Time series analysis of total and direct associations between high temperatures and preterm births in Detroit, Michigan.

OBJECTIVES: Preterm births (PTBs) represent significant health risks, and several studies have found associations between high outdoor temperatures and PTB. We estimated both the total and natural direct effects (independent of particulate matter, ozone and nitrogen dioxide air pollutants) of the prior 2-day mean apparent temperature (AT) on PTB. We evaluated effect modification by maternal age, race, education, smoking status and prenatal care. DESIGN AND SETTING: We obtained birth records and meteorological data for the Detroit, Michigan, USA area, for the warm months (May to September), 1991 to 2001. We used a time series Poisson regression with splines of AT, wind speed, solar radiation and citywide average precipitation to estimate total effects. To accommodate multiple mediators and exposure-mediator interactions, AT inverse odds weights, predicted by meteorological and air pollutant covariates, were added in a subsequent model to estimate direct effects. RESULTS: At 24.9°C relative to 18.6°C, 10.6% (95% CI: 3.8% to 17.2%) of PTBs were attributable to the total effects of AT, and 10.4% (95% CI: 2.2% to 17.5%) to direct effects. Relative excess risks of interaction indicated that the risk of PTB with increasing temperature above 18.6°C was significantly lower among black mothers and higher among mothers less than 19, older than 30, with late or no prenatal care and who smoked. CONCLUSION: This additional evidence of a direct association between high temperature and PTB may motivate public health interventions to reduce extreme heat exposures among pregnant women, particularly among those who may have enhanced vulnerability.

Emergency medicine practice environment and impact on concert examination performance.

OBJECTIVE: The ABEM ConCert Examination is a summative examination that ABEM-certified physicians are required to pass once in every 10-year cycle to maintain certification. This study was undertaken to identify practice settings of emergency physicians, and to determine if there was a difference in performance on the 2017 ConCert between physicians of differing practice types and settings. METHODS: This was a mixed methods cross sectional-study, using a post-examination survey and test performance data. All physicians taking the 2017 ConCert Examination who completed three survey questions pertaining to practice type, practice locations, and teaching were included. These three questions address different aspects of academia: self-identification, an academic setting, and whether the physician teaches. RESULTS: Among 2796 test administrations of the 2017 ConCert Examination, 2693 (96.3%) completed the three survey questions about practice environment. The majority (N = 2054; 76.3%) self-identified as primarily being a community physician, 528 (19.6%) as academic, and 111 (4.1%) as other. The average ConCert Examination score for community physicians was 83.5 (95% CI, 83.3-83.8); the academic group was 84.8 (95% CI, 84.3-85.3); and the other group was 82.3 (95% CI, 81.1-83.6). After controlling for initial ability as measured by the Qualifying Examination score, there was no significant difference in performance between academic and community physicians (p = .10). CONCLUSIONS: Academic emergency physicians and community emergency physicians scored similarly on the ConCert. Working at a community teaching hospital was associated with higher examination performance. Teaching medical learners, especially non-emergency medicine residents, was also associated with better examination performance.

Physician Age and Performance on the American Board of Emergency Medicine ConCert Examination.

OBJECTIVE: This study was undertaken to expand on results from a 2014 study on the association between physician age and performance on the American Board of Emergency Medicine (ABEM) ConCert examination. METHODS: This was a retrospective, longitudinal growth study comparing performance on the ConCert examination and physicians' ages at the time of examination. All examination attempts from 1990 to 2016 made by residency-trained physicians were eligible for inclusion. Multilevel growth models were constructed to examine the relationship between age at time of examination and performance, controlling for physician characteristics. RESULTS: The study group included 15,533 examination attempts by 12,786 physicians. The mean (±SD) age of the physicians across all examination administrations was 45.02 (±5.18) years (range = 35 to 72 years). The mean (±SD) ConCert examination score across all administrations was 85.39 (±5.71; range = 51 to 100). Among first-time ConCert examination takers, older age was associated with lower examination scores (r = -0.25, p < 0.0001). Across all examination attempts, age was negatively correlated to examination scores (r = -0.24; p < 0.0001). CONCLUSIONS: After physician characteristics were controlled for, there was an association between advancing age and declining performance on the ABEM ConCert examination. This information may be important to the individual physician to develop targeted competency assessment and professional development.

Vulnerability to extreme-heat-associated hospitalization in three counties in Michigan, USA, 2000-2009.

With climate change, extreme heat (EH) events are increasing, so it is important to understand who is vulnerable to heat-associated morbidity. We determined the association between EH and hospitalizations for all natural causes; cardiovascular, respiratory, and renal diseases; diabetes mellitus; and acute myocardial infarction in Michigan, USA, at different intensities and durations. We assessed confounding by ozone and how individual characteristics and health insurance payer (a proxy for income) modified these associations. We obtained Michigan Inpatient Database, National Climatic Data Center, and US Environmental Protection Agency ozone data for May-September, 2000-2009 for three Michigan counties. We employed a case-crossover design and modeled EH as an indicator for temperature above the 95th, 97th, or 99th percentile thresholds for 1, 2, 3, or 4 days. We examined effect modification by patient age, race, sex, and health insurance payer and pooled the county results. Among non-whites, the pooled odds ratio for hospitalization on EH (97th percentile threshold) vs. non-EH days for renal diseases was 1.37 (95 % CI = 1.13-1.66), which increased with increasing EH intensity, but was null among whites (OR = 1.00, 95 % CI = 0.81, 1.25). We observed a null association between EH and cardiovascular hospitalization. EH (99th percentile threshold) was associated with myocardial infarction hospitalizations. Confounding by ozone was minimal. EH was associated with hospitalizations for renal disease among non-whites. This information on vulnerability to heat-associated morbidity helps characterize the public health burden of EH and target interventions including patient education.

American Board of Emergency Medicine Report on Residency Training Information (2015-2016).

The American Board of Emergency Medicine (ABEM) gathers extensive background information on emergency medicine residency programs and the residents training in those programs. We present the 2016 annual report on the status of US emergency medicine training programs.

The American Board of Emergency Medicine ConCert Examination: Emergency Physicians' Perceptions of Learning and Career Benefits.

OBJECTIVE: As part of the American Board of Emergency Medicine (ABEM) Maintenance of Certification (MOC) program, ABEM-certified physicians are required to pass the Continuous Certification (ConCert) examination at least every 10 years. With the 2015 ConCert examination, ABEM sought to better understand emergency physicians' perceptions of the benefits of preparing for and taking the examination and the career benefits of staying ABEM-certified. METHODS: This was a prospective survey study. A voluntary postexamination survey was administered at the end of the 2015 ABEM ConCert examination (September 21-26, 2015). Physicians were asked about the benefits of preparing for the examination and maintaining ABEM certification. Examination performance was compared to perceptions of learning and career benefits. RESULTS: Of the 2,601 on-time test takers, 2,511 respondents participated (96.5% participation rate). The majority of participants (92.0%) identified a benefit to preparing for the ConCert examination, which included reinforced medical knowledge (73.9%), increased knowledge (66.8%), and making them a better clinician (39.4%). The majority of respondents (90.8%) identified a career benefit of maintaining ABEM certification, which included more employment options (73.8%), more positively viewed by other physicians (56.8%), and better financial outcomes (29.8%). There was a statistically significant association between the perception of knowledge reinforcement and examination performance (p < 0.001). There was also a statistically significant association between the perception that staying certified created more career opportunities and examination performance (p < 0.001). CONCLUSIONS: Most emergency physicians identified benefits of preparing for and taking the ABEM ConCert examination, which included reinforcing or adding medical knowledge and making them better clinicians. Most physicians also found career benefits to remaining ABEM-certified, which included greater employment choices, higher financial compensation, and higher esteem from other physicians. The belief that preparing for and taking the examination reinforced medical knowledge was associated with better examination performance.

Physician Preparation for the American Board of Emergency Medicine ConCert Examination.

