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

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Homography estimation for low-contrast IR image sequences utilizing GPS control points

Estimating the homographies for IR sequences of approaching objects in the infrared spectrum is a special problem. Due to the approaching movement of a helicopter towards measurement items, the objects are represented with few pixels in the beginning of the sequence and they are represented with a lot more pixels when reaching the destination area. This fact results in an assignment problem of finding point correspondences. This difficulty has led to drifting phenomena when using sophisticated methods for estimating the homographies. In this article a method is described which eliminates both the problem of finding point correspondences as well as the drifting issue. The presented procedure exploits information gathered by additional sensors (i.?e., a GPS receiver, an inertial measurement unit (IMU), and a compass) for the computation of camera projections for each frame. The camera mappings are used to project GPS control points into the frames. The use of the same GPS points for each frame results in naturally given point correspondences. Using these correspondences the homographies can be estimated. The results are compared to the state of the art

Evaluation of statistical methods for the evaluation of observer trials for the assessment of the effectiveness of signature measures

The statistical methods discussed in this paper are drawn from the area of machine learning or data mining as well as from descriptive statistics. These techniques are discussed with focus on their applicability to the results of observer trials in order to evaluate the effectiveness of signature measures. Signature measures aim at the change of the apparent signature of an object, e.g. a vehicle. So signature measures can be camouflage against infrared sensory, or they can be used for deception reasons. In order to evaluate the effectiveness of signature measures, observer trials provide an efficient method. The department of Signatorics of Fraunhofer IOSB developed a software tool named CARPET (Computer Aided inteRactive Performance Evaluation Tool) for the realization of observer trials. The benefit of this system is the reproducibility and uniformity of trials for every observer. The results from this system consist of marks, that were placed at particular times, as well as computer mouse positions recorded for each human observer. Based on the information gathered from these marks together with the known target object positions the statistical treatment can be done. For the statistics it has to be known to which target object the marks belong. The first problem considered in this paper concentrates on the correct labeling of the marks according to the target objects. The labeling is done using an expectation maximization scheme with the k-means clustering algorithm. The next step involves a second labeling. In this step a linear discriminant is used to decide whether a mark should be considered a hit or miss for every particular target object. After these decisions, a receiver-operating characteristics (ROC) analysis is performed in order to evaluate the detectability of each target object. Furthermore the sample mean and sample covariance formulas are used on the so called hit sets in order to approximate Gaussian distributions for every hit set. These Gaussians facilitate the evaluation of the accuracy and the precision of the hit sets. Accuracy and precision offer information about the quality of the marks set by the observers

A randomized phase 1 study of the safety and immunogenicity of 2 novel pneumococcal conjugate vaccines in healthy Japanese adults in the United States

Expanding serotype coverage of pneumococcal conjugate vaccines (PCVs) to target prevailing disease-causing serotypes could further reduce disease burden. To address this need, 2 different PCVs have been investigated: a 20-valent PCV (PCV20; includes the 13 serotypes in the 13-valent PCV [PCV13] plus 7 additional serotypes [8, 10A, 11A, 12F, 15B, 22F, 33F]) and a complementary 7-valent PCV (cPCV7; contains only the 7 additional serotypes). This phase 1b, randomized, controlled, double-blind study evaluated PCV20 and cPCV7 safety and immunogenicity in healthy Japanese adults 18–49 years of age residing in the United States for ≤5 years. Participants (n = 104) were randomized equally to receive a single dose of PCV20, cPCV7, or PCV13. Immunogenicity was assessed at baseline and 1 month after vaccination using serotype-specific opsonophagocytic activity (OPA) titers and serotype-specific immunoglobulin G (IgG) concentrations. Prompted local reactions and systemic events; adverse events (AEs); and serious AEs and newly diagnosed chronic disease were assessed 14 days, through 1 month, and upto 6 months following vaccination, respectively. OPA immune responses were robust for all 20 serotypes in the PCV20 group and for the 7 serotypes in the cPCV7 group 1 month after vaccination. IgG immune response showed similar trends. Injection site pain and muscle pain were the most common local reaction and systemic event; the majority were mild or moderate in severity. Few AEs and no severe AEs, serious AEs, or safety-related withdrawals were reported. Taken together, administration of PCV20 or cPCV7 in Japanese adults was well tolerated and induced robust serotype-specific functional immune responses. NCT03642847

Regards croisés sur la guerre sainte

Fruit d’un colloque international réuni à la Casa de Velázquez (Madrid) du 11 au 13 avril 2005, ce volume propose de lire l’histoire de la guerre sainte de façon moins linéaire que de coutume, en acceptant les ruptures, les discontinuités et les nombreux aménagements qui ont été rendus nécessaires par les usages multiples, contradictoires et parfois concurrents de cette notion. À partir d’un fonds commun de principes surgis à la charnière de l’Antiquité et du Moyen Âge, contenus dans les traditions politiques et religieuses des royaumes chrétiens, l’idée de guerre sainte a été périodiquement ravivée et chaque fois reconstruite à la mesure des besoins de ceux qui la sollicitaient et de leur environnement historique. Elle s’est aussi enrichie. L’appel de Clermont, en 1095, qui suscite la Première croisade et conduit à la conquête de Jérusalem par les Latins ne met pas fin à ce processus. Certes, il devient impossible, à partir du XIIe siècle, d’échapper totalement au modèle de guerre sainte forgé par la papauté, qui, pour l’imposer, dispose d’un contrôle sans précédent sur les mécanismes de sanctification et de pénitence. Cependant, durant tout le Moyen Âge, le référent pontifical qu’est la croisade n’est jamais figé et demeure perméable à tous les aménagements au bénéfice de ceux, rois et princes d’Occident, qui s’en réclament et se l’approprient. En admettant la diversité de la notion de guerre sainte et en croisant les regards portés sur elle, les spécialistes dont les contributions se trouvent ici rassemblées participent de façon importante au renouvellement d’un domaine de recherche qui a été le théâtre, depuis quelques années, de grandes controverses