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

Zonal-and-Wave Structure of Open Systems on Micro, Mega- and Macrolevels of the Universe

The analysis of formation of wave astrodynamics as the applied science that studying zonal-andwave structure of megasystems in the Universe is executed. The perspective of disclosure of physical essence of the phenomenon of rocks zonal disintegration around underground mine workings is analysed. The results of a research that received by means of well-known and new synergetic methods, which have discovered zonal-and-wave nature of the examined phenomenon, are described. The discovered phenomenon has been designated as zonal capsulation of mine working with definition of gradients of stresses, density, temperature and other factors of a power condition of the massif with formation of ring energy zones, their quantities, amount and shape, sinusoidal-and-wave stresses and ring areas of deformation. The regularities of distribution of matter and energy in systems with various large-scale levels have been investigated and accepted as comparative data for confirmation of level of convergence of the received results. Increase in large-scale level of system from micro to mega-and macrolevel led to equivalent increase in density of a core, constant of gravitation and the period of fluctuation of a surface, and the period of attenuation of wave fluctuations and a ratio of the sizes of energy zones remained constant. The received sedate dependence of a ratio of the sizes of energy zones for the examined systems coincides with the established verification of sedate dependences that describing a ratio of the sizes of energy zones in mine working’s capsule which convergence reaches up to 100%. The received results are the incontestable proof of the uniform nature of interaction of the open evolving systems at all large-scale levels and allows to draw analogies during development of methodological approaches to the solution of similar problems

Socio-Cultural Context of Innovative Development

The article presents the results of empirical studies of correlation of culture and innovations. Sociocultural factors of innovative development have been revealed. The present research has established the dual nature of innovations that finds itself in a symbiosis of an innovation and a creativity product. This fact allows us to view this phenomenon as a result of interaction of the economic and sociocultural spheres of society’s life activity: an innovative impulse arises from a person’s desire to gain an economic benefit, on the one hand, and from a desire to reach the originality that is specified by traditions of a certain culture, on the other hand. Consequently, innovative activity depends directly on socio-cultural values that determine human dispositions, habits and motivations. Sh. Schwartz’s calculation of value indices allowed us to reveal the human value priorities in twentyone countries of Europe in terms of their influence on person’s innovative dispositions, using the data body of International comparison project “European Social Survey” (2012-2016). It was shown that in the countries with dominant “Openness to Changes” values, inventiveness and innovativeness are more pronounced if compared to the countries where “Conservatism” values prevail. There has been demonstrated the special importance for innovative development of “Self-Transcendence” values that facilitate the formation of an environment favourable for implementing the institutional innovations. The research has proved that average Ukrainians have no value disposition to innovations. This fact creates a cultural barrier on the way of Ukraine’s innovative development and requires governmental impact on these processes. The authors have taken into account the global modern development tendencies that manifest themselves in strengthening the countries’ interdependency, particularly, in more rapid cultural convergence, gradual unification of values, with cultural diversity preserved. With this in mind, to intensify the innovative activity in Ukraine, the authors suggested a strategy of Ukraine’s deeper integration into the world science and technology space as an equal partner as well as searching for its niche in a constantly developing world segment of creative and innovative activity, with cultural diversity being a powerful source of development

The combined uterorelaxant effect of sildenafil and terbutalin in the rat: The potential benefit of co-administration of low doses

Aims: Our aims were to investigate the uterus relaxant effect of sildenafil alone and co-administered with β2-mimetic terbutaline in an isolated organ bath and to perform in vivo smooth muscle electromyographic studies in pregnant rats. The modifications in uterine cAMP/cGMP levels were also detected. Main methods: Contractions of non-pregnant and 5/15/18/20/22-day pregnant uterine rings were measured in an isolated organ bath system in the presence of sildenafil alone or with terbutaline. The uterine levels of cAMP and cGMP were determined by commercial ELISA assays. The in vivo efficacy of the combination was measured by smooth muscle electromyography. Key findings: Sildenafil reduced uterine contractions in vitro and in vivo; additionally, terbutaline significantly increased the uterorelaxant effect of sildenafil in the lower concentration or dose ranges. Terbutaline enhanced the cGMP level increasing effect of sildenafil. Significance: The co-administration of sildenafil and terbutaline could be a promising tocolytic combination to reduce maternal and foetal adverse events and increase efficacy