Baseline characteristics and enrichment results from the SONAR trial

Aim: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin‐to‐creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. Methods: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run‐in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non‐responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized. Results: Baseline characteristics were similar for atrasentan responders and non‐responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non‐responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was −48.8% (95% CI, −49.8% to −47.9%) and in non‐responders was −1.2% (95% CI, −6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non‐responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. Conclusions: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection

The Infrared Array Camera (IRAC) for the Spitzer Space Telescope

The Infrared Array Camera (IRAC) is one of three focal plane instruments in the Spitzer Space Telescope. IRAC is a four-channel camera that obtains simultaneous broad-band images at 3.6, 4.5, 5.8, and 8.0 microns. Two nearly adjacent 5.2x5.2 arcmin fields of view in the focal plane are viewed by the four channels in pairs (3.6 and 5.8 microns; 4.5 and 8 microns). All four detector arrays in the camera are 256x256 pixels in size, with the two shorter wavelength channels using InSb and the two longer wavelength channels using Si:As IBC detectors. IRAC is a powerful survey instrument because of its high sensitivity, large field of view, and four-color imaging. This paper summarizes the in-flight scientific, technical, and operational performance of IRAC.Comment: 7 pages, 3 figures. Accepted for publication in the ApJS. A higher resolution version is at http://cfa-www.harvard.edu/irac/publication

Validation of Up-the-Ramp Sampling with Cosmic Ray Rejection on IR Detectors

We examine cosmic ray rejection methodology on data collected from InSb and Si:As detectors. The application of an Up-the-Ramp sampling technique with cosmic ray identification and mitigation is the focus of this study. This technique is valuable for space-based observatories which are exposed to high-radiation environments. We validate the Up-the-Ramp approach on radiation-test data sets with InSb and Si:As detectors which were generated for SIRTF. The Up-the-Ramp sampling method studied in this paper is over 99.9% effective at removing cosmic rays and preserves the structure and photometric quality of the image to well within the measurement error.Comment: 30 pages, 13 figures. Accepted for publication in the PASP, 25 October 200

Semiconductor detector performance for low-energy x-rays

Factors that limit the capabilities of semiconductor detectors at photon energies below 5 keV include energy resolution, detector efficiency, and detector-related continuum background. These properties can be controlled to a certain extent by optimal detector design and fabrication techniques. We describe measurements on the low-energy response of Si(Li) detectors obtained using a tunable, low-energy monochromatic source. Window thicknesses have been measured for a number of devices using different materials for the entry contact. The interpretation of these results in terms of existing detector window models is discussed. Results obtained using a new contact structure demonstrate that a dramatic reduction in window-related absorption in Si(Li) detectors can be achieved

Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction

Importance  The angiotensin receptor neprilysin inhibitor sacubitril/valsartan was associated with a reduction in cardiovascular mortality, all-cause mortality, and hospitalizations compared with enalapril. Sacubitril/valsartan has been approved for use in heart failure (HF) with reduced ejection fraction in the United States and cost has been suggested as 1 factor that will influence the use of this agent. Objective  To estimate the cost-effectiveness of sacubitril/valsartan vs enalapril in the United States. Design, Setting, and Participants  Data from US adults (mean [SD] age, 63.8 [11.5] years) with HF with reduced ejection fraction and characteristics similar to those in the PARADIGM-HF trial were used as inputs for a 2-state Markov model simulated HF. Risks of all-cause mortality and hospitalization from HF or other reasons were estimated with a 30-year time horizon. Quality of life was based on trial EQ-5D scores. Hospital costs combined Medicare and private insurance reimbursement rates; medication costs included the wholesale acquisition cost for sacubitril/valsartan and enalapril. A discount rate of 3% was used. Sensitivity analyses were performed on key inputs including: hospital costs, mortality benefit, hazard ratio for hospitalization reduction, drug costs, and quality-of-life estimates. Main Outcomes and Measures  Hospitalizations, quality-adjusted life-years (QALYs), costs, and incremental costs per QALY gained. Results  The 2-state Markov model of US adult patients (mean age, 63.8 years) calculated that there would be 220 fewer hospital admissions per 1000 patients with HF treated with sacubitril/valsartan vs enalapril over 30 years. The incremental costs and QALYs gained with sacubitril/valsartan treatment were estimated at $35 512 and 0.78, respectively, compared with enalapril, equating to an incremental cost-effectiveness ratio (ICER) of$45 017 per QALY for the base-case. Sensitivity analyses demonstrated ICERs ranging from $35 357 to$75 301 per QALY. Conclusions and Relevance  For eligible patients with HF with reduced ejection fraction, the Markov model calculated that sacubitril/valsartan would increase life expectancy at an ICER consistent with other high-value accepted cardiovascular interventions. Sensitivity analyses demonstrated sacubitril/valsartan would remain cost-effective vs enalapril

Individual atrasentan exposure is associated with long-term kidney and heart failure outcomes in patients with type 2 diabetes and chronic kidney disease

Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase 2 trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase 3 SONAR trial (n=3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared to placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% CI: 0.28-0.85) for kidney events and 1.13 (95% CI: 1.03-2.20) for heart failure events. At the mean atrasentan exposure the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population

Uranium nitride-silicide advanced nuclear fuel: Higher efficiency and greater safety

The development of new nuclear fuel compositions is being driven by an interest in improving efficiency/lowering cost and increasing safety margins. Nuclear fuel efficiency is in large measure a function of the atomic density of the uranium, that is, the more fissionable uranium available per unit volume the less fuel volume that is required. Proliferation concerns limit the concentration of fissile 235U, and thus attention is directed to higher overall uranium content fuel. Among the options are the high temperature phases U3Si2 and composite UN- U3Si2 where the design would have the more water-stable U3Si2 surround the more soluble, but higher uranium density UN grains. (Uranium metal of course has the highest atomic density, however its low melting point, high degree of swelling under irradiation, and chemical reactivity eliminate it from consideration.) Another advantage of the nitride and silicide phases are their high thermal conductivity, greatly exceeding the current standard UO2 fuel, with the high conductivity potentially allowing the fuel to operate at a higher power density. Please click Additional Files below to see the full abstract