A Horseshoe Pit mixture model for Bayesian screening with an application to light sheet fluorescence microscopy in brain imaging

Finding parsimonious models through variable selection is a fundamental problem in many areas of statistical inference. Here, we focus on Bayesian regression models, where variable selection can be implemented through a regularizing prior imposed on the distribution of the regression coefficients. In the Bayesian literature, there are two main types of priors used to accomplish this goal: the spike-and-slab and the continuous scale mixtures of Gaussians. The former is a discrete mixture of two distributions characterized by low and high variance. In the latter, a continuous prior is elicited on the scale of a zero-mean Gaussian distribution. In contrast to these existing methods, we propose a new class of priors based on discrete mixture of continuous scale mixtures providing a more general framework for Bayesian variable selection. To this end, we substitute the observation-specific local shrinkage parameters (typical of continuous mixtures) with mixture component shrinkage parameters. Our approach drastically reduces the number of parameters needed and allows sharing information across the coefficients, improving the shrinkage effect. By using half-Cauchy distributions, this approach leads to a cluster-shrinkage version of the Horseshoe prior. We present the properties of our model and showcase its estimation and prediction performance in a simulation study. We then recast the model in a multiple hypothesis testing framework and apply it to a neurological dataset obtained using a novel whole-brain imaging technique

STITCH 2: an interaction network database for small molecules and proteins

Over the last years, the publicly available knowledge on interactions between small molecules and proteins has been steadily increasing. To create a network of interactions, STITCH aims to integrate the data dispersed over the literature and various databases of biological pathways, drug–target relationships and binding affinities. In STITCH 2, the number of relevant interactions is increased by incorporation of BindingDB, PharmGKB and the Comparative Toxicogenomics Database. The resulting network can be explored interactively or used as the basis for large-scale analyses. To facilitate links to other chemical databases, we adopt InChIKeys that allow identification of chemicals with a short, checksum-like string. STITCH 2.0 connects proteins from 630 organisms to over 74 000 different chemicals, including 2200 drugs. STITCH can be accessed at http://stitch.embl.de/

Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources.

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO\u27s interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Monitoring CRE-dependent Gene Expression Induced by Synaptic Activity in Live Networks of Neurons

During development, neuronal activity plays an important role in shaping functionalsynaptic networks. Moreover, in adults, neuronal activity is thought to produce long-termchanges during learning and memory. For these changes to persist, however, neuronalactivity must engage signaling pathways that result in alterations in gene expression.Pathways that activate the transcription factor CREB (cAMP-response element-bindingprotein), which binds to CREs (cAMP response elements) in gene promoters, have beenimplicated in this long-term, activity-dependent plasticity. The focus of my research is toinvestigate the mechanisms of CRE-dependent gene expression induced by physiologicalsynaptic activity. Together with my supervisor, I developed a sensitive biosensor tomeasure CRE-dependent gene expression in neurons; this biosensor consists of apromoter-reporter construct derived from the major immediate-early promoter/enhancerof the human cytomegalovirus (hCMV promoter) coupled to Green Fluorescent Protein(GFP). Our studies show that this promoter acts as an activity-dependent switch inneurons. The hCMV promoter functions poorly in unstimulated neurons, but is stronglyinduced by neuronal activity or other stimuli that activate CREB; moreover, site-directedmutagenesis of the five CREs in the promoter eliminated this inducibility. To express thisbiosensor in neurons, we used adenoviral-mediated gene transfer which has an efficiencyof>95%, allowing one to monitor reporter gene expression in individual neurons of afunctional network for several days. Using this system we, discovered that nicotine, atlow-levels in the range that circulates in smokers, acts in a distributed manner throughout a neuronal network to alter CRE-dependent gene expression induced by network activity . Further, exploiting the sensitivity of this biosensor, we found that weak neuronal activity,including spontaneous release of neurotransmitter, is a sufficient stimulus to recruitsignaling pathways that res

Acute stroke thrombolysis in end-stage renal disease:a national survey of nephrologist opinion

&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt; Systemic thrombolysis for acute ischaemic stroke is the standard of care in the UK. In the absence of trial data on the safety and efficacy of this treatment in patients with end-stage renal disease, we captured the views of UK nephrologists to highlight health care policy and research objectives. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Consultant nephrologists participated in an internet-based questionnaire. Respondents were asked about their involvement in thrombolysis decisions, safety concerns in dialysis patients, views on stroke rehabilitation and opinions on antiplatelet and warfarin use for stroke prevention. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; 122/433 (28%) clinicians responded. 75% wanted involvement in thrombolysis decisions although just 10% gave input in practice. 64% expressed a high degree of concern (≥7/10) regarding intracranial bleeding risk in haemodialysis (HD). Overall risks of intra- and extracranial bleeding were rated lower in peritoneal dialysis (PD; p &lt; 0.001). 85% felt the HD schedule impacted negatively on rehabilitation, whereas 63% felt this was the case in the context of PD (p = 0.001). More clinicians favoured warfarin for stroke prevention in PD patients with atrial fibrillation in comparison with HD patients (79 vs. 66%, p = 0.04). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; The majority of nephrologists want involvement in thrombolysis decisions relevant to their patients. Concerns about bleeding risks with thrombolysis are high and we identify a vital need to improve access to stroke rehabilitation in the UK, especially in HD patients.</jats:p