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

Substitution and price elasticity estimates using inter-country pooled data in a translog cost model

Pooled data across several developing countries and the U. S. were used to estimate long-run substitution and price elasticities in a translog framework for the paper, iron and steel, and aggregate manufacturing industries. While the quality of the estimates varies across the several industry-specific models, the results suggest higher values for these elasticities than appear commonly used in integrated assessment models. Estimates of own-price elasticities of energy range from - 0.80 to - 1.76 and are comparable to estimates from previous econometric studies in the context of developed countries (- 0.77 to - 0.87). Substitution elasticities show wider variation across countries and industries. For energy and capital they range from -1.96 to 9.80, for labor and energy from 2.61 to 7.11, and for energy and material from - 0.26 to 2.07

Culture-negative sepsis after pediatric cardiac surgery: Incidence and outcomes

Background : Significant proportion of congenital heart surgery (CHS) children exhibit sepsis, but have negative blood culture and defined “culture negative sepsis (CNS).” Aims and Objectives : Retrospective analysis of CNS patients undergoing CHS. Material and Methods : 437 consecutive CHS children grouped as controls (antibiotic prophylaxis), CNS, and culture positive sepsis (CPS). Results : Incidences of CNS and CPS were 16% and 7%. Median mechanical ventilation (MV) in hours among CPS, CNS, and control was 116 (45–271), 63 (23–112), and 18 (6–28) (P < 0.001), respectively. Multivariable linear regression identified CPS (median ratio: 3.1 [2.3–4.1], P < 0.001), CNS (median ratio: 5.6 [3.7–8.4], P < 0.001), and weight (kg) (median ratio: 0.98 [0.96–0.99], P = 0.009) as associations of MV. Intensive care unit (ICU) stay (hours) was 192 (120–288) in CNS, 288 (156–444) in CPS, and 72 (48–120) in controls (P < 0.0001). Multivariable linear regression showed CNS (median ratio: 2.4 [2.0–2.9], P< 0.001) CPS (median ratio: 3.3 [2.5–4.4], P < 0.001), and weight (median ratio: 0.98 [0.97–0.99], P = 0.001) prolonging ICU stay. Mortality was 10.7%, 2.9% and 1.2% in CPS, CNS, and control (P = 0.03). Multivariable regression identified CPS an independent predictor of mortality with odds ratio 8.6 (1.7–44.9; P = 0.010). 11.26% patients in CNS and 79.3% in CPS received antibiotics for more than 10 d ays. Conclusion : Incidence of CNS was 16%; duration of MV and ICU stay and mortality was significantly less in CNS than CPS patients

Distribution, relative abundance, and conservation status of Asian elephants in Karnataka, southern India

Karnataka state in southern India supports a globally significant and the country's largest population of the Asian elephant Elephas maximus. A reliable map of Asian elephant distribution and measures of spatial variation in their abundance, both vital needs for conservation and management action, are unavailable not only in Karnataka, but across its global range. Here, we use various data gathered between 2000 and 2015 to map the distribution of elephants in Karnataka at the scale of the smallest forest management unit, the `beat', while also presenting data on elephant dung density for a subset of `elephant beats.' Elephants occurred in 972 out of 2855 forest beats of Karnataka. Sixty percent of these 972 beats and 55% of the forest habitat lay outside notified protected areas (PM), and included lands designated for agricultural production and human dwelling. While median elephant dung density inside protected areas was nearly thrice as much as outside, elephants routinely occurred in or used habitats outside PM where human density, land fraction under cultivation, and the interface between human-dominated areas and forests were greater. Based on our data, it is clear that India's framework for elephant conservation which legally protects the species wherever it occurs, but protects only some of its habitats while being appropriate in furthering their conservation within PM, seriously falters in situations where elephants reside in and/or seasonally use areas outside PAs. Attempts to further elephant conservation in production and dwelling areas have extracted high costs in human, elephant, material and monetary terms in Karnataka. In such settings, conservation planning exercises are necessary to determine where the needs of elephants or humans must take priority over the other, and to achieve that in a manner that is based not only on reliable scientific data but also on a process of public reasoning. (C) 2015 Elsevier Ltd. All rights reserved

Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models.

FLT3 internal tandem duplication (FLT3-ITD) mutations account for ~25% of adult acute myeloid leukemia cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has limited monotherapy activity in relapsed/refractory acute myeloid leukemia with no responses observed in a small subset of FLT3-ITD+ patients. Further, FLT3-ITD mutations emerged at relapse following venetoclax monotherapy and combination therapy suggesting a potential mechanism of resistance. Therefore, we investigated the convergence of FLT3-ITD signaling on the BCL-2 family proteins and determined combination activity of venetoclax and FLT3-ITD inhibition in preclinical models. In vivo, venetoclax combined with quizartinib, a potent FLT3 inhibitor, showed greater anti-tumor efficacy and prolonged survival compared to monotherapies. In a patient-derived FLT3-ITD+ xenograft model, cotreatment with venetoclax and quizartinib at clinically relevant doses had greater anti-tumor activity in the tumor microenvironment compared to quizartinib or venetoclax alone. Use of selective BCL-2 family inhibitors further identified a role for BCL-2, BCL-XL and MCL-1 in mediating survival in FLT3-ITD+ cells in vivo and highlighted the need to target all three proteins for greatest anti-tumor activity. Assessment of these combinations in vitro revealed synergistic combination activity for quizartinib and venetoclax but not for quizartinib combined with BCL-XL or MCL-1 inhibition. FLT3-ITD inhibition was shown to indirectly target both BCL-XL and MCL-1 through modulation of protein expression, thereby priming cells toward BCL-2 dependence for survival. These data demonstrate that FLT3-ITD inhibition combined with venetoclax has impressive anti-tumor activity in FLT3-ITD+ acute myeloid leukemia preclinical models and provides strong mechanistic rational for clinical studies