SREBP1c-CRY1 signalling represses hepatic glucose production by promoting FOXO1 degradation during refeeding

published_or_final_versio

Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy.

Aim: Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Materials & methods: Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] \u3e= 300-\u3c400 or \u3c400 m). Meta-analyses examined 6MWD change from baseline to week 48.Results:Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2-34.1) m, p = 0.0473; \u3e= 300-\u3c400 m (n = 143), +43.9 (18.2-69.6) m, p = 0.0008; \u3c400 m (n = 216), +27.7 (6.4-49.0) m, p = 0.0109. Conclusion: These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD \u3e= 300-\u3c400 m (the ambulatory transition phase), thereby informing future trial design

A Rasch and factor analysis of the Functional Assessment of Cancer Therapy-General (FACT-G)

BACKGROUND: Although the Functional Assessment of Cancer Therapy – General questionnaire (FACT-G) has been validated few studies have explored the factor structure of the instrument, in particular using non-sample dependent measurement techniques, such as Rasch Models. Furthermore, few studies have explored the relationship between item fit to the Rasch Model and clinical utility. The aim of this study was to investigate the dimensionality and measurement properties of the FACT-G with Rasch Models and Factor analysis. METHODS: A factor analysis and Rasch analysis (Partial Credit Model) was carried out on the FACT-G completed by a heterogeneous sample of cancer patients (n = 465). For the Rasch analysis item fit (infit mean squares ≥ 1.30), dimensionality and item invariance were assessed. The impact of removing misfitting items on the clinical utility of the subscales and FACT-G total scale was also assessed. RESULTS: The factor analysis demonstrated a four factor structure of the FACT-G which broadly corresponded to the four subscales of the instrument. Internal consistency for these four scales was very good (Cronbach's alpha 0.72 – 0.85). The Rasch analysis demonstrated that each of the subscales and the FACT-G total scale had misfitting items (infit means square ≥ 1.30). All these scales with the exception of the Social & Family Well-being Scale (SFWB) were unidimensional. When misfitting items were removed, the effect sizes and the clinical utility of the instrument were maintained for the subscales and the total FACT-G scores. CONCLUSION: The results of the traditional factor analysis and Rasch analysis of the FACT-G broadly agreed. Caution should be exercised when utilising the Social & Family Well-being scale and further work is required to determine whether this scale is best represented by two factors. Additionally, removing misfitting items from scales should be performed alongside an assessment of the impact on clinical utility

Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients

Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. / Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. / Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. / ClinicalTrials.gov: NCT01557400

From design to implementation - The Joint Asia Diabetes Evaluation (JADE) program: A descriptive report of an electronic web-based diabetes management program

<p>Abstract</p> <p>Background</p> <p>The Joint Asia Diabetes Evaluation (JADE) Program is a web-based program incorporating a comprehensive risk engine, care protocols, and clinical decision support to improve ambulatory diabetes care.</p> <p>Methods</p> <p>The JADE Program uses information technology to facilitate healthcare professionals to create a diabetes registry and to deliver an evidence-based care and education protocol tailored to patients' risk profiles. With written informed consent from participating patients and care providers, all data are anonymized and stored in a databank to establish an Asian Diabetes Database for research and publication purpose.</p> <p>Results</p> <p>The JADE electronic portal (e-portal: <url>http://www.jade-adf.org</url>) is implemented as a Java application using the Apache web server, the mySQL database and the Cocoon framework. The JADE e-portal comprises a risk engine which predicts 5-year probability of major clinical events based on parameters collected during an annual comprehensive assessment. Based on this risk stratification, the JADE e-portal recommends a care protocol tailored to these risk levels with decision support triggered by various risk factors. Apart from establishing a registry for quality assurance and data tracking, the JADE e-portal also displays trends of risk factor control at each visit to promote doctor-patient dialogues and to empower both parties to make informed decisions.</p> <p>Conclusions</p> <p>The JADE Program is a prototype using information technology to facilitate implementation of a comprehensive care model, as recommended by the International Diabetes Federation. It also enables health care teams to record, manage, track and analyze the clinical course and outcomes of people with diabetes.</p

Bi-directional cell-pericellular matrix interactions direct stem cell fate

Modifiable hydrogels have revealed tremendous insight into how physical characteristics of cells’ 3D environment drive stem cell lineage specification. However, in native tissues, cells do not passively receive signals from their niche. Instead they actively probe and modify their pericellular space to suit their needs, yet the dynamics of cells’ reciprocal interactions with their pericellular environment when encapsulated within hydrogels remains relatively unexplored. Here, we show that human bone marrow stromal cells (hMSC) encapsulated within hyaluronic acid-based hydrogels modify their surroundings by synthesizing, secreting and arranging proteins pericellularly or by degrading the hydrogel. hMSC’s interactions with this local environment have a role in regulating hMSC fate, with a secreted proteinaceous pericellular matrix associated with adipogenesis, and degradation with osteogenesis. Our observations suggest that hMSC participate in a bi-directional interplay between the properties of their 3D milieu and their own secreted pericellular matrix, and that this combination of interactions drives fate

Fixation strength of biocomposite wedge interference screw in ACL reconstruction: effect of screw length and tunnel/screw ratio. A controlled laboratory study

