Sodium-glucose co-transporter 2 (SGLT2) inhibitors are glucose-lowering drugs that reduce plasma glucose levels by inhibiting glucose and sodium reabsorption in the kidneys, thus resulting in ...glucosuria. Their effects consequently include reductions in HbA1c, blood glucose levels, and blood pressure, but also reductions in body weight and adiposity. The ability to reduce body weight is consistently observed in individuals taking SGLT2 inhibitors, but this weight loss is moderate due to counter-regulatory mechanisms striving to maintain body weight. This has prompted exploration of SGLT2 inhibitors in combination with other agents acting via decreased food intake, e.g., glucagon-like peptide 1 receptor agonists (GLP1-RAs). The bodyweight effects are promising, and together with the signs of prevention of cardiovascular and renal events, such combinations including SGLT2 inhibitors are appealing. The weight loss is clinically important, as most individuals with type 2 diabetes are overweight or obese, but also because there is an unmet need for safe, effective, and durable weight loss interventions in obese individuals without diabetes.
Global controls on month-by-month fractional burnt area (2000-2005) were investigated by fitting a generalised linear model (GLM) to Global Fire Emissions Database (GFED) data, with 11 predictor ...variables representing vegetation, climate, land use and potential ignition sources. Burnt area is shown to increase with annual net primary production (NPP), number of dry days, maximum temperature, grazing-land area, grass/shrub cover and diurnal temperature range, and to decrease with soil moisture, cropland area and population density. Lightning showed an apparent (weak) negative influence, but this disappeared when pure seasonal-cycle effects were taken into account. The model predicts observed geographic and seasonal patterns, as well as the emergent relationships seen when burnt area is plotted against each variable separately. Unimodal relationships with mean annual temperature and precipitation, population density and gross domestic product (GDP) are reproduced too, and are thus shown to be secondary consequences of correlations between different controls (e.g. high NPP with high precipitation; low NPP with low population density and GDP). These findings have major implications for the design of global fire models, as several assumptions in current models - most notably, the widely assumed dependence of fire frequency on ignition rates - are evidently incorrect.
Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic ...progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined.
In this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival.
A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval CI, 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005). The frequency of grade 3 or 4 adverse events was 42.2% in the apalutamide group and 40.8% in the placebo group; rash was more common in the apalutamide group.
In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.).
A method for digestion of soils with high inorganic matter content (ranging from 50 to 92%) by microwave-induced combustion (MIC) is proposed for the first time for further halogens (F, Cl, Br, and ...I) determination by ion chromatography (IC) and also by inductively coupled plasma mass spectrometry (ICP-MS). Microcrystalline cellulose (100–500 mg), used as a combustion aid, was mixed with sample and water or NH4OH solutions (10–100 mmol L–1) were investigated for analytes absorption. The use of cellulose (400 mg) was mandatory to volatilize the halogens from soils with high inorganic matter. It was possible to use diluted absorbing solutions (up to 100 mmol L–1 NH4OH) for halogens retention, providing limits of quantification in the range of 0.06 (I) to 60 (Cl) μg g–1. Accuracy was evaluated using certified reference materials (CRMs), spiked samples, and pyrohydrolysis method. Recoveries for halogens after spiked samples were in the range of 94 to 103% and the results after digestion of CRMs by MIC were in agreement better than 95% to certified values. Blanks were low, relative standard deviation was below 8% for all soils and no statistical difference was observed for results by pyrohydrolysis and MIC methods showing the feasibility of the proposed method for further halogens determination in soil samples.
Teleparallel gravity and its popular generalization gravity can be formulated as fully invariant (under both coordinate transformations and local Lorentz transformations) theories of gravity. Several ...misconceptions about teleparallel gravity and its generalizations can be found in the literature, especially regarding their local Lorentz invariance. We describe how these misunderstandings may have arisen and attempt to clarify the situation. In particular, the central point of confusion in the literature appears to be related to the inertial spin connection in teleparallel gravity models. While inertial spin connections are commonplace in special relativity, and not something inherent to teleparallel gravity, the role of the inertial spin connection in removing the spurious inertial effects within a given frame of reference is emphasized here. The careful consideration of the inertial spin connection leads to the construction of a fully invariant theory of teleparallel gravity and its generalizations. Indeed, it is the nature of the spin connection that differentiates the relationship between what have been called good tetrads and bad tetrads and clearly shows that, in principle, any tetrad can be utilized. The field equations for the fully invariant formulation of teleparallel gravity and its generalizations are presented and a number of examples using different assumptions on the frame and spin connection are displayed to illustrate the covariant procedure. Various modified teleparallel gravity models are also briefly reviewed.
