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For many diseases there are delays in diagnosis due to a lack of objective biomarkers for disease onset. Here, in 41,931 individuals from the United Kingdom Biobank Pharma Proteomics Project, we integrated measurements of ~3,000 plasma proteins with clinical information to derive sparse prediction models for the 10-year incidence of 218 common and rare diseases (81-6,038 cases). We then compared prediction models developed using proteomic data with models developed using either basic clinical information alone or clinical information combined with data from 37 clinical assays. The predictive performance of sparse models including as few as 5 to 20 proteins was superior to the performance of models developed using basic clinical information for 67 pathologically diverse diseases (median delta C-index = 0.07; range = 0.02-0.31). Sparse protein models further outperformed models developed using basic information combined with clinical assay data for 52 diseases, including multiple myeloma, non-Hodgkin lymphoma, motor neuron disease, pulmonary fibrosis and dilated cardiomyopathy. For multiple myeloma, single-cell RNA sequencing from bone marrow in newly diagnosed patients showed that four of the five predictor proteins were expressed specifically in plasma cells, consistent with the strong predictive power of these proteins. External replication of sparse protein models in the EPIC-Norfolk study showed good generalizability for prediction of the six diseases tested. These findings show that sparse plasma protein signatures, including both disease-specific proteins and protein predictors shared across several diseases, offer clinically useful prediction of common and rare diseases., (© 2024. The Author(s).)

Introduction: Cardiac implantable electronic devices (CIEDs), including pacemakers, defibrillators, and resynchronization devices, significantly enhance patient outcomes, reduce sudden cardiac death, and improve health-related quality of life. CIED implantation is associated to persistent shoulder dysfunction in a considerable number of patients one-year post-implantation. This may result in disability, diminished quality of life, work absenteeism, and negative psychological effects. Restoring upper extremity function after CIED implantation should be a standard of cardiovascular care. Our systematic scoping review aimed to summarize available evidence, addressing vital questions about safety, effectiveness, exercise type, and time of exercise initiation immediately after CIED implantation., Methods: We conducted a comprehensive literature search in 5 electronic databases for original research in English, and a manual search on the references of included studies. We used Rayyan web application for study selection, and PRISMA-ScR to conduct and report the review. We assessed methodological quality using the Cochrane Risk of Bias Assessment Tool and Joanna Briggs Institute critical appraisal checklists., Results: This review included 6 studies that used upper extremity pendular, range of motion, stretching and strengthening exercises. Initiation time varied from the first postoperative day to the second postoperative week. All studies showed significant association between active upper extremity exercise and reduced dysfunction and disability after CIED implantation. There were no significant differences in complication rates between control and experimental groups., Conclusion: A limited number of low-to-average quality studies suggest active upper extremity exercise immediately after CIED implantation is safe, effective at reducing dysfunction, and improves quality of life. Higher-quality studies are needed to validate these findings., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Blood is an essential part of human life and blood donation has become a necessity that every society must take into consideration. Health care professionals have a major responsibility in raising community awareness on blood donation., Objective: This study aims to find out the knowledge and attitude of undergraduate medical students on blood donation and to determine the effectiveness of positive deviance (PD) approach., Methodology: This institutional based cross-sectional study was conducted as a part of World AIDS Days celebration by Red Ribbon club among 414 undergraduate students using convenient sampling technique. A baseline and endline survey were conducted using a pre-structured validated questionnaire. To address the knowledge gap PD approach was used for the students who had voluntarily donated blood, volunteered in providing health education, and shared their experience to their peers. Ethical principals were adhered., Results: The mean age of the students was 20.4 ± 1.2 years. Most respondents had moderate knowledge on blood donation and positivity attitude towards the same. The key finding of our study is that about 45 students (10.9%) have donated blood till now. As a result of PD training session more than half of them volunteered to donate blood in the future., Conclusion: This study shows that awareness about blood donation were minimal among the medical students with misconceptions. After PD approach, the willingness was increased from 10% to 66%. Thus, PD approach builds capacity and leadership in volunteers is considered as the best approach for behavior change among their own peers., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism 1-7 . This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases 8-11 . Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases., (© 2024. The Author(s).)

Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identify eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supports novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homoeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggests that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and serum creatinine. Finally, we demonstrate how a retinol polygenic score could identify individuals more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further investigation with respect to retinol related therapies or nutritional intervention., (© 2024. The Author(s).)

Background: Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets., Methods: We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent., Results: We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment., Conclusions: Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified 40 associated proteins, of which 16 are novel. Functionally validating these candidates by focusing on 2 selected novel protein-encoding genes, GOLM1 and B4GALT1, we demonstrated their pivotal roles in driving PDAC cell proliferation, migration, and invasion. Furthermore, we also identified potential drug repurposing opportunities for treating PDAC., Significance: PDAC is a notoriously difficult-to-treat malignancy, and our limited understanding of causal protein markers hampers progress in developing effective early detection strategies and treatments. Our study identifies novel causal proteins using genetic instruments and subsequently functionally validates selected novel proteins. This dual approach enhances our understanding of PDAC etiology and potentially opens new avenues for therapeutic interventions., (© The Author(s) 2024. Published by Oxford University Press GigaScience.)

Carbon-supported metal nanoparticles (NPs) comprise an important class of heterogeneous catalysts. The interaction between the metal and carbon support influences the overall material properties, viz., the catalytic performance. Herein we use in situ and ex situ transmission electron microscopy (TEM) in combination with in situ X-ray spectroscopy (XPS) to investigate the encapsulation of metallic iridium NPs by carbon in an Ir/C catalyst. Real-time atomic-scale imaging visualizes particle reshaping and increased graphitization of the carbon support upon heating of Ir/C in vacuum. According to in situ TEM results, carbon overcoating grows over Ir NPs during the heating process, starting from ca . 550 °C. With the carbon overlayers formed, no sintering and migration of Ir NPs is observed at 800 °C, yet the initial Ir NPs sinter at or below 550 °C, i.e., at a temperature associated with an incomplete particle encapsulation. The carbon overlayer corrugates when the temperature is decreased from 800 to 200 °C and this process is associated with the particle surface reconstruction and is reversible, such that the corrugated carbon overlayer can be smoothed out by increasing the temperature back to 800 °C. The catalytic performance (activity and stability) of the encapsulated Ir NPs in the hydrogen evolution reaction (HER) is higher than that of the initial (nonencapsulated) state of Ir/C. Overall, this work highlights microscopic details of the currently understudied phenomenon of the carbon encapsulation of supported noble metal NPs and demonstrates additionally that the encapsulation by carbon is an effective measure for tuning the catalytic performance.

