Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Shielding design for high-intensity Co-60 and Ir-192 gamma sources used in industrial radiography based on PHITS Monte Carlo simulations

Protection in industrial radiography facilities has been a worldwide concern for decades and the most appropriate protection for the public and operators in small-scale facilities is the engineering protection including shielding first, time and distance. Monte Carlo methods were used for thickness determination in shielding design for gamma imaging using gamma sources in fixed facilities. Computation was done to develop the concrete design that can slow down the effective dose rate of the gamma rays from 100 Ci (or less) of Co-60 and 50 Ci (or less) of Ir-192 less than the value of 2.5 μSv/h (the limit for Public area) as required by the ALARA principle and regulation of different countries. The minimum concrete wall thickness necessary to achieve the ALARA principle in the previous conditions was found to be 120 cm for Co-60 source and 70 cm for the Ir-192 source. From the optimized design using a single corner maze, it was found that the central source position gives rise to high exposure and should not be used as a source position. Only the left and right positions of the source are preferred depending on the facility’s dimensions. For Co-60 with a maze corridor less than 7 m, the right position of the source is the most appropriate while the left position is preferred for larger dimensions. For Ir-192, the right position if preferred if the corridor length is less than 5 m and the left otherwise. Double-corner maze design was found to be the most appropriate shielding design for gamma radiation with the left and right position of the sources the best for both sources used. The double-corner maze required only 4 m maze length to achieve 2.5 µSv/h or less ALARA principle while single corner design requires 12 m or 14 m for left and right positions, respectively

Maze influence to radiological protection around industrial radiographic sources (Co-60) under 100 Ci

peer reviewedThe shielded enclosure design around the gamma radiography facilities under 100 Ci cobalt-60 source was evaluated as well as the maze design and source positions contribution to the dose limitation consistent with the ALARA principle. It was found that the most effective maze type to shield gamma radiations was double (multiple by extension) corners maze type. From discussions on the source positions, practitioners should select the optimizing position from both left or right depending on the length of the maze in the case of a single corner type, but never at the central position. The obtained results provided an insightful contribution to the radiological protection in industrial radiography

Implementation of an LBE spallation target in an accelerator-driven molten salt subcritical reactor

An accelerator-driven system (ADS) combined with a subcritical molten salt reactor (MSR) is a type of hybrid reactor originally designed to use Th/U (or U/Pu ) fuel cycles. In most accelerator-driven molten salt reactor (AD-MSR) concepts, the salt material is also used as a target for inducing spallation neutrons. Although a neutron source is an important component in the design of ADS, only a few studies have addressed the effects of the neutron spallation source in the AD-MSR. Incidentally, there is no quantitative study on how much the beam power can be reduced by installing a spallation target in a sodium chloride-based fast reactor. We studied the proton and the neutron source efficiencies of an AD-MSR with chloride fuels by considering an Lead Bismuth Eutectic (LBE) spallation target. This LBE target is found to increase the proton source efficiency significantly. The required beam power for an AD-MSR can be reduced by 33 % and 16 % for NaCl-Th/233U and NaCl-U/Pu fuels, respectively, relative to the AD-MSR without the LBE spallation target by keeping the same keff. The energy gain can be increased up to 1.5 times and 1.2 times for NaCl-Th/233U and NaCl-U/Pu fuels, respectively. Thus, incorporating a spallation target module in an AD-MSR can significantly reduce the burden on the accelerator

Design of an accelerator-driven subcritical dual fluid reactor for transmutation of actinides

An accelerator-driven subcritical dual fluid reactor (AD-DFR), which is a hybrid core operated by a high power accelerator, is designed for the transmutation of minor actinides. The subcritical core is dual in the sense that a lead-bismuth-eutectic-cooled fast reactor (LFR) is combined with a molten salt reactor (MSR). Thus, the core has two loops: one for the liquid metal coolant and the other for the molten salt fuel. The combination of LFR and MSR can take advantages of both reactor types. A subcritical core allows for loading a high fraction of minor actinides in fuels. An 800MW_t AD-DFR can transmute minor actinides approximately 120kg/year with only the maximum beam power of 13MW

Development of a new nuclear data library based on ROOT

We develop a new C++ nuclear data library for the Evaluated Nuclear Data File (ENDF) data, which we refer to as TNudy. Main motivation of the development is to provide systematic, powerful and intuitive interfaces and functionalities for browsing, visualizing and manipulating the detailed information embodied in the ENDF. To achieve this aim efficiently, the TNudy project is based on the ROOT system. TNudy is still in the stage of development, and the current status and future plans will be presented

Development of a new nuclear data library based on ROOT

We develop a new C++ nuclear data library for the Evaluated Nuclear Data File (ENDF) data, which we refer to as TNudy. Main motivation of the development is to provide systematic, powerful and intuitive interfaces and functionalities for browsing, visualizing and manipulating the detailed information embodied in the ENDF. To achieve this aim efficiently, the TNudy project is based on the ROOT system. TNudy is still in the stage of development, and the current status and future plans will be presented