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

Simulation of LOX reorientation using magnetic positive positioning

A combination of both experimental and computational simulation results have recently provided strong evidence that magnetic positioning may be a feasible alternative technology for managing cryogenic propellants onboard spacecraft. One prerequisite in the assessment of magnetic propellant management is the ability of predicting propellant reorientation in full-scale propellant tanks. A computational simulation is used to model magnetically induced liquid oxygen (LOX) flows in reduced gravity. Simulations of magnetic positive positioning of LOX are presented and the influence of the magnetic field and background acceleration on reorientation timing is explored. A dimension-less reorientation time is sought to compliment the magnetic Bond number and Bond number as an additional predictive correlating parameter for scaling this process. Evidence is provided that supports the continued use of these correlating parameters to predict the magnetic fields required to reorient cryogenic propellants in full-scale spacecraft tanks. Further, this study supports the conclusion that magnetic positive positioning appears to be a viable emerging technology for cryogenic propellant management systems that merits further computational investigation and space-based experimentation to establish the technology base required for future spacecraft design. © Z-Tec Publishing

Simulation of Bulk Evaporation and Condensation using the Energy of Fluid Method

The design of cryogenic propellant storage systems for long duration space missions relies on accurate prediction of tank self-pressurization. Incident solar radiation heats the cryogenic liquids in the tank over time, vaporizing the cryogenic liquid. As the liquid vaporizes, the tank pressure increases. The objective of the current research is to develop a finite volume based Computational Fluid Dynamic (CFD) model of tank pressurization in reduced gravity using an Energy of Fluid (EOF) approach. A commercially available CFD model is significantly enhanced to include the EOF method, which will solve the energy equation in terms of internal energy. Model validation results are presented which include a comparison of temperature and pressure predictions to the data collected during the low gravity experiment conducted onboard the Saturn IB AS203 tank

Simulation of magnetic positive positioning for space based fluid management systems

Experimental and computational studies have shown that a sufficiently strong magnetic field can influence a magnetically susceptible liquid. An improved simulation integrates an electromagnetic field model and incompressible flow model to predict fluid reorientation using realistic magnetic fields. Flow fields are presented incorporating several realistic magnetic fields to verify and validate the connectivity of the integrated models. Conclusions are drawn about the fidelity of the integrated simulation in modeling magnetically induced fluid flows. The simulation is used to model the application of magnetic positive positioning of LOX in a reduced gravity experiment utilizing a realistic magnetic field. Preflight experiment predictions of the performance of the magnetic field in reorienting LOX are presented and recommendations are made for future design. © 2010 Elsevier Ltd. All rights reserved

Preflight prediction and optimization of a reduced gravity experiment to investigate magnetic positive positioning of lox

Simulation of magnetic positive positioning of propellants (MP 3) in full-scale applications depends on the ability to model the shape and strength of the magnetic fields required to induce fluid flow. A previous effort to integrate an electromagnetic field and incompressible fluid flow model yielded a unique tool that can be used to predict fluid motion induced by a magnetic field. The enhanced computational simulation is used to predict an optimal configuration for an upcoming flight experiment focused on studying the influence of a magnetic field on LOX in reduced gravity. Simulations of magnetic positive positioning of LOX are presented and the influence of the magnetic field and background acceleration on the settling time is investigated to determine an appropriate tank and liquid configuration to induce successful reorientation during the flight experiment. Variations in the magnet thickness, LOX tank size, background acceleration, and LOX tank fill are considered to predict the optimal experiment design. The magnetic Bond number and a dimensionless reorientation time are utilized as correlating parameters for this study and may be useful in future efforts to relate magnetically induced flows for small-scale experiments to the behavior of propellants in full-size systems

Simulating magnetic positive positioning of cryogenic propellants in a transient acceleration field

A computational simulation of magnetic positive positioning (MP2) is developed to model cryogenic propellant reorientation in reduced gravity. Previous efforts have successfully incorporated an electromagnetic field model into an axisymmetric, two-dimensional, incompressible fluid flow model yielding accurate predictions of fluid motion induced by a magnetic field. To simulate MP2, a three-dimensional magnetic field and magnetic force model was developed as a feature of a commercially available fluid flow model which has been well validated. The computational tool was then improved upon to model magnetically induced flows in a transient acceleration field. Simulation predictions obtained with the enhanced model are compared to available reduced gravity experiment data. Evidence is presented and conclusions are drawn that support the continued use of the simulation as viable modeling and predictive tool in the continuing study of MP2. © 2008 Elsevier Ltd. All rights reserved

Simulation of jet-induced geysers in reduced gravity

Control of cryogenic propellant tank pressure during tank refueling and expulsion in low gravity is an important technical challenge to overcome for future long duration missions in space. One method proposed to control tank pressurization involves the use of jet-induced geysers. Two-dimensional computational models have been developed and used with limited success in previous efforts to predict geyser heights in microgravity. A three-dimensional flow simulation is used to model jet-induced geysers in reduced gravity. Geyser flows are commonly characterized by the presence of turbulent jets, transient flow, deforming free surfaces, and surface tension effects. As is the case for many turbulent flow applications, accuracy in simulating complex turbulent flows is critically dependent on the selection of a suitable turbulence model. The sensitivity of the simulation geyser predictions to a suite of popular turbulence models is assessed. Simulation results are compared to available experiment results. By expanding upon the work already completed, the model is used to simulate a broad range of cases within the experiment test matrix. Simulation results suggest the two dimensional simulation using the k-ε turbulence model provides the most accurate results for jet-induced geysers in reduced gravity when compared to available experiment data. © 2008 Springer Science+Business Media B.V

Simulating Magnetic Positive Positioning of Liquids in a Transient Acceleration Field

A computational simulation of magnetic positive positioning (MP2) is used to model cryogenic propellant reorientation in reduced gravity. Previous efforts have successfully incorporated an electromagnetic field model into an axisymmetric, two-dimensional, incompressible flow model yielding accurate predictions of fluid motion induced by a magnetic field. To simulate MP 2, a three-dimensional magnetic field and magnetic force model was developed and validated as a feature of a commercially available fluid flow model. Simulation predictions obtained with the enhanced model are compared to available reduced gravity flight experiment data and include the effects of the transient acceleration environment. Evidence is presented and conclusions are drawn that support the continued use of the simulation as a viable modeling and predictive tool in the continuing study of MP2. Copyright © 2008 by Jeffrey G. Marchetta and Kevin M. Roos

Three dimensional modeling of jet-induced geysers in low gravity

Control of cryogenic propellant tank pressure during tank refueling and expulsion in low gravity is an important technical challenge to overcome for future long duration missions in space. One method proposed to control tank pressurization involves the use of jet-induced geysers. Two-dimensional computational models have been developed and used with limited success in previous efforts to predict geyser heights in microgravity. A three-dimensional flow simulation is used to model jet-induced geysers in reduced gravity. Geyser flows are commonly characterized by the presence of turbulent jets, transient flow, deforming free surfaces, and surface tension effects. As is the case for many turbulent flow applications, accuracy in simulating complex turbulent flows is critically dependent on the selection of a suitable turbulence model. The sensitivity of the simulation geyser predictions to a suite of popular turbulence models is assessed. Simulation results are compared to available experiment result. By expanding upon the work already completed, the model is used to simulate a broad range of cases within the experiment test matrix. Simulation results suggest the k-ε turbulence model provides the most accurate results for jet-induced geysers in reduced gravity when compared to available experiment data