Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke ...outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10
). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.
Between 7 and 25 May, 86 monkeypox cases were confirmed in the United Kingdom (UK). Only one case is known to have travelled to a monkeypox virus (MPXV) endemic country. Seventy-nine cases with ...information were male and 66 reported being gay, bisexual, or other men who have sex with men. This is the first reported sustained MPXV transmission in the UK, with human-to-human transmission through close contacts, including in sexual networks. Improving case ascertainment and onward-transmission preventive measures are ongoing.
Postgraduate trainees elevate the academic strength of institutions by conducting research, promoting innovation, securing grant funding, training undergraduate students, and building alliances. ...Rigorous and systematic program evaluation can help ensure that postgraduate training programs are achieving the program's intended outcomes. The purpose of this project was to develop evidence-based evaluation tools that could be shared across federally funded biomedical training programs to enhance program evaluation capacity. This manuscript describes the evidence-based process used to determine program evaluation needs of these programs at a research-intensive university. Using a multi-phased sequential exploratory mixed methods approach, data were collected from trainees, employers, leaders, and program directors. Data analyses included document analysis of program plans, inductive coding of focus groups and interviews, and descriptive analysis of surveys. Two overarching categories-Trainee Skills and Program Characteristics-were identified including six themes each. Program directors prioritized communication, social and behavioral skills, and collaboration as the trainee skills that they needed the most help evaluating. Furthermore, program directors prioritized the following program characteristics as those that they needed the most help evaluating: training environment, trainee outcomes, and opportunities offered. Surveys, interview scripts, and related resources for the categories and themes were developed and curated on a publicly available website for program directors to use in their program evaluations.
Higher body mass index (BMI) is a risk factor for thrombosis. Platelets are essential for hemostasis but contribute to thrombosis when activated pathologically. We hypothesized that higher BMI leads ...to changes in platelet characteristics, thereby increasing thrombotic risk. The effect of BMI on platelet traits (measured by Sysmex) was explored in 33 388 UK blood donors (INTERVAL study). Linear regression showed that higher BMI was positively associated with greater plateletcrit (PCT), platelet count (PLT), immature platelet count (IPC), and side fluorescence (SFL, a measure of mRNA content used to derive IPC). Mendelian randomization (MR), applied to estimate a causal effect with BMI proxied by a genetic risk score, provided causal estimates for a positive effect of BMI on both SFL and IPC, but there was little evidence for a causal effect of BMI on PCT or PLT. Follow-up analyses explored the functional relevance of platelet characteristics in a pre-operative cardiac cohort (COPTIC). Linear regression provided observational evidence for a positive association between IPC and agonist-induced whole blood platelet aggregation. Results indicate that higher BMI raises the number of immature platelets, which is associated with greater whole blood platelet aggregation in a cardiac cohort. Higher IPC could therefore contribute to obesity-related thrombosis.
Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index ...(BMI) on an extensive set of circulating proteins.
We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI.
Observationally, BMI was associated with 1576 proteins (P < 1.4 × 10
), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48-0.79, P = 1.6 × 10
), FABP4 (0.64 SD per SD BMI, 95% CI 0.46-0.83, P = 6.7 × 10
) and SHBG (-0.45 SD per SD BMI, 95% CI -0.65 to -0.25, P = 1.4 × 10
). There was agreement in the magnitude of observational and MR estimates (R
= 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease.
This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.
Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth ...snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10
) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
We have developed an efficient and inexpensive pipeline for streamlining large-scale collection and genome sequencing of bacterial isolates. Evaluation of this method involved a worldwide research ...collaboration focused on the model organism Salmonella enterica, the 10KSG consortium. Following the optimization of a logistics pipeline that involved shipping isolates as thermolysates in ambient conditions, the project assembled a diverse collection of 10,419 isolates from low- and middle-income countries. The genomes were sequenced using the LITE pipeline for library construction, with a total reagent cost of less than USD$10 per genome. Our method can be applied to other large bacterial collections to underpin global collaborations.
Comparisons of transfusion practice between organisations are time-consuming using manual methods for data collection. We performed a feasibility study to determine whether large-scale transfusion ...data from three English hospitals could be combined to allow comparisons of transfusion practice.
Clinical, laboratory and transfusion data from patients discharged between 1 April 2016 and 31 March 2017 were extracted from Patient Administration Systems (PAS), Laboratory Information Management Systems (LIMS), and electronic transfusion systems at three NHS hospitals, which are academic medical centres based in large cities outside London. A centralised database and business intelligence software were used to compare the data.
The dataset contained 748 982 episodes of patient care with 91 410 blood components transfused. The study confirms the results of previous studies finding peaks in the ages of transfusion in the 0-4 years age range, in women of childbearing ages, and in males over 60 years. The number of components transfused per 1000 bed days was used as a standardised comparator. Red cell utilisation was 42.4, 40.4 and 49.5 units/1000 bed days and platelet utilisation 11.69, 7.76, and 11.66 units/1000 bed days. 60.5% (6848/11 310) of Group O D negative red cell units were transfused to non-group O D negative recipients. An analysis of component usage highlighted variations in practice, for example platelet usage for cardiac surgery varied from 2.4% to 7.3% across the three hospitals.
This feasibility study demonstrates that large electronic datasets from hospitals can be combined to identify areas for targeted interventions to improve transfusion practice.
The fish-hunting marine cone snail
uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics ...relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins from
,
and
exhibit diverse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in nature. When tested in zebrafish and mice, venom insulins significantly lower blood glucose in the streptozotocin-induced model of diabetes. Our findings suggest that cone snails have evolved diverse strategies to activate the vertebrate insulin receptor and provide unique insight into the design of novel drugs for the treatment of diabetes.
The effective reproduction number
$ R $
was widely accepted as a key indicator during the early stages of the COVID-19 pandemic. In the UK, the
$ R $
value published on the UK Government Dashboard ...has been generated as a combined value from an ensemble of epidemiological models via a collaborative initiative between academia and government. In this paper, we outline this collaborative modelling approach and illustrate how, by using an established combination method, a combined
$ R $
estimate can be generated from an ensemble of epidemiological models. We analyse the
$ R $
values calculated for the period between April 2021 and December 2021, to show that this
$ R $
is robust to different model weighting methods and ensemble sizes and that using heterogeneous data sources for validation increases its robustness and reduces the biases and limitations associated with a single source of data. We discuss how
$ R $
can be generated from different data sources and show that it is a good summary indicator of the current dynamics in an epidemic.
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