Prostate cancer (PCa) brings huge public health burden in men. A growing number of conventional observational studies report associations of multiple circulating proteins with PCa risk. However, the existing findings may be subject to incoherent biases of conventional epidemiologic studies. To better characterize their associations, herein, we evaluated associations of genetically predicted concentrations of plasma proteins with PCa risk. We developed comprehensive genetic prediction models for protein levels in plasma. After testing 1308 proteins in 79 194 cases and 61 112 controls of European ancestry included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL, 24 proteins showed significant associations with PCa risk, including 16 previously reported proteins and eight novel proteins. Of them, 14 proteins showed negative associations and 10 showed positive associations with PCa risk. For 18 of the identified proteins, potential functional somatic changes of encoding genes were detected in PCa patients in The Cancer Genome Atlas (TCGA). Genes encoding these proteins were significantly involved in cancer-related pathways. We further identified drugs targeting the identified proteins, which may serve as candidates for drug repurposing for treating PCa. In conclusion, this study identifies novel protein biomarker candidates for PCa risk, which may provide new perspectives on the etiology of PCa and improve its therapeutic strategies., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: To examine the efficacy and safety of dapagliflozin in the treatment of hyperglycemia in cardiac surgery patients with type 2 diabetes (T2D)., Methods: Cardiac surgery patients with T2D (n = 250) were randomly assigned (1:1) to receive dapagliflozin plus basal-bolus insulin (DAPA group) or basal-bolus insulin alone (INSULIN group) in the early postoperative period. The primary outcome was mean difference in daily blood glucose (BG) concentrations between groups. The major safety outcomes were the occurrence of severe ketonemia/diabetic ketoacidosis (DKA) and hypoglycemia. All analyses were performed according to the intention-to-treat principle., Results: The median age of the patients was 61 years (range, 55-61), and 219 (87.6%) were men. Overall, the randomization blood glucose was 165 mg/dL (SD, 37) and glycated hemoglobin was 7.7% (SD, 1.4). There were no differences in mean daily BG concentrations (149 vs. 150 mg/dL), mean percentage of readings within target BG of 70-180 mg/dL (82.7% vs. 82.5%), total daily insulin dose (mean, 39 vs. 40 units/day), number of daily insulin injections (median, 3.9 vs. 4), length of hospital stay (median, 10 vs. 10 days), or hospital complications (21.6% vs. 24.8%) between the DAPA and INSULIN groups. The mean plasma ketone levels were significantly higher in the DAPA group than in the INSULIN group at day 3 (0.71 vs. 0.30 mmol/L) and day 5 (0.42 vs. 0.19 mmol/L) of randomization. Six patients in the DAPA group developed severe ketonemia, but no patient developed DKA. There were no differences in the proportion of patients with BG < 70 mg/dL (9.6% vs. 7.2%) between the two groups., Conclusion: Dapagliflozin complementary to basal-bolus insulin does not improve glycemia further over and above the basal-bolus insulin alone in hospitalized cardiac surgery patients. Dapagliflozin significantly increases plasma ketones levels. Safety of dapagliflozin in hospitalized patients needs further investigation. Trial registration ClinicalTrials.gov NCT05457933., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Early mobility and activity programmes following cardiac surgery are vital for improved patient outcomes, as they accelerate the recovery of functional capacity and walking distance. We observed that only 5.3% of our patients achieved a Functional Independence Measurement (FIM) score of 80% or more by the third postoperative day (POD). Additionally, the average 6-minute walk distance achieved by the fourth POD was only 188 m. Therefore, a quality improvement (QI) project was implemented with the aim of attaining a FIM score of 80% by the third POD for more than 80% of patient underwent/undergoing cardiac surgery without complications.A model-for-improvement framework was used to drive continuous improvement. This project was implemented in February 2021. Baseline data were prospectively collected between November 2020 and January 2021 (preintervention). Outcomes were analysed using standard control chart rules to detect changes over time. Unpaired Student t-tests assessed significant differences in mean levels between two groups, (preintervention vs postintervention).χ 2 tests were conducted between the two groups according to gender and patient satisfaction scores.The percentage of patients who achieved a FIM score of 80% or more by the third POD gradually increased to 91.4% 5 months following programme implementation and was sustained thereafter. The mean patient FIM score significantly improved to 81.20±3.77 (p<0.001) by the third POD. Similarly, the mean 6-minute walk distance increased to 267.90±36.10 m (p<0.001) by the fourth POD. The percentage of patients who displayed the level of confidence needed to carry out activities of daily living (ADL) and exercises independently at home increased to 89.4% (p<0.001) by the fifth POD. No adverse events associated with the mobility and activity programme were reported.This QI project demonstrated a substantial improvement in patient functional independence, walking distance and the level of confidence needed to independently carry out ADL and exercises following cardiac surgery., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A major group of the population, especially antenatal checkup (ANC) mothers and their spouses, people admitted for surgery, and people attending STI clinics, are reluctant to pretest counseling., Objectives: This study has been taken up to explore the barriers and possible solutions to improve the utilization of Facility based integrated counseling and testing center (F-ICTC) counseling services., Materials and Methods: Phase 1: In-depth interview and ranking with stakeholders from the F-ICTC center (n = 13) were conducted to identify the barriers to utilization of F-ICTC and solution for the same. Phase 2., A: Delphi panel with experts (n = 17) was invited through mail to find out the potential solution to improve the utilization of F-ICTC counseling services., Results: Possible barriers from the stakeholders' perspectives were fear of the disease, violate the privacy, unacceptance, gender bias, fear of social stigma and discrimination, and neglect attached to the disease. At third round of Delphi experts had arrived at a consensus regarding of following possible potential solutions: 1. Those who refuse pretest counseling they should be asked to answer a set of questions(which are usually told during counseling), only those questions not answered correctly by them can be corrected, 2.conducive hospital environment, 3.zero discrimination policy, 4. group counseling for ANC mothers and patients in waiting area of the hospital,5. phone counseling for unwilling patients and relocation of testing center and health education camping., Conclusion: Context-specific proactive evidence-based intervention will help in improving the proper utilization of the F-ICTC center., (Copyright © 2023 Copyright: © 2023 Indian Journal of Public Health.)

