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

Automated Ribosomal Intergenic Spacer Analysis to Detect Pathogenic Fungi in Dark-Colored Spots on Apple Fruits

Dark-colored spots (DCSs) found on apples at harvest time worldwide significantly reduce the commercial value of the fruits. In this study, we conducted an automated ribosomal intergenic spacer analysis (ARISA) to reliably detect fungal pathogens in these lesions. The fragment sizes of peaks for eight species and two species complexes that might cause DCSs on apples in northern Honshu Island, Japan, were determined on the basis of the ARISA. The fragment sizes for six species (Botryosphaeria kuwatsukai, Diplocarpon mali, Mycosphaerella pomi, Neonectria galligena, Phlyctema vagabunda, and Venturia inaequalis) were unique, enabling their detection in a single ARISA trial. However, two other species and two species complexes had similar fragment sizes. To identify these fungi, PCR amplifications using species- or genus-specific primers were needed. Using this method to examine the fresh tissue of DCSs (i.e., after removing the epidermis) on commercially produced apples resulted in the detection of six fungal species and two Colletotrichum species complexes. Because the pathogenic fungi in the tissue underlying lesions are most likely the causal agents, these fungi could be responsible for the DCSs on apple fruits. An automated analysis of the PCR products amplified for the ARISA enables the rapid examination of many samples. These results indicate that the ARISA-based technique developed in the present study is useful for the accurate, reliable, and comprehensive detection of the pathogens causing DCSs on apple fruits. [Graphic: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license

Urgent Gravity Measurements for the Eruption of Usu Volcano in 2000 : Construction of Absolute Gravity Network and the Co-eruptive and Post-eruptive Gravity Changes

After the eruption of Usu volcano, Japan, on 31 March, 2000, we carried out microgravity measurements around Mt. Usu. Comparing the gravity values acquired by previous measurements in June 1993, we detected significant gravity changes presumably associated with the magma movement. The largest change detected as of May 2000 was - 820μgal at the southern rim of the summit. Both gravity and height changes were successfully reproduced by prescribing a shallow inflation source and a deeper deflation source at depths of 2,000 and 3,000 meters, respectively. Total intruded mass flux is estimated to be 3.6×1010kg. We constructed an absolute gravity network consisting of three sites around Toya lake, and precisely determined absolute gravity values. Moreover, from 16 May to 29 June, we took continuous absolute gravity measurements at Usu volcano observatory, and detected a significant post eruptive gravity change. The absolute gravity continued to decrease by 10μgal until around 25 May when it began to increase After that, the absolute gravity gradually recovered to 10μgal for one month. We can interpret the inferred post-eruptive gravity changes as a continuing crustal uplift followed by a commence of the land subsidence