Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: The PioNEER 8 trial

OBJECTIVE To investigate the efficacy, safety, and tolerability of oral semaglutide added to insulin with or without metformin. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes uncontrolled on insulin with or without metformin were randomized to oral semaglutide 3 mg (N 5 184), 7 mg (N 5 182), or 14 mg (N 5 181) or to placebo (N 5 184) in a 52-week, double-blind trial. End points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands were defined: treatment policy (effect regardless of trial product discontinuation or rescue medication) and trial product (effect assuming trial product continuation without rescue medication) in randomized patients. RESULTS Oral semaglutide was superior to placebo in reducing HbA1c (estimated treatment difference [ETD] –0.5% [95% CI –0.7, –0.3], –0.9% [–1.1, –0.7], and –1.2% [–1.4, –1.0] for 3, 7, and 14 mg, respectively; P < 0.001) and body weight (ETD 20.9 kg [95% CI 21.8, 20.0], 22.0 kg [23.0, 21.0], and 23.3 kg [24.2, 22.3]; P 5 0.0392 for 3 mg, P £ 0.0001 for 7 and 14 mg) at week 26 (treatment policy estimand). Significantly greater dose-dependent HbA1c and body weight reductions versus placebo were achieved with oral semaglutide at weeks 26 and 52 (both estimands). The most frequent adverse event with oral semaglutide was nausea (11.4–23.2% of patients vs. 7.1% with placebo; mostly mild to moderate). CONCLUSIONS Oral semaglutide was superior to placebo in reducing HbA1c and body weight when added to insulin with or without metformin in patients with type 2 diabetes. The safety profile was consistent with other glucagon-like peptide 1 receptor agonists

Description and performance of track and primary-vertex reconstruction with the CMS tracker

A description is provided of the software algorithms developed for the CMS tracker both for reconstructing charged-particle trajectories in proton-proton interactions and for using the resulting tracks to estimate the positions of the LHC luminous region and individual primary-interaction vertices. Despite the very hostile environment at the LHC, the performance obtained with these algorithms is found to be excellent. For tbar t events under typical 2011 pileup conditions, the average track-reconstruction efficiency for promptly-produced charged particles with transverse momenta of pT > 0.9GeV is 94% for pseudorapidities of |η| < 0.9 and 85% for 0.9 < |η| < 2.5. The inefficiency is caused mainly by hadrons that undergo nuclear interactions in the tracker material. For isolated muons, the corresponding efficiencies are essentially 100%. For isolated muons of pT = 100GeV emitted at |η| < 1.4, the resolutions are approximately 2.8% in pT, and respectively, 10μm and 30μm in the transverse and longitudinal impact parameters. The position resolution achieved for reconstructed primary vertices that correspond to interesting pp collisions is 10–12μm in each of the three spatial dimensions. The tracking and vertexing software is fast and flexible, and easily adaptable to other functions, such as fast tracking for the trigger, or dedicated tracking for electrons that takes into account bremsstrahlung

Observation of long-range, near-side angular correlations in proton-proton collisions at the LHC

This is the pre-print version of the Published Article, which can be accessed from the link below - Copyright @ 2010 Springer VerlagResults on two-particle angular correlations for charged particles emitted in proton-proton collisions at center-of-mass energies of 0.9, 2.36, and 7 TeV are presented, using data collected with the CMS detector over a broad range of pseudorapidity (eta) and azimuthal angle (phi). Short-range correlations in Delta(eta), which are studied in minimum bias events, are characterized using a simple "independent cluster" parametrization in order to quantify their strength (cluster size) and their extent in eta (cluster decay width). Long-range azimuthal correlations are studied differentially as a function of charged particle multiplicity and particle transverse momentum using a 980 inverse nb data set at 7 TeV. In high multiplicity events, a pronounced structure emerges in the two-dimensional correlation function for particle pairs with intermediate transverse momentum of 1-3 GeV/c, 2.0< |Delta(eta)| <4.8 and Delta(phi) near 0. This is the first observation of such a long-range, near-side feature in two-particle correlation functions in pp or p p-bar collisions

Observation of long-range, near-side angular correlations in proton-proton collisions at the LHC

