Redefining hypoglycemia in clinical trials: validation of definitions recently adopted by the American Diabetes Association/European Association for the study of diabetes

OBJECTIVE The purpose of this study was to determine if the International Hypoglycemia Study Group (IHSG) level 2 low glucose definition could identify clinically relevant hypoglycemia in clinical trials and offer value as an end point for future trials. RESEARCH DESIGN AND METHODS A post hoc analysis of the SWITCH (SWITCH 1: n = 501, type 1 diabetes; SWITCH 2: n = 721, type 2 diabetes) and the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE; n = 7,637, type 2 diabetes) using the IHSG low glucose definitions. Patients in all trials were randomized to either insulin degludec or insulin glargine 100 units/mL. In the main analysis, the following definitions were compared: 1) American Diabetes Association (ADA) 2005 (plasma glucose [PG] confirmed ≤3.9 mmol/L with symptoms); and 2) IHSG level 2 (glucose confirmed <3.0 mmol/L). RESULTS In SWITCH 2, the estimated rate ratios of hypoglycemic events indicated increasing differences between treatments with decreasing PG levels until 3.0 mmol/L, following which no additional treatment differences were observed. In SWITCH 2, the IHSG level 2 definition produced a rate ratio that was lower than the ADA 2005 definition. Similar results were observed for the SWITCH 1 trial. CONCLUSIONS The IHSG level 2 definition was validated in a series of clinical trials, demonstrating its ability to discriminate between basal insulins. This definition is therefore recommended to be uniformly adopted by regulatory bodies and used in future clinical trials

Lower rates of hypoglycaemia in older individuals with type 2 diabetes using insulin degludec versus insulin glargine U100 : results from SWITCH 2

Aim This study aimed to investigate the safety of insulin degludec (degludec) in relation to age and risk of hypoglycaemia post hoc in individuals with type 2 diabetes (T2D) (SWITCH 2 trial). Methods In this crossover study, individuals with T2D who were at risk of hypoglycaemia were randomized to double‐blind treatment with degludec or insulin glargine 100 units/mL (glargine U100) ± oral antidiabetic drugs. After 32 weeks, patients crossed over to the other treatment. Primary endpoint was number of overall severe (positively adjudicated) or glucose‐confirmed (plasma glucose <56 mg/dL; 3.1 mmol/L) symptomatic hypoglycaemia events during the two 16‐week maintenance periods. Results For individuals ≤65 (n = 450) and >65 (n = 270) years, baseline median (range) duration of diabetes was 12 (1–40) vs 15 (1–54) years, mean HbA1c was 7.7% vs 7.4% and mean estimated glomerular filtration rate was 87.0 vs 63.7 mL/min/1.73 m2, respectively. No significant differences in HbA1c reduction were seen in individuals ≤65 or >65 years. During both maintenance periods, treatment with degludec lowered rates of hypoglycaemia (overall/nocturnal symptomatic) vs those with glargine U100 in individuals ≤65 (31% vs 43%) and >65 (30% vs 41%) years. With degludec and glargine U100, respectively, six vs nine severe hypoglycaemic events occurred in individuals ≤65 years and four vs eight events occurred in those >65 years. Adverse event rates were 3.2 and 3.3 events/patient‐year for individuals ≤65 years and were 3.5 and 4.1 events/patient‐year for individuals >65 years with degludec and glargine U100, respectively. Conclusion Treatment with degludec was safe and effective, with a frequency of hypoglycaemia lower than that with glargine U100 in both younger and older individuals (>65 years) with T2D

Construction of markov processes from hitting distributions

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47648/1/440_2004_Article_BF00538487.pd

Spatial Periodicity of Galaxy Number Counts, CMB Anisotropy, and SNIa Hubble Diagram Based on the Universe Accompanied by a Non-Minimally Coupled Scalar Field

We have succeeded in establishing a cosmological model with a non-minimally coupled scalar field $\phi$ that can account not only for the spatial periodicity or the {\it picket-fence structure} exhibited by the galaxy $N$-$z$ relation of the 2dF survey but also for the spatial power spectrum of the cosmic microwave background radiation (CMB) temperature anisotropy observed by the WMAP satellite. The Hubble diagram of our model also compares well with the observation of Type Ia supernovae. The scalar field of our model universe starts from an extremely small value at around the nucleosynthesis epoch, remains in that state for sufficiently long periods, allowing sufficient time for the CMB temperature anisotropy to form, and then starts to grow in magnitude at the redshift $z$ of $\sim 1$, followed by a damping oscillation which is required to reproduce the observed picket-fence structure of the $N$-$z$ relation. To realize such behavior of the scalar field, we have found it necessary to introduce a new form of potential $V(\phi)\propto \phi^2\exp(-q\phi^2)$, with $q$ being a constant. Through this parameter $q$, we can control the epoch at which the scalar field starts growing.Comment: 19 pages, 18 figures, Accepted for publication in Astrophysics & Space Scienc

