Search

Aims: The aim of the present study was to quantitate the hypoglycaemic effects of dipeptidyl peptidase‐4 inhibitors (DPP‐4i), glucagon‐like peptide‐1 receptor agonists (GLP‐1r) and sodium glucose cotransporter 2 inhibitors (SGLT2i) as add‐on treatments to metformin monotherapy in patients with type 2 diabetes mellitus (T2DM) using a model‐based meta‐analysis (MBMA). Methods: A systematic literature search of public databases was conducted to develop models that describe the time courses of the fasting plasma glucose (FPG)‐ and haemoglobin A1c (HbA1c)‐lowering effects of three antidiabetic classes using NONMEM 7.3.0. Results: Seventy‐six publications were eligible for this study, and 873 FPG and 1086 HbA1c values were collected. We developed a physiological indirect response model that described the time courses of FPG and HbA1c and simulated reductions in these values 90 days after the initiation of add‐on treatments. FPG and HbA1c reductions with once weekly exenatide, liraglutide and dulaglutide were greater than those with other drugs. Mean changes from baseline FPG and HbA1c with these drugs were as follows: exenatide (−22.5 and −16.6%), liraglutide (−22.1 and −16.3%), and dulaglutide (−19.3 and −14.3%). The hypoglycaemic effects of DPP‐4i and SGLT2i were similar. Conclusions: Once weekly exenatide, liraglutide and dulaglutide provided better hypoglycaemic effects among the antidiabetic drugs analysed. Long‐acting GLP‐1r appears to be more useful for T2DM patients inadequately controlled with metformin monotherapy. [ABSTRACT FROM AUTHOR]

T2DM is a complex disease underlined by multiple pathogenic defects responsible for the development and progression of hyperglycaemia. Each of these factors can now be tackled in a more targeted manner thanks to glucose‐lowering drugs that have been made available in the past 2 to 3 decades. Recognition of the multiplicity of the mechanisms underlying hyperglycaemia calls for treatments that address more than 1 of these mechanisms, with more emphasis placed on the earlier use of combination therapies. Although chronic hyperglycaemia contributes to and amplifies cardiovascular risk, several trials have failed to show a marked effect from intensive glycaemic control. During the past 10 years, the effect of specific glucose‐lowering agents on cardiovascular risk has been explored with dedicated trials. Overall, the cardiovascular safety of the new glucose‐lowering agents has been proven with some of the trials summarized in this review, showing significant reduction of cardiovascular risk. Against this background, pioglitazone, in addition to exerting a sustained glucose‐lowering effect, also has ancillary metabolic actions of potential interest in addressing the cardiovascular risk of T2DM, such as preservation of beta‐cell mass and function. As such, it seems a logical agent to combine with other oral anti‐hyperglycaemic agents, including dipeptidyl peptidase‐4 inhibitors (DPP4i). DPP4i, which may also have a potential to preserve beta‐cell function, is available as a fixed‐dose combination with pioglitazone, and could, potentially, attenuate some of the side effects of pioglitazone, particularly if a lower dose of the thiazolidinedione is used. This review critically discusses the potential for early combination of pioglitazone and DPP4i. [ABSTRACT FROM AUTHOR]

There is a relative lack of long-term data for individual glucose-lowering therapies for the treatment of type 2 diabetes mellitus. A systematic search of published literature reporting data of approximately ≥3 years of follow-up from randomized controlled trials and their extensions was conducted. Trials to evaluate the efficacy and/or safety of glucose-lowering drugs currently approved for the treatment of adults with type 2 diabetes were included. Search results included long-term published data for traditional oral glucose-lowering drugs, insulin, α-glucosidase inhibitors, and incretin-based therapies. In general, results indicated that the short-term risk/benefit profile of these therapies is in line with longer-term evaluations. Individual results from these trials are reviewed in this report. These findings support the use of approved drug classes for longer-term treatment of type 2 diabetes. [ABSTRACT FROM PUBLISHER]

Type 2 diabetes (T2D) is a wide-spread, chronic metabolic disorder, affecting millions of people worldwide. The epidemic of diabetes has placed a huge strain on public health, longevity and economy. T2D occurs as a result of both genetic and environmental factors and is heterogeneous in its presentation across individuals. This review gives an overview of the genetic variations identified by genome-wide association studies which predispose individuals to T2D and those which are responsible for variable drug response across patients, and the necessity to adopt a personalized approach to diabetes management. We also include a perspective on diabetes in Arabs, given the high incidence of T2D and consanguineous marriages, and the need to understand associated genetic components in this vulnerable population. [ABSTRACT FROM AUTHOR]

S100A7 is expressed in many squamous cell carcinomas ( SCCs), such as SCC of the skin, and well-differentiated SCC always displays stronger staining of this protein. A431 cells, an epidermal cancer cell line, were selected as a cell model to investigate the roles and mechanism of S100A7 in SCC of the skin. In this study, we demonstrated that the overexpression of S100A7 in A431 cells significantly promoted cell proliferation in vitro and tumor growth in vivo, whereas it suppressed the expression of GATA-3, caspase-14 and three squamous differentiation markers, keratin-1, TG-1 and involucrin. Conversely, the overexpression of caspase-14 not only significantly decreased cell proliferation and delayed tumor growth but also markedly induced the expression of three squamous differentiation markers, whereas S100A7 and GATA-3 were not influenced. Further evidence showed that silencing GATA-3 greatly inhibited the expression of caspase-14 and three differentiation markers, while the expression of S100A7 was not changed; contrary results were obtained when overexpressing GATA-3. Importantly, restoring the expression of GATA-3 and caspase-14 in A431-S100A7 cells could bypass the ability of S100A7 to increase cell viability and repress squamous differentiation. These data suggested that S100A7 expression in SCC may play an important role in the maintenance of SCC cell dedifferentiation, at least in SCC of the skin. [ABSTRACT FROM AUTHOR]