This study deals with the development of a low momentum whirling laminar plume that results from the interaction between a plume and a circulating flow imposed by a cylindrical rotating screen. ...Numerical simulations were performed by direct simulation of the fully three-dimensional flow governed by the compressible Navier-Stokes and energy equations. The rotating thermal plume forms a columnar vortex governed by the Grashof (GR) and nondimensional rotation velocity (Reynolds number (ReR)), based on the cylindrical domain’s radius and the angular frequency of rotation of the permeable lateral surface. Numerical solutions were obtained in the range 102<Gr<106 and 10<ReR<150. The vortex generated bifurcates into a pair of steady co-rotating vortices within the range 104<Gr<2×105 and 30<ReR<100. The steady state configuration of the flow is described and analysed, showing the evolution of the vorticity contours in cross-sections that start out as circlets, gradually turn into an ellipse and end up bifurcating into a pair of co-rotating vortices. The role of the boundary layer is also described, showing an increase in the distance between the co-rotating vortex pair for a given Gr and ReR numbers but in the absence of a boundary layer. At last, the temporal evolution of the vortex splitting process is compared to measurements of merging of two co-rotating vortices available in the literature, uncovering that the two phenomena take similar timescales to occur.
Antibiotic therapy (AT) is the cornerstone of the management of severe community-acquired pneumonia (CAP). However, the best treatment strategy is far from being established.
To evaluate the impact ...of different aspects of AT on the outcome of critically ill patients with CAP, we performed a post hoc analysis of all CAP patients enrolled in a prospective, observational, multicentre study.
Of the 502 patients included, 76% received combination therapy, mainly a β-lactam with a macrolide (80%). AT was inappropriate in 16% of all microbiologically documented CAP (n=177). Hospital and 6months mortality were 34% and 35%. In adjusted multivariate logistic regression analysis, combination AT with a macrolide was independently associated with a reduction in hospital (OR 0.17, 95%CI 0.06–0.51) and 6months (OR 0.21, 95%CI 0.07–0.57) mortality. Prolonged AT (>7days) was associated with a longer ICU (14 vs. 7days; p<0.001) and hospital length of stay (LOS) (25 vs. 17days; p<0.001).
Combination AT with a macrolide may be the most suitable AT strategy to improve both short and long term outcome of severe CAP patients. AT >7days had no survival benefit and was associated with a longer LOS.
•In SCAP, combination of antibiotics that includes a macrolide is associated a better hospital and 6 months survival.•Courses of therapy longer than 7 days are not associated with survival benefit but lead to longer ICU and hospital LOS.•Serum lactate showed to be a good prognostic marker of hospital mortality in SCAP patients.
In general relativity, inertia and gravitation are both included in the Levi–Civita connection. As a consequence, the gravitational action, as well as the corresponding energy–momentum density, are ...in general contaminated by spurious contributions coming from inertial effects. In teleparallel gravity, on the other hand, because the spin connection represents inertial effects only, it is possible to separate inertia from gravitation. Relying on this property, it is shown that to each tetrad there is naturally associated a spin connection that
locally removes the inertial effects
from the action. The use of the appropriate spin connection can be viewed as a renormalization process in the sense that the computation of energy and momentum naturally yields the physically relevant values. A self-consistent method for solving field equations and determining the appropriate spin connection is presented.
A
bstract
A two-dimensional field theory of a fermion chirally coupled to Toda field plus a scalar self-coupling potential is considered. Using techniques of integrable systems we obtain analytical ...zero modes, in-gap states and bound states in the continuum (BIC) for topological configurations of the scalar field. Fermion-soliton duality mappings are uncovered for the bound state spectrum, which interpolates the weak and strong coupling sectors of the model and give rise to novel Thirring-like and multi-frequency sine-Gordon models, respectively. The non-perturbative effects of the back-reaction of the fermion bound states on the kink are studied and it is shown that the zero mode would catalyze the emergence of a new kink with lower topological charge and greater slope at the center, in the strong coupling limit of the model. For special topological charges and certain relative phases of the fermion components the kinks can host Majorana zero modes. The Noether, topological and a novel nonlocal charge densities satisfy a formula of the Atiyah-Patodi-Singer-type. Our results may find applications in several branches of non-linear physics, such as confinement in QCD
2
, braneworld models, high
T
c
superconductivity and topological quantum computation. We back up our results with numerical simulations for continuous families of topological sectors.
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