Magnitude of the Difference Between Clinic and Ambulatory Blood Pressures and Risk of Adverse Outcomes in Patients With Chronic Kidney Disease.

Background Obtaining 24-hour ambulatory blood pressure ( BP ) is recommended for the detection of masked or white-coat hypertension. Our objective was to determine whether the magnitude of the difference between ambulatory and clinic BP s has prognostic implications. Methods and Results We included 610 participants of the AASK (African American Study of Kidney Disease and Hypertension) Cohort Study who had clinic and ambulatory BPs performed in close proximity in time. We used Cox models to determine the association between the absolute systolic BP ( SBP ) difference between clinic and awake ambulatory BPs (primary predictor) and death and end-stage renal disease. Of 610 AASK Cohort Study participants, 200 (32.8%) died during a median follow-up of 9.9 years; 178 (29.2%) developed end-stage renal disease. There was a U-shaped association between the clinic and ambulatory SBP difference with risk of death, but not end-stage renal disease. A 5- to <10-mm Hg higher clinic versus awake SBP (white-coat effect) was associated with a trend toward higher (adjusted) mortality risk (adjusted hazard ratio, 1.84; 95% CI, 0.94-3.56) compared with a 0- to <5-mm Hg clinic-awake SBP difference (reference group). A ≥10-mm Hg clinic-awake SBP difference was associated with even higher mortality risk (adjusted hazard ratio, 2.31; 95% CI, 1.27-4.22). A ≥-5-mm Hg clinic-awake SBP difference was also associated with higher mortality (adjusted hazard ratio, 1.82; 95% CI, 1.05-3.15) compared with the reference group. Conclusions A U-shaped association exists between the magnitude of the difference between clinic and ambulatory SBP and mortality. Higher clinic versus ambulatory BPs (as in white-coat effect) may be associated with higher risk of death in black patients with chronic kidney disease

Multiple primary tumours in women following breast cancer, 1973–2000

We investigated the predictors of the risk of developing a second primary cancer after breast cancer, this occurring in about 12% of affected women. The analysis included 335 191 females, registered in the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database, who had been diagnosed with breast cancer. Observed numbers of subsequent cancers in the SEER database with a first breast cancer diagnosed from 1973 to 2000 were compared with the expected numbers based on age-adjusted incidence rates to calculate standardised incidence ratios. Kaplan–Meier curves were conducted to determine the median time until the second primary cancer diagnosis. Average number of years until diagnosis varied by site and by age as well as median years until second cancer diagnosis. Most cancer risks decreased with age, but there was an increase in aging-related cancers such as lung cancer. The median years of follow-up were well beyond the 5-year mark. Breast cancer survivors should be advised of their increased risk for developing certain cancers in their lifetime

Peptide Ligands for Pro-survival Protein Bfl-1 from Computationally Guided Library Screening

Pro-survival members of the Bcl-2 protein family inhibit cell death by binding short helical BH3 motifs in pro-apoptotic proteins. Mammalian pro-survival proteins Bcl-x[subscript L], Bcl-2, Bcl-w, Mcl-1, and Bfl-1 bind with varying affinities and specificities to native BH3 motifs, engineered peptides, and small molecules. Biophysical studies have determined interaction patterns for these proteins, particularly for the most-studied family members Bcl-x[subscript L] and Mcl-1. Bfl-1 is a pro-survival protein implicated in preventing apoptosis in leukemia, lymphoma, and melanoma. Although Bfl-1 is a promising therapeutic target, relatively little is known about its binding preferences. We explored the binding of Bfl-1 to BH3-like peptides by screening a peptide library that was designed to sample a high degree of relevant sequence diversity. Screening using yeast-surface display led to several novel high-affinity Bfl-1 binders and to thousands of putative binders identified through deep sequencing. Further screening for specificity led to identification of a peptide that bound to Bfl-1 with K[subscript d] < 1 nM and very slow dissociation from Bfl-1 compared to other pro-survival Bcl-2 family members. A point mutation in this sequence gave a peptide with ~50 nM affinity for Bfl-1 that was selective for Bfl-1 in equilibrium binding assays. Analysis of engineered Bfl-1 binders deepens our understanding of how the binding profiles of pro-survival proteins differ and may guide the development of targeted Bfl-1 inhibitors.National Institute of General Medical Sciences (U.S.) (Award GM084181)National Institute of General Medical Sciences (U.S.) (Award P50-GM68762

Tigers of Sundarbans in India: Is the Population a Separate Conservation Unit?

