaluate and report poisoning cases, their management and outcome in northwest Ethiopia. METHODS: This is a retrospective study of all poisoning cases admitted and managed in the emergency centres of Gondar Teaching Referral Hospital and Metema and Debark district hospitals, from September 2010 to December 2014. Data was collected through retrospective chart review of patients who were admitted due to poisoning. RESULTS: There were 543 registered poisoning cases listed in the registry during the study period, of which 344 cases (63.4%) had complete data and were included in the final analysis. There were 48,619 emergency centre visits during the study period, with poisoning cases accounting for 1.1%. Females (60%) were predominant among intentional as well as unintentional poisoning cases. Patients between 15 and 24 years of age accounted for 55% of the cases. Patients poisoned with organophosphate and bleaching agents accounted for 35% and 25%, respectively. Among the poisoning patients, 74% were treated with decontamination, while those exposed to organophosphate were treated with atropine 45.5% (55/121) of the time. DISCUSSION: Young females comprise a group at increased risk for suicidal poisonings. As a developing nation, pesticide and bleaching agents remain a significant cause of acute poisonings in Ethiopia. Intentional poisoning remains the most significant identified cause of poisoning overall.

INTRODUCTION: Avec la disponibilité largement répandue d'un grand nombre de produits chimiques et de médicaments, les intoxications aiguës constituent une urgence médicale fréquente partout dans le monde. En dépit du succès des interventions visant à prévenir l'ingestion de substances toxiques, l'intoxication aiguë reste un problème de santé publique important. En raison de la faiblesse des réglementations et des services de soins de santé limités dans les pays en voie de développement, les effets indésirables des intoxications y prévalent davantage que dans le monde développé. En raison des limites de la littérature éthiopienne sur cette question, le principal objectif de cette étude était d'évaluer et de rendre compte des cas d'intoxication, de leur traitement et de leurs conclusions dans le Nord-ouest de l'Ethiopie. MÉTHODES: Cette étude est une étude rétrospective de tous les cas d'intoxication ayant fait l'objet d'une admission et d'un traitement dans les services des urgences de l'hôpital universitaire de Gondar et des hôpitaux de district de Metema et de Debark de septembre 2010 à décembre 2014. Des données ont été recueillies au moyen d'un examen rétrospectif des dossiers de patients admis pour intoxication. RÉSULTATS: 543 cas d'intoxication ont été inscrits dans le registre au cours de la période couverte par l'étude, 344 dossiers (63,4%) qui disposaient de données complètes ont été inclus dans l'analyse finale. Au cours de la période à l'étude, 48 619 visites ont été enregistrées aux services des urgences, les cas d'intoxication totalisant 1,1% de ces visites. Les femmes (60%) étaient prédominantes, tant pour les cas d'empoisonnement intentionnel que d'intoxication non intentionnelle. Les patients âgés de 15 à 24 ans constituaient 55% des cas. Les patients souffrant d'une intoxication aux organophosphates et agents blanchissants totalisaient respectivement 35% et 25% des cas d'intoxication. Parmi les patients souffrant d'intoxication, 74% étaient traités par voie de décontamination et ceux exposés aux organophosphates étaient traités à l'atropine dans 45,5% des cas (55/121). DISCUSSION: Les jeunes femmes constituent un groupe présentant un risque accru de suicide par empoisonnement. En raison de sa situation de pays en voie de développement, les pesticides et agents de blanchiment restent une cause significative d'intoxication aiguë en Ethiopie. Les empoisonnements intentionnels restent la cause d'intoxication globale la plus importante.