<p>Abstract</p> <p>Background</p> <p>Primary stability of the graft is essential in anterior cruciate ligament surgery. An optimal method of fixation should be easy to insert and provide great resistance against pull-out forces.</p> <p>A controlled laboratory study was designed to test the primary stability of ACL tendinous grafts in the tibial tunnel. The correlation between resistance to traction forces and the cross-section and length of the screw was studied.</p> <p>Methods</p> <p>The tibial phase of ACL reconstruction was performed in forty porcine tibias using digital flexor tendons of the same animal. An 8 mm tunnel was drilled in each specimen and two looped tendons placed as graft. Specimens were divided in five groups according to the diameter and length of the screw used for fixation. Wedge interference screws were used. Longitudinal traction was applied to the graft with a Servohydraulic Fatigue System. Load and displacement were controlled and analyzed.</p> <p>Results</p> <p>The mean loads to failure for each group were 295,44 N (Group 1; 9 × 23 screw), 564,05 N (Group 2; 9 × 28), 614,95 N (Group 3; 9 × 35), 651,14 N (Group 4; 10 × 28) and 664,99 (Group 5; 10 × 35). No slippage of the graft was observed in groups 3, 4 and 5. There were significant differences in the load to failure among groups (ANOVA/P < 0.001).</p> <p>Conclusions</p> <p>Longer and wider interference screws provide better fixation in tibial ACL graft fixation. Short screws (23 mm) do not achieve optimal fixation and should be implanted only with special requirements.</p

Anthropometry, carbohydrate and lipid metabolism in the East Flanders Prospective Twin Survey: heritabilities

AIMS/HYPOTHESIS: We determined the genetic contribution of 18 anthropometric and metabolic risk factors of type 2 diabetes using a young healthy twin population. METHODS: Traits were measured in 240 monozygotic (MZ) and 138 dizygotic (DZ) twin pairs aged 18 to 34 years. Twins were recruited from the Belgian population-based East Flanders Prospective Twin Survey, which is characterised by its accurate zygosity determination and extensive collection of perinatal and placental data, including information on chorionicity. Heritability was estimated using structural equation modelling implemented in the Mx software package. RESULTS: Intra-pair correlations of the anthropometric and metabolic characteristics did not differ between MZ monochorionic and MZ dichorionic pairs; consequently heritabilities were estimated using the classical twin approach. For body mass, BMI and fat mass, quantitative sex differences were observed; genetic variance explained 84, 85 and 81% of the total variation in men and 74, 75 and 70% in women, respectively. Heritability estimates of the waist-to-hip ratio, sum of four skinfold thicknesses and lean body mass were 70, 74 and 81%, respectively. The heritability estimates of fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance and beta cell function, as well as insulin-like growth factor binding protein-1 levels were 67, 49, 48, 62 and 47%, in that order. Finally, for total cholesterol, LDL-cholesterol, HDL-cholesterol, total cholesterol:HDL-cholesterol ratio, triacylglycerol, NEFA and leptin levels, genetic factors explained 75, 78, 76, 79, 58, 37 and 53% of the total variation, respectively. CONCLUSIONS/INTERPRETATION: Genetic factors explain the greater part of the variation in traits related to obesity, glucose intolerance/insulin resistance and dyslipidaemia

Non-Invasive Mapping of the Gastrointestinal Microbiota Identifies Children with Inflammatory Bowel Disease

Background: Pediatric inflammatory bowel disease (IBD) is challenging to diagnose because of the non-specificity of symptoms; an unequivocal diagnosis can only be made using colonoscopy, which clinicians are reluctant to recommend for children. Diagnosis of pediatric IBD is therefore frequently delayed, leading to inappropriate treatment plans and poor outcomes. We investigated the use of 16S rRNA sequencing of fecal samples and new analytical methods to assess differences in the microbiota of children with IBD and other gastrointestinal disorders. Methodology/Principal Findings: We applied synthetic learning in microbial ecology (SLiME) analysis to 16S sequencing data obtained from i) published surveys of microbiota diversity in IBD and ii) fecal samples from 91 children and young adults who were treated in the gastroenterology program of Children’s Hospital (Boston, USA). The developed method accurately distinguished control samples from those of patients with IBD; the area under the receiver-operating-characteristic curve (AUC) value was 0.83 (corresponding to 80.3% sensitivity and 69.7% specificity at a set threshold). The accuracy was maintained among data sets collected by different sampling and sequencing methods. The method identified taxa associated with disease states and distinguished patients with Crohn’s disease from those with ulcerative colitis with reasonable accuracy. The findings were validated using samples from an additional group of 68 patients; the validation test identified patients with IBD with an AUC value of 0.84 (e.g. 92% sensitivity, 58.5% specificity). Conclusions/Significance: Microbiome-based diagnostics can distinguish pediatric patients with IBD from patients with similar symptoms. Although this test can not replace endoscopy and histological examination as diagnostic tools, classification based on microbial diversity is an effective complementary technique for IBD detection in pediatric patients.Natural Sciences and Engineering Research Council of Canada (Award NSERC PGS D)National Institutes of Health (U.S.) (1-R21-A1084032-01A1