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

First-principles Calculation of the Formation Energy in MgO-CaO Solid Solutions

The electronic structure and total energy were calculated for ordered and disordered MgO-CaO solid solutions within the multiple scattering theory in real space and the local density approximation. Based on the dependence of the total energy on the unit cell volume the equilibrium lattice parameter and formation energy were determined for different solution compositions. The formation energy of the solid solutions is found to be positive that is in agreement with the experimental phase diagram, which shows a miscibility gap.Comment: 11 pages, 3 figure

The Prevalence of Children with a History of Sexual Abuse Hospitalized in the Psychiatric Setting

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72548/1/j.1744-6171.1991.tb00489.x.pd

A translational research experience in Argentina.

Background: The Argentinean programwas initiatedmore than a decade ago as the first experience of systematic translational research focused on NCL in Latin America. The aim was to overcome misdiagnoses and underdiagnoses in the region. Subjects: 216 NCL suspected individuals from 8 different countries and their direct family members. Methods: Clinical assessment, enzyme testing, electron microscopy, and DNA screening. Results and discussion: 1) The study confirmed NCL disease in 122 subjects. Phenotypic studies comprised epileptic seizures and movement disorders, ophthalmology, neurophysiology, image analysis, rating scales, enzyme testing, and electron microscopy, carried out under a consensus algorithm; 2) DNA screening and validation of mutations in genes PPT1 (CLN1), TPP1 (CLN2), CLN3, CLN5, CLN6, MFSD8 (CLN7), and CLN8: characterization of variant types, novel/knownmutations and polymorphisms; 3) Progress of the epidemiological picture in Latin America; and 4) NCL-like pathology studies in progress. The Translational Research Program was highly efficient in addressing the misdiagnosis/underdiagnosis in the NCL disorders. The study of “orphan diseases” in a public administrated hospital should be adopted by the health systems, as it positively impacts upon the family's quality of life, the collection of epidemiological data, and triggers research advances. This article is part of a Special Issue entitled: “Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)”publishedVersio

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

Early Response in Albuminuria and Long-Term Kidney Protection during Treatment with an Endothelin Receptor Antagonist:A Prespecified Analysis from the SONAR Trial

BACKGROUND: Whether early reduction in albuminuria with atrasentan treatment predicts its long-term kidney-protective effect is unknown. METHODS: To assess the long-term effects on kidney outcomes of atrasentan versus placebo in the SONAR trial, we enrolled patients who had type 2 diabetes and CKD (stage 2-4) and a urinary albumin creatinine ratio (UACR) of 300-5000 mg/g; participants were receiving maximum tolerated renin-angiotensin system inhibition. After 6 weeks exposure to 0.75 mg/day atrasentan (enrichment period), participants were randomized (stratified by UACR response during enrichment, ranging from ≤60% to >0%) to continue atrasentan or transition to placebo. Primary kidney outcome was a composite of sustained serum creatinine doubling or ESKD. RESULTS: UACR response to atrasentan during enrichment persisted throughout the double-blind treatment phase and predicted the primary kidney outcome, whereas UACR levels with placebo remained below pre-enrichment values in the two highest UACR response strata, and exceeded pre-enrichment values in the two lowest strata. As a result, early UACR response to atrasentan during enrichment was also associated with the primary kidney outcome during placebo. Accordingly, the predictive effect of early albuminuria changes during atrasentan was eliminated after placebo correction, leading to a consistent relative risk reduction for the primary kidney outcome with atrasentan compared with placebo, irrespective of the initial UACR response. The difference between atrasentan and placebo in UACR during double-blind treatment was also consistent across UACR response strata. CONCLUSIONS: Our findings do not support UACR response as a causal predictor of atrasentan's treatment effect. However, the variable trajectory in UACR with placebo, aspects of the trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed

First-principles study of As interstitials in GaAs: Convergence, relaxation, and formation energy

Convergence of density-functional supercell calculations for defect formation energies, charge transition levels, localized defect state properties, and defect atomic structure and relaxation is investigated using the arsenic split interstitial in GaAs as an example. Supercells containing up to 217 atoms and a variety of {\bf k}-space sampling schemes are considered. It is shown that a good description of the localized defect state dispersion and charge state transition levels requires at least a 217-atom supercell, although the defect structure and atomic relaxations can be well converged in a 65-atom cell. Formation energies are calculated for the As split interstitial, Ga vacancy, and As antisite defects in GaAs, taking into account the dependence upon chemical potential and Fermi energy. It is found that equilibrium concentrations of As interstitials will be much lower than equilibrium concentrations of As antisites in As-rich, $n$-type or semi-insulating GaAs.Comment: 10 pages, 5 figure

The Effect of Lattice Vibrations on Substitutional Alloy Thermodynamics

A longstanding limitation of first-principles calculations of substitutional alloy phase diagrams is the difficulty to account for lattice vibrations. A survey of the theoretical and experimental literature seeking to quantify the impact of lattice vibrations on phase stability indicates that this effect can be substantial. Typical vibrational entropy differences between phases are of the order of 0.1 to 0.2 k_B/atom, which is comparable to the typical values of configurational entropy differences in binary alloys (at most 0.693 k_B/atom). This paper describes the basic formalism underlying ab initio phase diagram calculations, along with the generalization required to account for lattice vibrations. We overview the various techniques allowing the theoretical calculation and the experimental determination of phonon dispersion curves and related thermodynamic quantities, such as vibrational entropy or free energy. A clear picture of the origin of vibrational entropy differences between phases in an alloy system is presented that goes beyond the traditional bond counting and volume change arguments. Vibrational entropy change can be attributed to the changes in chemical bond stiffness associated with the changes in bond length that take place during a phase transformation. This so-called ``bond stiffness vs. bond length'' interpretation both summarizes the key phenomenon driving vibrational entropy changes and provides a practical tool to model them.Comment: Submitted to Reviews of Modern Physics 44 pages, 6 figure

Systematic review of vestibular disorders related to human immunodeficiency virus and acquired immunodeficiency syndrome

INTRODUCTION: Disorders of the auditory and vestibular system are often associated with human immunodeficiency virus infection and acquired immunodeficiency syndrome. However, the extent and nature of these vestibular manifestations are unclear. OBJECTIVE: To systematically review the current peer-reviewed literature on vestibular manifestations and pathology related to human immunodeficiency virus and acquired immunodeficiency syndrome. METHOD: Systematic review of peer-reviewed articles related to vestibular findings in individuals with human immunodeficiency virus infection and acquired immunodeficiency syndrome. Several electronic databases were searched. RESULTS: We identified 442 records, reduced to 210 after excluding duplicates and reviews. These were reviewed for relevance to the scope of the study. DISCUSSION: We identified only 13 reports investigating vestibular functioning and pathology in individuals affected by human immunodeficiency virus and acquired immunodeficiency syndrome. This condition can affect both the peripheral and central vestibular system, irrespective of age and viral disease stage. Peripheral vestibular involvement may affect up to 50 per cent of patients, and central vestibular involvement may be even more prevalent. Post-mortem studies suggest direct involvement of the entire vestibular system, while opportunistic infections such as oto- and neurosyphilis and encephalitis cause secondary vestibular dysfunction resulting in vertigo, dizziness and imbalance. CONCLUSION: Patients with human immunodeficiency virus and acquired immunodeficiency syndrome should routinely be monitored for vestibular involvement, to minimise functional limitations of quality of life.http://journals.cambridge.org/action/displayJournal?jid=JL