Results on two-particle angular correlations for charged particles emitted in proton-proton collisions at center-of-mass energies of 0.9, 2.36, and 7TeV are presented, using data collected with the CMS detector over a broad range of pseudorapidity (eta) and azimuthal angle (phi). Short-range correlations in Delta(eta), which are studied in minimum bias events, are characterized using a simple "independent cluster" parametrization in order to quantify their strength (cluster size) and their extent in eta (cluster decay width). Long-range azimuthal correlations are studied differentially as a function of charged particle multiplicity and particle transverse momentum using a 980 nb(-1) data set at 7TeV. In high multiplicity events, a pronounced structure emerges in the two-dimensional correlation function for particle pairs with intermediate p(T) of 1-3 GeV/c, 2.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990�2015: a systematic analysis for the Global Burden of Disease Study 2015

Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors�the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25 over the same period. All risks jointly evaluated in 2015 accounted for 57·8 (95 CI 56·6�58·8) of global deaths and 41·2 (39·8�42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million 192·7 million to 231·1 million global DALYs), smoking (148·6 million 134·2 million to 163·1 million), high fasting plasma glucose (143·1 million 125·1 million to 163·5 million), high BMI (120·1 million 83·8 million to 158·4 million), childhood undernutrition (113·3 million 103·9 million to 123·4 million), ambient particulate matter (103·1 million 90·8 million to 115·1 million), high total cholesterol (88·7 million 74·6 million to 105·7 million), household air pollution (85·6 million 66·7 million to 106·1 million), alcohol use (85·0 million 77·2 million to 93·0 million), and diets high in sodium (83·0 million 49·3 million to 127·5 million). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Fgf8a mutation affects craniofacial development and skeletal gene expression in zebrafish larvae

Contains fulltext : 208498.pdf (publisher's version ) (Open Access

Disruption of the foxe1 gene in zebrafish reveals conserved functions in development of the craniofacial skeleton and the thyroid.

Introduction: Mutations in the FOXE1 gene are implicated in cleft palate and thyroid dysgenesis in humans. Methods: To investigate whether zebrafish could provide meaningful insights into the etiology of developmental defects in humans related to FOXE1, we generated a zebrafish mutant that has a disruption in the nuclear localization signal in the foxe1 gene, thereby restraining nuclear access of the transcription factor. We characterized skeletal development and thyroidogenesis in these mutants, focusing on embryonic and larval stages. Results: Mutant larvae showed aberrant skeletal phenotypes in the ceratohyal cartilage and had reduced whole body levels of Ca, Mg and P, indicating a critical role for foxe1 in early skeletal development. Markers of bone and cartilage (precursor) cells were differentially expressed in mutants in post-migratory cranial neural crest cells in the pharyngeal arch at 1 dpf, at induction of chondrogenesis at 3 dpf and at the start of endochondral bone formation at 6 dpf. Foxe1 protein was detected in differentiated thyroid follicles, suggesting a role for the transcription factor in thyroidogenesis, but thyroid follicle morphology or differentiation were unaffected in mutants. Discussion: Taken together, our findings highlight the conserved role of Foxe1 in skeletal development and thyroidogenesis, and show differential signaling of osteogenic and chondrogenic genes related to foxe1 mutation

Ag85B-ESAT-6 adjuvanted with IC31® promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in volunteers with previous BCG vaccination or tuberculosis infection

New TB vaccines are urgently needed because of the apparent lack of effect of the BCG vaccine on rates of adult contagious pulmonary tuberculosis and the risk of disseminated BCG disease in immunocompromised individuals. Since BCG appears to protect children, the primary target for vaccine development is a booster vaccine for adults but such vaccines ideally need to be able to efficiently prime mycobacterially naïve individuals as well as boost individuals previously vaccinated with BCG and those latently infected with TB. Protective immunity against Mycobacterium tuberculosis depends mainly on the generation of a Th1-type cellular immune response characterized by interferon-gamma (IFN-γ) production. In the present study, we monitored safety and IFN-γ responses in healthy BCG-vaccinated and prior or latently TB-infected individuals receiving a novel vaccine composed of the fusion protein Ag85B-ESAT-6 combined with the adjuvant IC31(®), administered at 0 and 2 months. Vaccination caused few local or systemic adverse effects besides transient soreness at the injection site, but it elicited strong antigen-specific T cell responses against Ag85B-ESAT-6 and both the Ag85B and ESAT-6 components, that could be augmented by second vaccination. The strong responses persisted through 32 weeks of follow-up, indicating the induction of a persistent memory response in the vaccine recipients