Formation of ethane and propane via abiotic reductive conversion of acetic acid in hydrothermal sediments

A mechanistic understanding of formation pathways of lowmolecular- weight hydrocarbons is relevant for disciplines such as atmospheric chemistry, geology, and astrobiology. The patterns of stable carbon isotopic compositions (δ13C) of hydrocarbons are commonly used to distinguish biological, thermogenic, and abiotic sources. Here, we report unusual isotope patterns of nonmethane hydrocarbons in hydrothermally heated sediments of the Guaymas Basin; these nonmethane hydrocarbons are notably 13Cenriched relative to sedimentary organic matter and display an isotope pattern that is reversed relative to thermogenic hydrocarbons (i.e., δ13C ethane > δ13C propane > δ13C n-butane > δ13C n-pentane). We hypothesized that this pattern results from abiotic reductive conversion of volatile fatty acids, which were isotopically enriched due to prior equilibration of their carboxyl carbon with dissolved inorganic carbon. This hypothesis was tested by hydrous pyrolysis experiments with isotopically labeled substrates at 350°C and 400 bar that demonstrated 1) the exchange of carboxyl carbon of C2 to C5 volatile fatty acids with 13C-bicarbonate and 2) the incorporation of 13C from 13C-2-acetic acid into ethane and propane. Collectively, our results reveal an abiotic formation pathway for nonmethane hydrocarbons, which may be sufficiently active in organic-rich, geothermally heated sediments and petroleum systems to affect isotopic compositions of nonmethane hydrocarbons

Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7)

Aims: The aim of this study was to describe the risks of cardiovascular (CV) events and severe hypoglycaemia with insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) aged 65 years or older. Materials and methods: A total of 7637 patients in the DEVOTE trial, a treat-to-target, randomized, double-blind trial evaluating the CV safety of degludec vs glargine U100, were divided into three age groups (50-64 years, n = 3682; 65-74 years, n = 3136; ≥75 years, n = 819). Outcomes by overall age group and randomized treatment differences were analysed for major adverse cardiovascular events (MACE), all-cause mortality, severe hypoglycaemia and serious adverse events (SAEs). Results: Patients with increasing age had higher risks of CV death, all-cause mortality and SAEs, and there were non-significant trends towards higher risks of MACE and severe hypoglycaemia. Treatment effects on the risk of MACE, all-cause mortality, severe hypoglycaemia and SAEs were consistent across age groups, based on the non-significant interactions between treatment and age with regard to these outcomes. Conclusions: There were higher risks of CV death, all-cause mortality and SAEs, and trends towards higher risks of MACE and severe hypoglycaemia with increasing age after adjusting for baseline differences. The effects across age groups of degludec vs glargine U100 on MACE, all-cause mortality and severe hypoglycaemia were comparable, suggesting that the risk of MACE, as well as all-cause mortality, is similar and the risk of severe hypoglycaemia is lower with degludec regardless of age. Evidence is conclusive only until 74 years of age

Extrapolating SMBH correlations down the mass scale: the case for IMBHs in globular clusters

Empirical evidence for both stellar mass black holes M_bh<10^2 M_sun) and supermassive black holes (SMBHs, M_bh>10^5 M_sun) is well established. Moreover, every galaxy with a bulge appears to host a SMBH, whose mass is correlated with the bulge mass, and even more strongly with the central stellar velocity dispersion sigma_c, the `M-sigma' relation. On the other hand, evidence for "intermediate-mass" black holes (IMBHs, with masses in the range 1^2 - 10^5 M_sun) is relatively sparse, with only a few mass measurements reported in globular clusters (GCs), dwarf galaxies and low-mass AGNs. We explore the question of whether globular clusters extend the M-sigma relationship for galaxies to lower black hole masses and find that available data for globular clusters are consistent with the extrapolation of this relationship. We use this extrapolated M-sigma relationship to predict the putative black hole masses of those globular clusters where existence of central IMBH was proposed. We discuss how globular clusters can be used as a constraint on theories making specific predictions for the low-mass end of the M-sigma relation.Comment: 14 pages, 3 figures, accepted for publication in Astrophysics and Space Science; fixed typos and a quote in Sec.

Neutralino Dark Matter, b-tau Yukawa Unification and Non-Universal Sfermion Masses

We study the implications of minimal non-Universal Boundary Conditions in the sfermion Soft SUSY Breaking (SSB) masses of mSUGRA. We impose asymptotic b-tau Yukawa coupling Unification and we resort to a parameterization of the deviation from Universality in the SSB motivated by the multiplet structure of SU(5) GUT. A set of cosmo-phenomenological constraints, including the recent results from WMAP, determines the allowed parameter space of the models under consideration. We highlight a new coannihilation corridor where neutralino-sbottom and neutralino-tau sneutrino-stau coannihilations significantly contribute to the reduction of the neutralino relic density.Comment: 38 pages, 27 Figures, Latex; Version accepted for publication in PR

Large-scale association analyses identify host factors influencing human gut microbiome composition

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis