The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Very low birth weight infant care: adherence to a new nutrition protocol improves growth outcomes and reduces infectious risk.

BACKGROUND: Very low birth weight (VLBW) infants are at risk for postnatal growth restriction due to inadequate nutrient delivery and concomitant illness. Integrated clinical pathways or protocols can improve growth outcomes by decreasing practice variability. METHODS: A comprehensive nutrition bundle comprising standardized recommendations for initiating, advancing, and fortifying enteral feedings, and timely discontinuation of central lines was implemented in July 2012. Eligible were infants with a birth weight ofpost-intervention, respectively. The primary aim was to determine if the intervention improved anthropometric parameter delta z scores at 36 weeks PMA. Secondary aims included time to first and full enteral feedings, central line-days, and rates of necrotizing enterocolitis (NEC) and sepsis/sepsis-like episodes. RESULTS: A total of 299 infants were included, of which 156 received the proposed intervention (Nutrition bundle group), and 143 received non-standardized nutrition practices (Conventional group). Median delta z scores for length (-1.2 versus -1.71; p=0.01) and head circumference (-0.73 versus -1.21; p=0.03) but not weight at 36 weeks PMA (-1.42 versus -1.58; p=0.74) were significantly higher in the Nutrition bundle group as compared to the Conventional group. Fewer infants in the intervention group had severe growth restriction. Time to first feed, full feeds, and central line duration were significantly shorter in the intervention period. The incidence of NEC and sepsis/sepsis-like episodes decreased with the intervention. CONCLUSIONS: A strategy using a comprehensive nutrition bundle improved linear and head circumference growth, reduced postnatal growth restriction, and decreased comorbidities in VLBW infants

Electronic Interventions for Alcohol Misuse and Alcohol Use Disorders: A Systematic Review.

BACKGROUND: The use of electronic interventions (e-interventions) may improve treatment of alcohol misuse. PURPOSE: To characterize treatment intensity and systematically review the evidence for efficacy of e-interventions, relative to controls, for reducing alcohol consumption and alcohol-related impairment in adults and college students. DATA SOURCES: MEDLINE (via PubMed) from January 2000 to March 2015 and the Cochrane Library, EMBASE, and PsycINFO from January 2000 to August 2014. STUDY SELECTION: English-language, randomized, controlled trials that involved at least 50 adults who misused alcohol; compared an e-intervention group with a control group; and reported outcomes at 6 months or longer. DATA EXTRACTION: Two reviewers abstracted data and independently rated trial quality and strength of evidence. DATA SYNTHESIS: In 28 unique trials, the modal e-intervention was brief feedback on alcohol consumption. Available data suggested a small reduction in consumption (approximately 1 drink per week) in adults and college students at 6 months but not at 12 months. There was no statistically significant effect on meeting drinking limit guidelines in adults or on binge-drinking episodes or social consequences of alcohol in college students. LIMITATIONS: E-interventions that ranged in intensity were combined in analyses. Quantitative results do not apply to short-term outcomes or alcohol use disorders. CONCLUSION: Evidence suggests that low-intensity e-inter ventions produce small reductions in alcohol consumption at 6 months, but there is little evidence for longer-term, clinically significant effects, such as meeting drinking limits. Future e-interventions could provide more intensive treatment and possibly human support to assist persons in meeting recommended drinking limits. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs

Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms

Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additiona

Effects of dietary SCFAs on food intake and locomotor activity.

<p>(A-C) Three-month-old lean C57BL/6N mice were switched to HFD containing sodium salts of butyrate (5%), propionate (4.3%), and acetate (3.7%) for nine days. Daily food intake, cumulative food intake, and cumulative locomotor activity are shown. L: light phase. D: dark phase. (D, E) Dose titration of sodium butyrate and sodium propionate in HFD was performed in three-month-old lean C57BL/6N mice. Eight-day cumulative body weight change and food intake are shown. Data are mean ± SEM. N=8. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. control diet.</p

Effects of orally administered fatty acids on incretins and other hormones.

<p>(A-F) Three-month-old lean C57BL/6N mice were fasted overnight and orally dosed with saline, sodium butyrate, sodium propionate, sodium acetate, an SCFA admixture (65% sodium acetate, 20% sodium propionate, 15% sodium butyrate), octanoic acid (OA), or α-linolenic acid (LA), all at 400mg/kg body weight. Plasma levels of total GLP-1, active GLP-1, GIP, PYY, insulin, and amylin were measured 10 minutes after dosing. Intra-assay CV% was below 8.9% for all immunoassays. Data are mean ± SEM. N=8. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. saline. NS: not significant.</p