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics 1 ., (© 2023. The Author(s).)

Background Objectives: In view of anecdotal reports of sudden unexplained deaths in India's apparently healthy young adults, linking to coronavirus disease 2019 (COVID-19) infection or vaccination, we determined the factors associated with such deaths in individuals aged 18-45 years through a multicentric matched case-control study., Methods: This study was conducted through participation of 47 tertiary care hospitals across India. Cases were apparently healthy individuals aged 18-45 years without any known co-morbidity, who suddenly (<24 h of hospitalization or seen apparently healthy 24 h before death) died of unexplained causes during 1 st October 2021-31 st March 2023. Four controls were included per case matched for age, gender and neighborhood. We interviewed/perused records to collect data on COVID-19 vaccination/infection and post-COVID-19 conditions, family history of sudden death, smoking, recreational drug use, alcohol frequency and binge drinking and vigorous-intensity physical activity two days before death/interviews. We developed regression models considering COVID-19 vaccination ≤42 days before outcome, any vaccine received anytime and vaccine doses to compute an adjusted matched odds ratio (aOR) with 95 per cent confidence interval (CI)., Results: Seven hundred twenty nine cases and 2916 controls were included in the analysis. Receipt of at least one dose of COVID-19 vaccine lowered the odds [aOR (95% CI)] for unexplained sudden death [0.58 (0.37, 0.92)], whereas past COVID-19 hospitalization [3.8 (1.36, 10.61)], family history of sudden death [2.53 (1.52, 4.21)], binge drinking 48 h before death/interview [5.29 (2.57, 10.89)], use of recreational drug/substance [2.92 (1.1, 7.71)] and performing vigorous-intensity physical activity 48 h before death/interview [3.7 (1.36, 10.05)] were positively associated. Two doses lowered the odds of unexplained sudden death [0.51 (0.28, 0.91)], whereas single dose did not., Interpretation Conclusions: COVID-19 vaccination did not increase the risk of unexplained sudden death among young adults in India. Past COVID-19 hospitalization, family history of sudden death and certain lifestyle behaviors increased the likelihood of unexplained sudden death., (Copyright © 2023 Copyright: © 2023 Indian Journal of Medical Research.)

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization., (© 2023. The Author(s).)

Background: Pregnant Health Care Professionals (HCPs), who serve as front-line warriors of COVID-19 will invariably experience a stressful pregnancy period. Ensuring their well-being during this COVID-19 pandemic period is a big challenge and guidelines or standard operating procedures (SOP) for the same are non-existent or are scarce., Objectives: To explore the challenges and experiences of pregnant HCPs during the COVID-19 pandemic., Methods: A qualitative study was conducted among 19 pregnant HCPs (14 Doctors and 5 staff nurses) working in Pondicherry, who were selected using purposive sampling for in-depth interviews. After obtaining informed written consent, face-to-face interviews were conducted until the attainment of the point of saturation. Audio recordings of the interviews were transcribed in English. Transcripts were proofread and manually analyzed for content. Codes obtained from the analysis of transcripts were merged to form broad categories., Results: The majority 15 (78.9%) of HCPs belonged to the clinical department and had work experience from 2-4 years. The mean age of the respondents was 29.4 ± 3.6 years. Four broad categories (of challenges), namely, Personnel level (Fear of infection in workplace, Inadequate antenatal care), Family level (Family pressure to quit job, Guilt of spreading the infection to family members), society level (Criticism by neighbor for working, Stigma), and work level challenges (Fear of losing the job, Uncomfortable work environment) emerged from the study., Conclusion and Recommendations: Challenges faced by the pregnant HCPs due to their nature of work remain by and large not addressed. Hence, specific guidelines or SOPs addressing these issues of pregnant health care workers and their swift and strict implementation are the need of the hour., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Occupational and Environmental Medicine.)

