Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Automatic speaker verification experiments using HMM

Abstract — This paper addresses the design and implementation of automatic speaker verification (ASV) systems. There is great interest in developing and increasing the performance of ASV applications, taking into account the advantages offered when compared to other biometrical methods. State-of-the-art speaker recognizers are based on statistical models such as GMM, HMM, SVM, ANN or hybrid models. This work reports experiments on prompted text speaker verification on a Romanian corpus. First, a Hidden Markov Model (HMM) based continuous speech recognizer is built at context independent, single mixture, monophone level. Then the client model and the world model are built using appropriate speech data. The text-prompted speaker verification system is based on sentence HMMs, constructed for the key text by concatenating corresponding acoustic models. In the verification stage, the normalized log-likelihood is derived as the difference between the log-likelihood obtained through Viterbi forced alignment of the client model and world model, respectively. Finally a procedure used to determine the verification performances is presented. Keywords-component; Automatic speaker verification systems; acoustic modeling; Hidden Markov Models. I

The Remote Experiment in the Light of the Learning Theories

The interference of technology in education requires the development of new theories of learning. The paper analyzes connectivism as the most important representative of the theories related to the “digital age.” From the point of view of the environment, called a remote experiment, learning occurs initially at the individual level, encompassing all three classic theories of learning: behaviorism, cognitivism, and constructivism. It shows that the virtual environment has introduced a powerful lever of imbalance for the real environment. This is how we arrived at the explanation of learning theories in real-virtual environments through the theory of chaos or complex environments. Like any knowledge storage network with nodes between which connections can be made, even the remote experiment is subject to random laws. The addition of knowledge is not simply the sum of the effects produced by each individual node (the system is not linear). A distinction is made between information and knowledge. Even if the information in the nodes can be read, this aspect does not represent learning. The remote experiment not only expanded the realm of knowledge but also emphasized the critical role of time. The time remained constant, while the amount of information increased. The teacher, as a knowledge synthesizer, can help orient the student to this vast amount of information, especially when time is limited. Additionally, the student can also play an active role in organizing and systematizing the information. Two examples of experiments are given, which, being inter- and transdisciplinary, can contribute to the introduction of the elements of non-linearity and unpredictability as a method of designing the educational environment, precisely to be able to transform it into a thinking system suitable for the mixture between real and virtual environments in which we live more and more intensely

On the Vibrations of a Rigid Solid Hung by Kinematic Chains

In this paper we consider two situations. In the first, all kinematic chains are elastic, while the second situation is characterized by one rigid kinematic chain, with the rest of them being elastic. In addition, the kinematic joints are considered to be rigid. The calculations are performed using the screw coordinates. For the free vibrations of the rigid solid we determined the rigidity matrix and the eigenpulsations in both cases. It was proved that the results in the second case cannot be considered as limits for the results of the first situation, putting infinite values for the elements of the rigidity matrix of one kinematic chain. We also developed the theory for the forced vibrations of the system. A numerical application is considered and a great variety of cases are developed and discussed. The results obtained for the forced vibrations are presented and discussed. The paper combines elastic and rigid kinematic chains, as well as general configurations of the kinematic chains. The method presented here may be used for any number of kinematic chains, no matter if the structure is symmetrical or asymmetrical

Analysis of the Effect of Fiber Orientation on Mechanical and Elastic Characteristics at Axial Stresses of GFRP Used in Wind Turbine Blades

Due to its physical and mechanical properties, glass-fiber-reinforced polymer (GFRP) is utilized in wind turbine blades. The loads given to the blades of wind turbines, particularly those operating offshore, are relatively significant. In addition to the typical static stresses, there are also large dynamic stresses, which are mostly induced by wind-direction changes. When the maximum stresses resulting from fatigue loading change direction, the reinforcing directions of the material used to manufacture the wind turbine blades must also be considered. In this study, sandwich-reinforced GFRP materials were subjected to tensile testing in three directions. The parameters of the stress–strain curve were identified and identified based on the three orientations in which samples were cut from the original plate. Strain gauge sensors were utilized to establish the three-dimensional elasticity of a material. After a fracture was created by tensile stress, SEM images were taken to highlight the fracture’s characteristics. Using finite element analyses, the stress–strain directions were determined. In accordance to the three orientations and the various reinforcements used, it was established that the wind turbine blades are operational

Evaluation of Keratin/Bacterial Cellulose Based Scaffolds as Potential Burned Wound Dressing

The study presents the preparation and characterization of new scaffolds based on bacterial cellulose and keratin hydrogel which were seeded with adipose stem cells. The bacterial cellulose was obtained by developing an Acetobacter xylinum culture and was visualized using SEM (scanning electron microscopy) and elementally determined through EDAX (dispersive X-ray analysis) tests. Keratin species (β–keratose and γ-keratose) was extracted by hydrolytic degradation from non-dyed human hair. SEM, EDAX and conductometric titration tests were performed for physical–chemical and morphological evaluation. Cytocompatibility tests performed in vitro confirmed the material non-toxic effect on cells. The scaffolds, with and without stem cells, were grafted on the burned wounds on the rabbit’s dorsal region and the grafts were monitored for 21 days after the application on the wounds. The clinical monitoring of the grafts and the histopathological examination demonstrated the regenerative potential of the bacterial cellulose–keratin scaffolds, under the test conditions

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791