OBJECTIVES: To maintain certification by the American Board of Emergency Medicine (ABEM), physicians are required to pass the Continuous Certification (ConCert) examination at least every 10 years. On the 2014 ConCert postexamination survey, ABEM sought to understand the manner in which ABEM diplomates prepared for the test and to identify associations between test preparation approaches and performance on the ConCert examination. METHODS: This was a cross-sectional survey study. The survey was administered at the end of the 2014 ConCert examination. Analyses included chi-square and linear regression to determine the association of preparation methods with performance. RESULTS: Of the 2,431 on-time test-takers, 2,338 (96.2%) were included. The most commonly used study approach was the review of written materials designed for test preparation (1,585; 67.8%), followed by an online training course (1,006; 43.0%). There were 758 (32.4%) physicians who took a single onsite board review course, while 41 (1.8%) took two or more onsite courses. Most physicians (1,611; 68.9%) spent over 35 hours preparing for the ConCert examination. The study method that was most associated with favorable test scores was the review of written materials designed for test preparation (p < 0.001). Attending an onsite preparation course was associated with poorer performance (p < 0.001). There was a significant association between no additional preparation and failing the examination (chi-square with Yates correction; p = 0.001). CONCLUSIONS: A substantial majority (97.8%) of physicians taking the 2014 ABEM ConCert examination prepared for it. The majority of physicians used written materials specifically designed for test preparation. Reviewing written materials designed for test preparation was associated with the highest performance.

Racial Disparities in Asthma Hospitalizations Following Implementation of the Smoke-Free Air Law, Michigan, 2002-2012.

INTRODUCTION: Exposure to secondhand smoke has immediate adverse respiratory and cardiovascular effects. A growing body of literature examining health trends following the implementation of public smoking bans has demonstrated reductions in the rates of myocardial infarction and stroke, but there has been no extensive work examining asthma hospitalizations. The aim of this study was to determine the impact of the Michigan Smoke-Free Air Law (SFA law) on the rate of asthma hospitalizations among adults in Michigan and to determine any differential effects by race or sex. METHODS: Data on adult asthma hospitalizations were obtained from the Michigan Inpatient Database (MIDB). Poisson regression was used to model relative risks for asthma hospitalization following the SFA law with adjustments for sex, race, age, insurance type, and month of year. Race-based and sex-based analyses were performed. RESULTS: In the first year following implementation of the SFA law, adjusted adult asthma hospitalization rates decreased 8% (95% confidence interval [CI], 7%-10%; P < .001). While asthma hospitalization rates for both blacks and whites declined in the 12 months following implementation of the SFA law, blacks were 3% more likely to be hospitalized for asthma than whites (95% CI, 0%-7%; P = .04). The rate of decline in adult asthma hospitalizations did not differ by sex. CONCLUSION: The implementation of the SFA law was associated with a reduction in adult asthma hospitalization rates, with a greater decrease in hospitalization rates for whites compared with blacks. These results demonstrate that the SFA law is protecting the public's health and saving health care costs.

American Board of Emergency Medicine report on residency training information (2014-2015).

The American Board of Emergency Medicine (ABEM) gathers extensive background information on emergency medicine residency programs and the residents in those programs. We present the 2015 annual report on the status of US emergency medicine training programs.

An Orally Available BACE1 Inhibitor That Affords Robust CNS Aß Reduction without Cardiovascular Liabilities.

BACE1 inhibition to prevent Aß peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aß levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.

Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease.

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

Lead optimization and modulation of hERG activity in a series of aminooxazoline xanthene ß-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.

The optimization of a series of aminooxazoline xanthene inhibitors of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aß lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aß reduction in a rat pharmacodynamic model (78% Aß reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

Inhibitors of ß-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718).

We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Aß levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.

Nursing home-acquired pneumonia: course and management in the emergency department.