The Sundarbans tiger inhabits a unique mangrove habitat and are morphologically distinct from the recognized tiger subspecies in terms of skull morphometrics and body size. Thus, there is an urgent need to assess their ecological and genetic distinctiveness and determine if Sundarbans tigers should be defined and managed as separate conservation unit. We utilized nine microsatellites and 3 kb from four mitochondrial DNA (mtDNA) genes to estimate genetic variability, population structure, demographic parameters and visualize historic and contemporary connectivity among tiger populations from Sundarbans and mainland India. We also evaluated the traits that determine exchangeability or adaptive differences among tiger populations. Data from both markers suggest that Sundarbans tiger is not a separate tiger subspecies and should be regarded as Bengal tiger (P. t. tigris) subspecies. Maximum likelihood phylogenetic analyses of the mtDNA data revealed reciprocal monophyly. Genetic differentiation was found stronger for mtDNA than nuclear DNA. Microsatellite markers indicated low genetic variation in Sundarbans tigers (He= 0.58) as compared to other mainland populations, such as northern and Peninsular (Hebetween 0.67- 0.70). Molecular data supports migration between mainland and Sundarbans populations until very recent times. We attribute this reduction in gene flow to accelerated fragmentation and habitat alteration in the landscape over the past few centuries. Demographic analyses suggest that Sundarbans tigers have diverged recently from peninsular tiger population within last 2000 years. Sundarbans tigers are the most divergent group of Bengal tigers, and ecologically non-exchangeable with other tiger populations, and thus should be managed as a separate "evolutionarily significant unit" (ESU) following the adaptive evolutionary conservation (AEC) concept.Wildlife Institute of India, Dehra Dun (India)

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Intellectual Property, Open Science and Research Biobanks

In biomedical research and translational medicine, the ancient war between exclusivity (private control over information) and access to information is proposing again on a new battlefield: research biobanks. The latter are becoming increasingly important (one of the ten ideas changing the world, according to Time magazine) since they allow to collect, store and distribute in a secure and professional way a critical mass of human biological samples for research purposes. Tissues and related data are fundamental for the development of the biomedical research and the emerging field of translational medicine: they represent the “raw material” for every kind of biomedical study. For this reason, it is crucial to understand the boundaries of Intellectual Property (IP) in this prickly context. In fact, both data sharing and collaborative research have become an imperative in contemporary open science, whose development depends inextricably on: the opportunities to access and use data, the possibility of sharing practices between communities, the cross-checking of information and results and, chiefly, interactions with experts in different fields of knowledge. Data sharing allows both to spread the costs of analytical results that researchers cannot achieve working individually and, if properly managed, to avoid the duplication of research. These advantages are crucial: access to a common pool of pre-competitive data and the possibility to endorse follow-on research projects are fundamental for the progress of biomedicine. This is why the "open movement" is also spreading in the biobank's field. After an overview of the complex interactions among the different stakeholders involved in the process of information and data production, as well as of the main obstacles to the promotion of data sharing (i.e., the appropriability of biological samples and information, the privacy of participants, the lack of interoperability), we will firstly clarify some blurring in language, in particular concerning concepts often mixed up, such as “open source” and “open access”. The aim is to understand whether and to what extent we can apply these concepts to the biomedical field. Afterwards, adopting a comparative perspective, we will analyze the main features of the open models – in particular, the Open Research Data model – which have been proposed in literature for the promotion of data sharing in the field of research biobanks. After such an analysis, we will suggest some recommendations in order to rebalance the clash between exclusivity - the paradigm characterizing the evolution of intellectual property over the last three centuries - and the actual needs for access to knowledge. We argue that the key factor in this balance may come from the right interaction between IP, social norms and contracts. In particular, we need to combine the incentives and the reward mechanisms characterizing scientific communities with data sharing imperative

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 &gt;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