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.

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.

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.

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.

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 (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.

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.

American Board of Emergency Medicine report on residency training information (2012-2013), American Board of Emergency Medicine.

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 2013 annual report on the status of US emergency medicine training programs.

Association of daily asthma emergency department visits and hospital admissions with ambient air pollutants among the pediatric Medicaid population in Detroit: time-series and time-stratified case-crossover analyses with threshold effects.

BACKGROUND: Asthma morbidity has been associated with ambient air pollutants in time-series and case-crossover studies. In such study designs, threshold effects of air pollutants on asthma outcomes have been relatively unexplored, which are of potential interest for exploring concentration-response relationships. METHODS: This study analyzes daily data on the asthma morbidity experienced by the pediatric Medicaid population (ages 2-18 years) of Detroit, Michigan and concentrations of pollutants fine particles (PM2.5), CO, NO2 and SO2 for the 2004-2006 period, using both time-series and case-crossover designs. We use a simple, testable and readily implementable profile likelihood-based approach to estimate threshold parameters in both designs. RESULTS: Evidence of significant increases in daily acute asthma events was found for SO2 and PM2.5, and a significant threshold effect was estimated for PM2.5 at 13 and 11 µg m(-3) using generalized additive models and conditional logistic regression models, respectively. Stronger effect sizes above the threshold were typically noted compared to standard linear relationship, e.g., in the time series analysis, an interquartile range increase (9.2 µg m(-3)) in PM2.5 (5-day-moving average) had a risk ratio of 1.030 (95% CI: 1.001, 1.061) in the generalized additive models, and 1.066 (95% CI: 1.031, 1.102) in the threshold generalized additive models. The corresponding estimates for the case-crossover design were 1.039 (95% CI: 1.013, 1.066) in the conditional logistic regression, and 1.054 (95% CI: 1.023, 1.086) in the threshold conditional logistic regression. CONCLUSION: This study indicates that the associations of SO2 and PM2.5 concentrations with asthma emergency department visits and hospitalizations, as well as the estimated PM2.5 threshold were fairly consistent across time-series and case-crossover analyses, and suggests that effect estimates based on linear models (without thresholds) may underestimate the true risk.

Asthma exacerbation and proximity of residence to major roads: a population-based matched case-control study among the pediatric Medicaid population in Detroit, Michigan.

BACKGROUND: The relationship between asthma and traffic-related pollutants has received considerable attention. The use of individual-level exposure measures, such as residence location or proximity to emission sources, may avoid ecological biases. METHOD: This study focused on the pediatric Medicaid population in Detroit, MI, a high-risk population for asthma-related events. A population-based matched case-control analysis was used to investigate associations between acute asthma outcomes and proximity of residence to major roads, including freeways. Asthma cases were identified as all children who made at least one asthma claim, including inpatient and emergency department visits, during the three-year study period, 2004-06. Individually matched controls were randomly selected from the rest of the Medicaid population on the basis of non-respiratory related illness. We used conditional logistic regression with distance as both categorical and continuous variables, and examined non-linear relationships with distance using polynomial splines. The conditional logistic regression models were then extended by considering multiple asthma states (based on the frequency of acute asthma outcomes) using polychotomous conditional logistic regression. RESULTS: Asthma events were associated with proximity to primary roads with an odds ratio of 0.97 (95% CI: 0.94, 0.99) for a 1 km increase in distance using conditional logistic regression, implying that asthma events are less likely as the distance between the residence and a primary road increases. Similar relationships and effect sizes were found using polychotomous conditional logistic regression. Another plausible exposure metric, a reduced form response surface model that represents atmospheric dispersion of pollutants from roads, was not associated under that exposure model. CONCLUSIONS: There is moderately strong evidence of elevated risk of asthma close to major roads based on the results obtained in this population-based matched case-control study.

German Association of Endocrine Surgeons practice guidelines for the surgical treatment of benign thyroid disease.