BACKGROUND: Pneumonia is among the foremost causes of hospitalization and mortality in patients residing in extended care facilities. Despite its prevalence, there is currently little literature focusing on the course and management of nursing home-acquired pneumonia (NHAP) in the emergency department (ED). Our objective was to investigate the ED presentation, course, management and outcomes in patients admitted through the ED with NHAP. METHODS: A retrospective chart review of nursing home patients with a presumptive or final diagnosis of pneumonia admitted through the ED was performed at two large hospitals in Detroit, Michigan. RESULTS: A total of 296 patients were included in the study from 2002 to 2007 with a mean age of 81.1 years (SD ± 10.95) and 55.4% females. Blood cultures were performed on 90.8% of patients in the ED; 17.8% of these revealed growths, but half of these were considered contaminants. Initial chest x-ray in the ED was read as possible pneumonia in 18.2% of patients; 73.9% were started on antibiotics (ABX) in the ED. Mean hospital length of stay (LOS) was 10.75 days (SD ± 9.35) and in-hospital mortality was 16.2%. Time until first ABX in univariate analysis was nearly significant (p = 0.053) for mortality prediction, and the appropriate versus inappropriate ABX (per the Infectious Diseases Society of America and American Thoracic Society guidelines) did not affect mortality. Patients treated with a single ABX had significantly increased LOS (p = 0.0089). There was poor correlation between LOS and time until first ABX as well as LOS and time until appropriate ABX with a correlation coefficient of -0.048 (p = 0.42) and -0.08 (p = 0.43), respectively. CONCLUSIONS: In this data set of NHAP patients admitted through the ED, we found a surprisingly low prevalence of true-positive blood cultures, high incidence of antibiotic pre-treatment at nursing homes prior to admission, high hospital mortality and low immunization rates. There was a wide spectrum of pathogens grown in blood culture. Only two thirds of the patients had dyspnea at presentation, and less than half had either cough or fever. On physical examination, about one fourth had no clinical findings consistent with pneumonia. Further, less than one fifth of chest x-rays were interpreted as possible pneumonia.

American Board of Emergency Medicine report on residency training information (2013-2014), American Board of Emergency Medicine.

The American Board of Emergency Medicine gathers extensive background information on emergency medicine residency programs and the residents in them. We present the 2014 annual report on the status of US emergency medicine training programs.

Hypovitaminosis D presenting as diffuse myalgia in a 22-year-old woman: a case report.

BACKGROUND: Caused predominantly by insufficient conversion of vitamin D precursors by sunlight, hypovitaminosis D is an issue of increasing importance worldwide. Although it has been associated with a range of diseases, musculoskeletal effects dominate the clinical picture and can lead to significant physical debility, whether acute or chronic. Although diagnosis of vitamin D deficiency typically occurs in the outpatient setting, it is an easily treatable condition, and timely intervention can dramatically improve one's quality of life. As highlighted by this case report, hypovitaminosis D may be an important but underappreciated etiology of undifferentiated myalgia that, when present, warrants initiation of vitamin D repletion therapy even from the emergency department (ED). CASE REPORT: A 22-year-old African-American female presented to our ED with diffuse myalgia for 4 months. She reported significant debility from these symptoms with difficulty ambulating and performing activities of daily living. There had been no upper respiratory infection symptoms. The patient had discussed all of this with her primary care physician who, despite an extensive laboratory work-up, had not identified a definitive etiology. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Chronic pain has stricken the ED patient population across the board. Studies demonstrate that the myalgia caused by hypovitaminosis D can have a profound and negative impact on an individual's lifestyle. Our patient was found to have hypovitaminosis D and had substantial improvement with her myalgia and quality of life after treatment. The purpose of this report is to help the emergency physician appreciate this disease and consider it when clinically appropriate.

Discovery of Small-Molecule Glucokinase Regulatory Protein Modulators That Restore Glucokinase Activity.

In the nuclei of hepatocytes, glucokinase regulatory protein (GKRP) modulates the activity of glucokinase (GK), a key regulator of glucose homeostasis. Currently, direct activators of GK (GKAs) are in development for the treatment of type 2 diabetes. However, this approach is generally associated with a risk of hypoglycemia. To mitigate such risk, we target the GKRP regulation, which indirectly restores GK activity. Here we describe a screening strategy to look specifically for GKRP modulators, in addition to traditional GKAs. Two high-throughput screening campaigns were performed with our compound libraries using a luminescence assay format, one with GK alone and the other with a GK/GKRP complex in the presence of sorbitol-6-phosphate (S6P). By a subtraction method in the hit triage process of these campaigns, we discovered two close analogs that bind GKRP specifically with sub-µM potency to a site distinct from where fructose-1-phosphate binds. These small molecules are first-in-class allosteric modulators of the GK/GKRP interaction and are fully active even in the presence of S6P. Activation of GK by this particular mechanism, without altering the enzymatic profile, represents a novel pharmacologic modality of intervention in the GK/GKRP pathway.

Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept.

Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.

Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors.

Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic ß-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.

Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity.

We describe a systematic study of how macrocyclization in the P1-P3 region of hydroxyethylamine-based inhibitors of ß-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid ß-peptide (Aß)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.