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

Subjective bayesian networks and human-in-the-loop situational understanding

In this paper we present a methodology to exploit human-machine coalitions for situational understanding. Situational understanding refers to the ability to relate relevant information and form logical conclusions, as well as identify gaps in information. This process for comprehension of the meaning information requires the ability to reason inductively, for which we will exploit the machines’ ability to ‘learn’ from data. However, important phenomena are often rare in occurrence with high degrees of uncertainty, thus severely limiting the availability of instance data for training, and hence the applicability of many machine learning approaches. Therefore, we present the benefits of Subjective Bayesian Networks—i.e., Bayesian Networks with imprecise probabilities—for situational understanding, and the role of conversational interfaces for supporting decision makers in the evolution of situational understanding

Learning and Reasoning in Complex Coalition Information Environments: A Critical Analysis

In this paper we provide a critical analysis with metrics that will inform guidelines for designing distributed systems for Collective Situational Understanding (CSU). CSU requires both collective insight-i.e., accurate and deep understanding of a situation derived from uncertain and often sparse data and collective foresight-i.e., the ability to predict what will happen in the future. When it comes to complex scenarios, the need for a distributed CSU naturally emerges, as a single monolithic approach not only is unfeasible: It is also undesirable. We therefore propose a principled, critical analysis of AI techniques that can support specific tasks for CSU to derive guidelines for designing distributed systems for CSU

Dynamic action in virtual environments: Constraints on the accessibility of action knowledge in children and adults

In a series of three experiments, we probed the accessibility of action knowledge in different versions of a virtual environment (VE) with 7-year-old children and adults. Using a PHANToM [TM] haptic interface, participants performed a virtual throwing task in which they tried to propel a ball from a table to hit a target on the ground. In Experiments 1 and 2, the virtual scene was presented on a computer monitor, and, in Experiment 3, it was projected by using a video projector so that the vertical and horizontal dimensions and the spatial location of the VE corresponded to the real-world dimensions. Results indicate that action knowledge is accessible even in a nonimmersive VE, but also suggest that the need to recalibrate perceptual-motor mappings constrains the accessibility of this kind of intuitive knowledge