INTRODUCTION: Benign thyroid disorders are among the most common diseases in Germany, affecting around 15 million people and leading to more than 100,000 thyroid surgeries per year. Since the first German guidelines for the surgical treatment of benign goiter were published in 1998, abundant new information has become available, significantly shifting surgical strategy towards more radical interventions. Additionally, minimally invasive techniques have been developed and gained wide usage. These circumstances demanded a revision of the guidelines. METHODS: Based on a review of relevant recent guidelines from other groups and additional literature, unpublished data, and clinical experience, the German Association of Endocrine Surgeons formulated new recommendations on the surgical treatment of benign thyroid diseases. These guidelines were developed through a formal expert consensus process and in collaboration with the German societies of Nuclear Medicine, Endocrinology, Pathology, and Phoniatrics & Pedaudiology as well as two patient organizations. Consensus was achieved through several moderated conferences of surgical experts and representatives of the collaborating medical societies and patient organizations. RESULTS: The revised guidelines for the surgical treatment of benign thyroid diseases include recommendations regarding the preoperative assessment necessary to determine when surgery is indicated. Recommendations regarding the extent of resection, surgical techniques, and perioperative management are also given in order to optimize patient outcomes. CONCLUSIONS: Evidence-based recommendations for the surgical treatment of benign thyroid diseases have been created to aid the surgeon and to support optimal patient care, based on current knowledge. These recommendations comply with the Association of the Scientific Medical Societies in Germany requirements for S2k guidelines.

Healthy Homes University: a home-based environmental intervention and education program for families with pediatric asthma in Michigan.

Environmental conditions within the home can exacerbate asthmatic children's symptoms. To improve health outcomes among this group, we implemented an in-home environmental public health program-Healthy Homes University--for low-income families in Lansing, Michigan, from 2005 to 2008. Families received four visits during a six-month intervention. Program staff assessed homes for asthma triggers and subsequently provided products and services to reduce exposures to cockroaches, dust mites, mold, tobacco smoke, and other triggers. We also provided asthma education that included identification of asthma triggers and instructions on specific behaviors to reduce exposures. Based on self-reported data collected from 243 caregivers at baseline and six months, the impact of asthma on these children was substantially reduced, and the proportion who sought acute unscheduled health care for their asthma decreased by more than 47%.

Real-time ultrasound elastography--a noninvasive diagnostic procedure for evaluating dominant thyroid nodules.

PURPOSE: Ultrasound elastography (USE) is a newly developed technique for the evaluation of tissue stiffness. It is known that malignancies often show a low-strain value. So far, only limited data for thyroid nodules is available. METHODS: This study included 309 prospective evaluated patients with dominant, nontoxic thyroid nodules. All patients were referred to surgery. USE was performed preoperatively. Three measuring groups were formed: hard (< 0.15), intermediate (0.16-0.3), and soft (> 0.31). The measurements were correlated to the final histological findings. RESULTS: The strain rated from 0.01 to 0.84 (mean 0.26 ± 0.13). A total of 50 thyroid malignancies (35 papillara carcinoma, 9 medullary carcinoma, and 6 follicular carcinoma) were observed. Patients (81) were within the hard group, 35 of them (43.2%) had thyroid cancer (TC) in final histology. Out of 132 patients in the intermediate group, 15 patients had TC (11.4%). All 96 patients from the soft group showed benign histological results (NPV 100%). Seventy percent of patients with TC were within the hard group (PPV 42%). These results were highly significant (p < 0.001). Coarse calcifications and cystic nodules were not connected with reliable measurements and therefore are not suitable for USE. CONCLUSION: USE is a useful adjunctive tool in the workup of thyroid nodules. A low strain value needs surgical intervention, whereas a high strain value predicts a benign histology. It might substitute fine-needle aspiration cytology in the future.

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.

Temporal trends in bull semen quality: a comparative model for human health?

INTRODUCTION: A decline in human semen quality over the past 30-60 years has been reported in numerous epidemiological studies from the United States and Europe. We evaluated temporal trends in semen quality parameters in dairy bulls. The long-term management of dairy bulls for artificial insemination presented a unique opportunity to evaluate temporal trends in semen quality and explore this relationship as a potential animal model for reproductive abnormalities in humans. MATERIALS AND METHODS: Bull semen analysis data from 1965 through 1995 were collected from a large artificial insemination organization. Semen analyses from 12- to 18-month-old Holstein dairy bulls were included in the study and consisted of daily sperm concentration, daily ejaculate volume, total daily sperm output, percentage of sperm with normal morphology, and percentage of sperm with normal post-thaw motility. Multiple regression analysis, logistic regression, and general linear modeling were used to determine temporal trends over the 30-year period. RESULTS AND DISCUSSION: Semen quality appears to have declined from 1970 to 1980 or 1985 as manifested by declines in daily ejaculate volume, daily sperm concentration, and total daily sperm output. In contrast, sperm morphology and motility improved over the same period. In approximately 1980 or 1985, depending on the parameter, ejaculate volume, sperm concentration, total sperm, and motility improved. However, normal morphology began to deteriorate during this same period. Methodological inconsistencies over time introduce uncertainty in analyses of temporal trends in semen quality in this and previous human studies. However, changes in technology do not appear to be solely responsible for the temporal trends observed. The source of the decline in semen quality in the bulls studied is unknown. If the decline in semen quality were due to exposure to endocrine disrupting chemicals, then a continued decline or a leveling-off would be expected. Instead, a rise in semen quality was observed during the latter portion of the observation period.

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.

Early malignant progression of hereditary medullary thyroid cancer.

BACKGROUND: An age-related progression from C-cell hyperplasia to medullary thyroid carcinoma is associated with various germ-line mutations in the rearranged during transfection (RET) proto-oncogene that could be used to identify the optimal time for prophylactic surgery. METHODS: In this European multicenter study conducted from July 1993 to February 2001, we enrolled patients who had a RET point mutation in the germ line, were 20 years of age or younger, were asymptomatic, and had undergone total thyroidectomy after confirmation of the RET mutation. Exclusion criteria were medullary thyroid carcinomas of more than 10 mm in greatest dimension and distant metastasis. RESULTS: Altogether, 207 patients from 145 families were identified. There was a significant age-related progression from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, nodal metastasis in patients whose RET mutations were grouped according to the extracellular- and intracellular-domain codons affected and in those with the codon 634 genotype. No lymph-node metastases were noted in patients younger than 14 years of age. The age-related penetrance was unaffected by the type of amino acid substitution encoded by the various codon 634 mutations. The codon-specific differences in the age at presentation of cancer and the familial rates of concomitant adrenal and parathyroid involvement suggest that the risk of progression was based on the transforming potential of the individual RET mutation. CONCLUSIONS: These data provide initial guidelines for the timing of prophylactic thyroidectomy in asymptomatic carriers of RET gene mutations.

Arsenic in drinking water and cerebrovascular disease, diabetes mellitus, and kidney disease in Michigan: a standardized mortality ratio analysis.

BACKGROUND: Exposure to arsenic concentrations in drinking water in excess of 300 microg/L is associated with diseases of the circulatory and respiratory system, several types of cancer, and diabetes; however, little is known about the health consequences of exposure to low-to-moderate levels of arsenic (10-100 microg/L). METHODS: A standardized mortality ratio (SMR) analysis was conducted in a contiguous six county study area of southeastern Michigan to investigate the relationship between moderate arsenic levels and twenty-three selected disease outcomes. Disease outcomes included several types of cancer, diseases of the circulatory and respiratory system, diabetes mellitus, and kidney and liver diseases. Arsenic data were compiled from 9251 well water samples tested by the Michigan Department of Environmental Quality from 1983 through 2002. Michigan Resident Death Files data were amassed for 1979 through 1997 and sex-specific SMR analyses were conducted with indirect adjustment for age and race; 99% confidence intervals (CI) were reported. RESULTS: The six county study area had a population-weighted mean arsenic concentration of 11.00 microg/L and a population-weighted median of 7.58 microg/L. SMR analyses were conducted for the entire six county study area, for only Genesee County (the most populous and urban county), and for the five counties besides Genesee. Concordance of results across analyses is used to interpret the findings. Elevated mortality rates were observed for both males (M) and females (F) for all diseases of the circulatory system (M SMR, 1.11; CI, 1.09-1.13; F SMR, 1.15; CI, 1.13,-1.17), cerebrovascular diseases (M SMR, 1.19; CI, 1.14-1.25; F SMR, 1.19; CI, 1.15-1.23), diabetes mellitus (M SMR, 1.28; CI, 1.18-1.37; F SMR, 1.27; CI, 1.19-1.35), and kidney diseases (M SMR, 1.28; CI, 1.15-1.42; F SMR, 1.38; CI, 1.25-1.52). CONCLUSION: This is some of the first evidence to suggest that exposure to low-to-moderate levels of arsenic in drinking water may be associated with several of the leading causes of mortality, although further epidemiologic studies are required to confirm the results suggested by this ecologic SMR analysis.