Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

A naturally occurring bovine APOBEC3 confers resistance to bovine lentiviruses: implication for the co-evolution of bovids and their lentiviruses

Mammals have co-evolved with lentiviruses for a long time. As evidence, viral infectivity factor (Vif), encoded by lentiviruses, antagonizes the anti-viral action of cellular APOBEC3 of their hosts. Here, we address the co-evolutionary dynamics of bovine APOBEC3 and the following two bovine lentiviruses: bovine immunodeficiency virus (BIV) and Jembrana disease virus (JDV). We determined the sequences of three APOBEC3 genes of bovids belonging to the genera Bos and Bison and showed that bovine APOBEC3Z3 is under a strong positive selection. We found that APOBEC3Z3 of gaur, a bovid in the genus Bos, acquired resistance to JDV Vif-mediated degradation after diverging from the other bovids through conversion of the structural composition of the loop 1 domain. Interestingly, the resistance of gaur APOBEC3Z3 can be attributed to the positive selection of residue 62. This study provides the first evidence, suggesting that a co-evolutionary arms race between bovids and lentiviruses occurred in Asia

Coevolutionary dynamics between tribe Cercopithecini tetherins and their lentiviruses

Human immunodeficiency virus, a primate lentivirus (PLV), causes AIDS in humans, whereas most PLVs are less or not pathogenic in monkeys. These notions suggest that the co-evolutionary process of PLVs and their hosts associates with viral pathogenicity, and therefore, that elucidating the history of virus-host co-evolution is one of the most intriguing topics in the field of virology. To address this, recent studies have focused on the interplay between intrinsic anti-viral proteins, such as tetherin, and viral antagonists. Through an experimental-phylogenetic approach, here we investigate the co-evolutionary interplay between tribe Cercopithecini tetherin and viral antagonists, Nef and Vpu. We reveal that tribe Cercopithecini tetherins are positively selected, possibly triggered by ancient Nef-like factor(s). We reconstruct the ancestral sequence of tribe Cercopithecini tetherin and demonstrate that all Nef proteins are capable of antagonizing ancestral Cercopithecini tetherin. Further, we consider the significance of evolutionary arms race between tribe Cercopithecini and their PLVs

WINERED High-resolution Near-infrared Line Catalog: A-type Star

We present a catalog of absorption lines in the z', Y, and J bands that we identified in 21 Lyn, a slowly rotating A0.5 V star. We detected 155 absorption features in the high-resolution (0.90–1.35 μm, R = 28,000) spectrum obtained with the WINERED spectrograph after the telluric absorption was carefully removed using a spectrum of a B-type star as a telluric standard. With a visual comparison with synthetic spectra, we compiled a catalog of 219 atomic lines for the 155 features, some of which are composed of multiple fine structure lines. The high-quality WINERED spectrum enabled us to detect a large number of weak lines down to ~1% in depth, which are identified for an A-type star for the first time. The catalog includes the lines of H, C, N, O, Mg, Al, Si, S, Ca, Fe, and Sr. These new lines are expected to be useful for spectral classification and chemical abundance analyses, while the line catalog is useful for observers who plan to use A-type stars as telluric standards because it is necessary to distinguish between stellar lines and telluric absorption lines in high-resolution spectra. ASCII versions of the spectra are available in the online version of the journal

Fe i Lines in 0.91–1.33 μm Spectra of Red Giants for Measuring the Microturbulence and Metallicities

For a detailed analysis of stellar chemical abundances, high-resolution spectra in the optical have mainly been used, while the development of near-infrared (NIR) spectrograph has opened new wavelength windows. Red giants have a large number of resolved absorption lines in both the optical and NIR wavelengths, but the characteristics of the lines in different wave passbands are not necessarily the same. We present a selection of Fe I lines in the z′, Y, and J bands (0.91–1.33 μm). On the basis of two different lists of lines in this range, the Vienna Atomic Line Database (VALD) and the catalog published by Meléndez & Barbuy in 1999 (MB99), we selected sufficiently strong lines that are not severely blended and compiled lists with 107 Fe I lines in total (97 and 75 lines from VALD and MB99, respectively). Combining our lists with high-resolution (λ/Δλ=28,000) and high signal-tonoise (>500) spectra taken with an NIR spectrograph, WINERED, we present measurements of the iron abundances of two prototype red giants: Arcturus and μLeo. A bootstrap method for determining the microturbulence and abundance together with their errors is demonstrated. The standard deviations of log Fe values from individual Fe I lines are significantly smaller when we use the lines from MB99 instead of those from VALD. With the MB99 list, we obtained x = 1.20 0.11 km s-1 and log Fe = 7.01 0.05 dex for Arcturus, and x = 1.54 0.17 km s-1 and log Fe = 7.73 0.07 dex for μLeo. These final values show better agreements with previous values in the literature than the corresponding values we obtained with VALD

Cancer-Associated Venous Thromboembolism in the Real World --From the COMMAND VTE Registry--

Background:There is a paucity of data on the management and prognosis of cancer-associated venous thromboembolism (VTE), leading to uncertainty about optimal management strategies. Methods and Results:The COMMAND VTE Registry is a multicenter registry enrolling 3, 027 consecutive acute symptomatic VTE patients in Japan between 2010 and 2014. We divided the entire cohort into 3 groups: active cancer (n=695, 23%), history of cancer (n=243, 8%), and no history of cancer (n=2089, 69%). The rate of anticoagulation discontinuation was higher in patients with active cancer (43.5%, 27.0%, and 27.0%, respectively, at 1 year, P<0.001). The cumulative 5-year incidences of recurrent VTE, major bleeding, and all-cause death were higher in patients with active cancer (recurrent VTE: 17.7%, 10.2%, and 8.6%, P<0.001; major bleeding: 26.6%, 8.8%, and 9.3%, P<0.001; all-cause death: 73.1%, 28.6%, 14.6%, P<0.001). Among the 4 groups classified according to active cancer status, the cumulative 1-year incidence of recurrent VTE was higher in the metastasis group (terminal stage group: 6.4%, metastasis group: 22.1%, under chemotherapy group: 10.8%, and other group: 5.8%, P<0.001). Conclusions:In a current real-world VTE registry, patients with active cancer had higher risk for VTE recurrence, bleeding, and death, with variations according to cancer status, than patients without active cancer. Anticoagulation therapy was frequently discontinued prematurely in patients with active cancer in discordance with current guideline recommendations