A direct WIMP (weakly interacting massive particle) detector with a neutron veto system is designed to better reject neutrons. The experimental configuration is studied in this paper involves 984 Ge modules placed inside a reactor-neutrino detector. The neutrino detector is used as a neutron veto device. The neutron background for the experimental design is estimated using the Geant4 simulation. The results show that the neutron background can decrease to O(0.01) events per year per tonne of high-purity germanium and it can be ignored in comparison with electron recoils. [ABSTRACT FROM AUTHOR]

This review discusses detector physics and Monte Carlo techniques for cryogenic, radiation detectors that utilize combined phonon and ionization readout. A general review of cryogenic phonon and charge transport is provided along with specific details of the Cryogenic Dark Matter Search detector instrumentation. In particular, this review covers quasidiffusive phonon transport, which includes phonon focusing, anharmonic decay, and isotope scattering. The interaction of phonons in the detector surface is discussed along with the downconversion of phonons in superconducting films. The charge transport physics include a mass tensor which results from the crystal band structure and is modeled with a Herring-Vogt transformation. Charge scattering processes involve the creation of Neganov-Luke phonons. Transition-edge-sensor (TES) simulations include a full electric circuit description and all thermal processes including Joule heating, cooling to the substrate, and thermal diffusion within the TES, the latter of which is necessary to model normal-superconducting phase separation. Relevant numerical constants are provided for these physical processes in germanium, silicon, aluminum, and tungsten. Random number sampling methods including inverse cumulative distribution function (CDF) and rejection techniques are reviewed. To improve the efficiency of charge transport modeling, an additional second order inverse CDF method is developed here along with an efficient barycentric coordinate sampling method of electric fields. Results are provided in a manner that is convenient for use in Monte Carlo and references are provided for validation of these models. [ABSTRACT FROM AUTHOR]

A scenario that removes the contradiction between the suppression of the η(1475) → γγ decay width and the strong coupling of η(1475) to the ρρ, ωω, and γρ channels and which leads to a nontrivial prediction for the manifestation of η(1475) in γγ*( Q) collisions is considered. Data on the dependence of the cross section for the reaction γγ*( Q) → $K\bar K\pi $ on the photon virtuality in the energy range 1.35-1.55 GeV are explained here by the production of an η(1475) resonance in contrast to their standard interpretation in terms of the f(1420) resonance. Experimental verification of the present explanation requires determining the spin-parity of resonance contributions, R, in the reactions γγ*( Q) R → R → $K\bar K\pi $ and J/ψ → γ R → γ(γρ, γϕ). [ABSTRACT FROM AUTHOR]

An extension of the new standard model, by introducing a mixing of the low mass “active” neutrinos with heavy ones, or by any model with lepton flavor violation, is considered. This leads to non-orthogonal neutrino production and detection states and to modifications of neutrino oscillations in both vacuum and matter. The possibility of the discovery of such effects in current and future neutrino oscillation experiments is discussed. First order approximation formulas for the flavor transition probabilities in constant density matter, for all experimentally available channels, are given. Numerical calculations of flavor transition probabilities for two sets of new physics parameters describing a single “effective” heavy neutrino state, both satisfying present experimental constraints, have been performed. Two energy ranges and several baselines, assuming both the current (±2σ) and the expected future errors (±3%) of the neutrino oscillation parameters are considered, keeping their present central values. It appears that the biggest potential of the discovery of the possible presence of any new physics is pronounced in oscillation channels in which νe and νē are not involved at all, especially for two baselines, L=3000 km and L=7500 km, which for other reasons are also called “magic” for future Neutrino Factory experiments. [ABSTRACT FROM AUTHOR]

In this paper, we study the pseudoscalar-scalar meson (PS) weak decays of D-mesons in the non-relativistic quark model using factorization scheme. Branching ratios for the Cabibbo angle-favored decays are calculated. [ABSTRACT FROM AUTHOR]

We present polarization measurements of extragalactic radio sources observed during the cosmic microwave background polarization survey of the Q/U Imaging Experiment (QUIET), operating at 43 GHz (Q-band) and 95 GHz (W-band). We examine sources selected at 20 GHz from the public, >40 mJy catalog of the Australia Telescope (AT20G) survey. There are ∼480 such sources within QUIET’s four low-foreground survey patches, including the nearby radio galaxies Centaurus A and Pictor A. The median error on our polarized flux density measurements is 30–40 mJy per Stokes parameter. At signal-to-noise ratio > 3 significance, we detect linear polarization for seven sources in Q-band and six in W-band; only 1.3 ± 1.1 detections per frequency band are expected by chance. For sources without a detection of polarized emission, we find that half of the sources have polarization amplitudes below 90 mJy (Q-band) and 106 mJy (W-band), at 95% confidence. Finally, we compare our polarization measurements to intensity and polarization measurements of the same sources from the literature. For the four sources with WMAP and Planck intensity measurements >1 Jy, the polarization fractions are above 1% in both QUIET bands. At high significance, we compute polarization fractions as much as 10%–20% for some sources, but the effects of source variability may cut that level in half for contemporaneous comparisons. Our results indicate that simple models—ones that scale a fixed polarization fraction with frequency—are inadequate to model the behavior of these sources and their contributions to polarization maps. [ABSTRACT FROM AUTHOR]