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The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 2·2, 95% CI 1·4 to 3·3; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group. Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification. National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

This trial showed that two types of behavioral interventions, one based on remote, call-center support and the other on in-person support, resulted in significant weight loss among obese patients. These results provide templates for effective weight-loss programs in primary care practices. Obesity is an important and growing public health problem around the world. In the United States, approximately one third of adults are obese. 1 Obesity adversely affects each of the major cardiovascular risk factors — blood pressure, lipid profile, and diabetes. As a consequence, obese persons have an increased risk of death, especially from cardiovascular disease. 2 , 3 The economic burden of the obesity epidemic is enormous; the estimated direct and indirect costs related to obesity exceed $110 billion annually in the United States. 4 An extensive body of evidence from efficacy trials has shown that weight loss is achievable and that modest . . .

Factors that determine disease severity in nonalcoholic fatty liver disease (NAFLD) are unclear, but exercise is a recommended treatment. We evaluated the association between physical activity intensity and histological severity of NAFLD. We conducted a retrospective analysis of adults with biopsy-proven NAFLD enrolled in the NASH CRN (Nonalcoholic Steatohepatitis Clinical Research Network). Using self-reported time spent in physical activity, we classified participants as inactive or as meeting the US guidelines for either moderate or vigorous exercise. Histology was reviewed by a central pathology committee. Frequency and odds of steatohepatitis (NASH) and advanced fibrosis were compared between subjects who either met or did not meet exercise recommendations, and by the total amount of exercise per week. A total of 813 adults (males=302, females=511) with NAFLD were included, with a mean age of 48 years. Neither moderate-intensity exercise nor total exercise per week was associated with NASH or stage of fibrosis. Meeting vigorous recommendations was associated with a decreased adjusted odds of having NASH (odds ratio (OR): 0.65 (0.43-0.98)). Doubling the recommended time spent in vigorous exercise, as is suggested for achieving additional health benefits, was associated with a decreased adjusted odds of advanced fibrosis (OR: 0.53 (0.29-0.97)). These data support an association of vigorous but not moderate or total exercise with the severity of NAFLD. Optimal doses of exercise by duration and intensity for the prevention or treatment of NASH have not been established; however, intensity may be more important than duration or total volume.

BackgroundGut microbiota likely impact obesity and metabolic diseases. We evaluated the changes in gut microbiota after surgical versus medical weight loss in adults with diabetes and obesity.MethodsWe performed 16S rRNA amplicon sequencing to identify the gut microbial composition at baseline and at 10% weight loss in adults with diabetes who were randomized to medical weight loss (MWL, n = 4), adjustable gastric banding (AGB, n = 4), or Roux-en-Y gastric bypass (RYGB, n = 4).ResultsAll participants were female, 75% reported black race with mean age of 51 years. At similar weight loss amount and glycemic improvement, the RYGB group had the most number of bacterial species (10 increased, 1 decreased) that significantly changed (p < 0.05) in relative abundance. Alpha-diversity at follow-up was significantly lower in AGB group compared to MWL and RYGB (observed species for AGB vs. MWL, p = 0.0093; AGB vs. RYGB, p = 0.0093). The relative abundance of Faecalibacterium prausnitzii increased in 3 participants after RYGB, 1 after AGB, and 1 after MWL.ConclusionsAt similar weight loss and glycemic improvement, the greatest alteration in gut microbiota occurred after RYGB with an increase in the potentially beneficial bacterium, F. prausnitzii. Gut microbial diversity tended to decrease after AGB and increase after RYGB and MWL. Future studies are needed to determine the impact and durability of gut microbial changes over time and their role in long-term metabolic improvement after bariatric surgery in adults with type 2 diabetes.Clinical Trial RegistrationNCTDK089557—ClinicalTrials.gov

To address the obesity epidemic, there is a need for novel paradigms, including those that address the timing of eating and sleep in relation to circadian rhythms. Electronic health records (EHRs) are an efficient way to identify potentially eligible participants for health research studies. Mobile health (mHealth) apps offer available and convenient data collection of health behaviors, such as timing of eating and sleep. The aim of this descriptive analysis was to report on recruitment, retention, and app use from a 6-month cohort study using a mobile app called Daily24. Using an EHR query, adult patients from three health care systems in the PaTH clinical research network were identified as potentially eligible, invited electronically to participate, and instructed to download and use the Daily24 mobile app, which focuses on eating and sleep timing. Online surveys were completed at baseline and 4 months. We described app use and identified predictors of app use, defined as 1 or more days of use, versus nonuse and usage categories (ie, immediate, consistent, and sustained) using multivariate regression analyses. Of 70,661 patients who were sent research invitations, 1021 (1.44%) completed electronic consent forms and online baseline surveys; 4 withdrew, leaving a total of 1017 participants in the analytic sample. A total of 53.79% (n=547) of the participants were app users and, of those, 75.3% (n=412), 50.1% (n=274), and 25.4% (n=139) were immediate, consistent, and sustained users, respectively. Median app use was 28 (IQR 7-75) days over 6 months. Younger age, White race, higher educational level, higher income, having no children younger than 18 years, and having used 1 to 5 health apps significantly predicted app use (vs nonuse) in adjusted models. Older age and lower BMI predicted early, consistent, and sustained use. About half (532/1017, 52.31%) of the participants completed the 4-month online surveys. A total of 33.5% (183/547), 29.3% (157/536), and 27.1% (143/527) of app users were still using the app for at least 2 days per month during months 4, 5, and 6 of the study, respectively. EHR recruitment offers an efficient (ie, high reach, low touch, and minimal participant burden) approach to recruiting participants from health care settings into mHealth research. Efforts to recruit and retain less engaged subgroups are needed to collect more generalizable data. Additionally, future app iterations should include more evidence-based features to increase participant use.

Serum Ferritin and Risk of the Metabolic Syndrome in U.S. Adults Megan Jehn , MHS 1 , Jeanne M. Clark , MD 1 2 and Eliseo Guallar , MD 1 1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Address correspondence and reprint requests to Eliseo Guallar, MD, DrPH, Welch Center for Prevention, Epidemiology & Clinical Research, 2024 E. Monument St., Suite 2-639, Baltimore, MD 21205. E-mail: eguallar{at}jhsph.edu Abstract OBJECTIVE —We examined the relationship among iron stores, the metabolic syndrome, and insulin resistance. RESEARCH DESIGN AND METHODS —We conducted a cross-sectional study of 6,044 adults >20 years of age who participated in the Third National Health and Nutrition Examination Survey. Metabolic syndrome was defined as the presence of at least three of the following: elevated blood pressure, low HDL cholesterol, elevated serum triglycerides, elevated plasma glucose, and abdominal obesity. Insulin resistance was estimated using homeostasis model assessment (for insulin resistance), fasting insulin, and triglyceride–to–HDL cholesterol ratio. RESULTS —After excluding individuals with likely hemochromatosis, mean serum ferritin values in premenopausal women, postmenopausal women, and men were 33.6, 93.4, and 139.9 μg/l, respectively. Metabolic syndrome was more common in those with the highest compared with the lowest levels of serum ferritin in premenopausal women (14.9 vs. 6.4%, P = 0.002), postmenopausal women (47.5 vs. 28.2%, P < 0.001), and men (27.3 vs. 13.8%, P < 0.001). Insulin resistance also increased across quartiles of serum ferritin for men and postmenopausal women and persisted after adjustment for age, race/ethnicity, C-reactive protein, smoking, alcohol intake, and BMI. CONCLUSIONS —Elevated iron stores were positively associated with the prevalence of the metabolic syndrome and with insulin resistance. ALT, alanine aminotranferase AST, aspartate aminotransferase CRP, C-reactive protein HOMA-IR, homeostasis model assessment for insulin resistance NHANES III, Third National Health and Nutrition Examination Survey Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted June 23, 2004. Received May 11, 2004. DIABETES CARE

Chronic arsenic exposure has been suggested to contribute to diabetes development. We performed a systematic review of the experimental and epidemiologic evidence on the association of arsenic and type 2 diabetes. We identified 19 in vitro studies of arsenic and glucose metabolism. Five studies reported that arsenic interfered with transcription factors involved in insulin-related gene expression: upstream factor 1 in pancreatic β-cells and peroxisome proliferative-activated receptor γ in preadipocytes. Other in vitro studies assessed the effect of arsenic on glucose uptake, typically using very high concentrations of arsenite or arsenate. These studies provide limited insight on potential mechanisms. We identified 10 in vivo studies in animals. These studies showed inconsistent effects of arsenic on glucose metabolism. Finally, we identified 19 epidemiologic studies (6 in high-arsenic areas in Taiwan and Bangladesh, 9 in occupational populations, and 4 in other populations). In studies from Taiwan and Bangladesh, the pooled relative risk estimate for diabetes comparing extreme arsenic exposure categories was 2.52 (95% confidence interval, 1.69-3.75), although methodologic problems limit the interpretation of the association. The evidence from occupational studies and from general populations other than Taiwan or Bangladesh was inconsistent. In summary, the current available evidence is inadequate to establish a causal role of arsenic in diabetes. Because arsenic exposure is widespread and diabetes prevalence is reaching epidemic proportions, experimental studies using arsenic concentrations relevant to human exposure and prospective epidemiologic studies measuring arsenic biomarkers and appropriately assessing diabetes should be a research priority.

Aims/hypothesis SLC30A8 encodes a zinc transporter in the beta cell; individuals with a common missense variant (rs13266634; R325W) in SLC30A8 demonstrate a lower early insulin response to glucose and an increased risk of type 2 diabetes. We hypothesised that zinc supplementation may improve insulin secretion in a genotype-dependent manner. Methods We evaluated the early insulin response to glucose (using frequently sampled intravenous glucose tolerance testing) by R325W genotype before and after 14 days of supplementation with oral zinc acetate (50 mg elemental zinc) twice daily in healthy non-diabetic Amish individuals ( N  = 55). Results Individuals with RW/WW genotypes ( n  = 32) had the lowest insulin response to glucose at 5 and 10 min at baseline (vs RR homozygotes [ n  = 23]). After zinc supplementation, the RW/WW group experienced 15% and 14% increases in the insulin response to glucose at 5 and 10 min, respectively ( p  ≤ 0.04), and, compared with RR homozygotes, experienced a 26% ( p  = 0.04) increase in insulin at 5 min. We observed reciprocal decreases in proinsulin:insulin in the RW/WW ( p  = 0.002) vs RR group ( p  = 0.048), suggesting a genotype-specific improvement in insulin processing. Conclusions/interpretation Zinc supplementation appears to affect the early insulin response to glucose differentially by rs13266634 genotype and could be beneficial for diabetes prevention and/or treatment for some individuals based on SLC30A8 variation. Trial registration: ClinicalTrials.gov NCT00981448

Background Pregnancy provides an opportunity to promote healthy lifestyle behaviors. This study’s aim was to explore the perspectives of pregnant and postpartum women and obstetric providers around behavioral lifestyle changes in pregnancy and postpartum. Methods We conducted a qualitative study with pregnant and postpartum patients recruited from 2 prenatal care clinics at an urban, academic hospital in the United States. In-depth interviews with 23 pregnant or postpartum women and 11 obstetric providers were completed between October 2015–April 2016. Interviews were audio-recorded and transcribed verbatim. We coded transcripts for thematic content and applied the PRECEDE-PROCEED framework for results to directly inform program development. Results Six themes highlighted the predisposing, enabling and reinforcing factors that enable and sustain health behavior changes in pregnancy and postpartum: 1) “Motivation to have a healthy baby” during pregnancy and to “have my body back” after delivery, 2) Pre-pregnancy knowledge and experiences about pregnancy and the postpartum period, 3) Prioritizing wellness during pregnancy and postpartum, 4) The power of social support, 5) Accountability, 6) Integration with technology to reinforce behavior change. Conclusions In this qualitative study, pregnant and postpartum women and obstetric providers described themes that are aimed at encouraging lifestyle changes to promote healthy weight gain in pregnancy and can directly inform the development of a behavioral weight management intervention for pregnant and postpartum women that is patient-centered and tailored to their needs.

Background Clinical decision support systems (CDSS) are electronic health record tools that support practitioners' decision‐making at the point‐of‐care. CDSS may aid clinical care but are not often centered on patients or practitioners. Aims To develop and preliminarily test a CDSS designed to support evidence‐based obesity treatment, promote a patient‐centered experience, and integrate with clinical workflows. Materials & Methods The CDSS allowed patients to complete a pre‐visit questionnaire via the patient portal, which activated multiple elements for the primary care practitioner (PCP). A 3‐month proof‐of‐concept study was conducted among 10 PCPs at 5 clinics to determine usefulness, usability, and acceptability through validated surveys (mean score ≥ 2.5 signified positive outcome; max 5). Using t‐tests, pre‐post differences in PCPs' frequency of self‐reported clinical practices (1‐never; 5‐always) were examined. Results Most PCPs were physicians with mean experience of 10.8 years (SD 7.5). Overall, mean scores for usefulness, usability, and acceptability were 3.2 (SD 0.8), 3.5 (SD 0.9), and 3.6 (SD 0.9), respectively. PCPs reported significant increases in three key clinical practices—counseling on behavioral interventions (3.1 vs. 3.9 [p < 0.01]), referring to weight‐loss programs (2.8 vs. 3.5 [p < 0.01]), and discussing anti‐obesity medications (3.3 vs. 3.8 [p = 0.02]). Conclusion This weight management CDSS was useful and usable for PCPs and improved obesity‐related practice habits. Future studies need to evaluate its impact on patient outcomes.