The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics 1 . Here we examine a large cohort (the INTERVAL study 2 ; n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank 3 to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal ( https://www.omicspred.org/ ) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Metabolic biomarker data quantified by nuclear magnetic resonance (NMR) spectroscopy in approximately 121,000 UK Biobank participants has recently been released as a community resource, comprising absolute concentrations and ratios of 249 circulating metabolites, lipids, and lipoprotein sub-fractions. Here we identify and characterise additional sources of unwanted technical variation influencing individual biomarkers in the data available to download from UK Biobank. These included sample preparation time, shipping plate well, spectrometer batch effects, drift over time within spectrometer, and outlier shipping plates. We developed a procedure for removing this unwanted technical variation, and demonstrate that it increases signal for genetic and epidemiological studies of the NMR metabolic biomarker data in UK Biobank. We subsequently developed an R package, ukbnmr, which we make available to the wider research community to enhance the utility of the UK Biobank NMR metabolic biomarker data and to facilitate rapid analysis., (© 2023. The Author(s).)

Aims: To compare the efficacy and safety of degludec U100 versus glargine U300 for the early postoperative management of patients with type 2 diabetes mellitus (T2D) undergoing coronary artery bypass graft (CABG) surgery., Methods: A total of 239 patients were randomly assigned (1:1) to receive a basal-bolus regimen in the early postoperative period using degludec U100 (n = 122) or glargine U300 (n = 117) as basal and glulisine before meals. The primary outcome was mean differences between groups in their daily BG concentrations. The major safety outcome was the occurrence of hypoglycemia., Results: There were no differences in mean daily BG concentrations (157 vs. 162 mg/dl), mean percentage of readings within target BG of 70-180 mg/dl (74% vs. 73%), daily basal insulin dose (19 vs. 21 units/day), length of stay (median [IQR]: 9 vs. 9 days), or hospital complications (21.3% vs. 21.4%) between treatment groups. There were no differences in the proportion of patients with BG <70 mg/dl (15.6% vs. 23.1%) or <54 mg/dl (1.6% vs. 4.3%) between degludec-100 and glargine-300 groups., Conclusions: Treatment with degludec U100 is as effective and safe as glargine U300 for the early postoperative hospital management of patients with T2D undergoing CABG., (© 2022 Diabetes UK.)

Voice Handicap Index (VHI) is the most commonly used tool to assess the quality of life in voice disordered patients. A validated Tamil language version of VHI is not developed yet. Hence, this study was undertaken to translate and validate the Voice Handicap Index in Tamil language, which can potentially benefit Tamil speaking patients with voice disorders. This was a translation and tool validation study done at a tertiary care teaching hospital using an analytical, follow up design according to WHO guidelines. Dysphonic (Group A) and Normal (Group B) respondents were purposively invited to fill a self administered VHI-Tamil questionnaire. The content validity, response process validity, internal consistency and clinical validity of the questionnaire was calculated using appropriate statistical analysis methods using SPSS version 24.0 software. Out of 117 respondents, 61 respondents were dysphonic (Group A) and 56 respondents were normal (Group B). Overall index for content validation was over 0.84, and response process validation was 1.00 in all domains. Overall internal consistency was excellent, with Cronbach's alpha of 0.993. Excellent test-retest reliability was identified using the Spearman rank correlation coefficient (r = 0.96; p-value < 0.001). For clinical validity, a statistically significant difference between the dysphonic and the normal groups, for the overall VHI-Tamil scores and each of the three domain scores was noted. VHI-Tamil was found to be reliable and valid for assessing the quality of life in patients with voice disorders. It can be recommended for future use among Tamil speaking population., Competing Interests: Conflict of interestThe authors have no conflicts of interest to declare that are relevant to the content of this article, (© Association of Otolaryngologists of India 2021.)

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 -11 ) 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., (© 2022. The Author(s).)

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 -4 ). 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., (© 2022. The Author(s).)

Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts., Competing Interests: Declaration of interests John Danesh reports grants, personal fees, and non-financial support from Merck Sharp & Dohme (MSD); grants, personal fees, and non-financial support from Novartis; grants from Pfizer; and grants from AstraZeneca outside the submitted work. John Danesh sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING) member, London (since 2013); the MRC High Throughput Science ‘Omics Panel Member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the AstraZeneca Genomics Advisory Board (2018). Adam Butterworth reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Merk and Sanofi. During the course of the project Praveen Surendran became an employee of GSK, Lorenzo Bomba became an employee of BioMarin, Mohd Karim became an employee of Variant Bio and Qi Guo became an employee of BenevolentAI., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. All rights reserved.)

Background: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI)., Methods and Findings: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds., Conclusions: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CL is an Academic Editor on PLOS Medicine’s editorial board; ASB reports institutional grants outside of this work from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Novartis, Regeneron and Sanofi; during the course of this project, PS became a full-time employee of GSK. No other conflicts of interest have been declared by the authors.

Early mobilisation following cardiac surgery is vital for improved patient outcomes, as it has a positive effect on a patient's physical and psychological recovery following surgery. We observed that patients admitted to the cardiothoracic intensive care unit (CTICU) following cardiac surgery had only bed exercises and were confined to bed until the chest tubes were removed, which may have delayed patients achieving functional independence. Therefore, the CTICU team implemented a quality improvement (QI) project aimed at the early mobilisation of patients after cardiac surgery.A retrospective analysis was undertaken to define the current mobilisation practices in the CTICU. The multidisciplinary team identified various practice gaps and tested several changes that led to the implementation of a successful early mobility programme. The tests were carried out and reported using rapid cycle changes. A model for improvement methodology was used to run the project. The outcomes of the project were analysed using standard 'run chart rules' to detect changes in outcomes over time and Welch's t-test to assess the significance of these outcomes.This project was implemented in 2015. Patient compliance with early activity and mobilisation gradually reached 95% in 2016 and was sustained over the next 3 years. After the programme was implemented, the mean hours required for initiating out-of-bed-mobilisation was reduced from 22.77 hours to 11.74 hours. Similarly, functional independence measures and intensive care unit mobility scores also showed a statistically significant (p<0.005) improvement in patient transfers out of the CTICU.Implementing an early mobility programme for post-cardiac surgery patients is both safe and feasible. This QI project allowed for early activity and mobilisation, a substantial reduction in the number of hours required for initiating out-of-bed mobilisation following cardiac surgery, and facilitated the achievement of early ambulation and functional milestones in our patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175&#95;88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders., (Copyright © 2021 American Society of Human Genetics. All rights reserved.)

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10 -6 ; IFNAR2, P = 9.8 × 10 -11 and IL-10RB, P = 2.3 × 10 -14 ) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

Background: Vaccine hesitancy (VH) has been identified by the World Health Organization as one among the top ten threats to global public health. There is limited literature regarding VH from developing countries like India. Methods: In this facility based cross-sectional study, 172 mothers of under-five children were assessed regarding VH using the parental attitude towards childhood vaccination questionnaire (PACV). Results: The prevalence of VH was 3.4% (n=6). Only 7.6% (n=13) of the study participants had ever refused vaccination for their child and the most common reason cited for their refusal was that they thought it was not safe (n=6). Government health facilities was the place of routine immunization for 60.5% (n=104) participants. Health care providers (n =79, 46%) were the major source of information regarding vaccines. Conclusions: Our study highlights the presence of very low prevalence of VH in Mangalore compared to similar studies from India and other parts of the world. The limited number of participants had refused vaccination due to concerns related to vaccine safety., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Thapar R et al.)

Background: Vaccine hesitancy (VH) has been identified by the World Health Organization as one among the top ten threats to global public health. There is limited literature regarding VH from developing countries like India. Methods: In this facility based cross-sectional study, 172 mothers of under-five children were assessed regarding VH using the parental attitude towards childhood vaccination questionnaire (PACV). Results: The prevalence of VH was 3.4% (n=6). Only 7.6% (n=13) of the study participants had ever refused vaccination for their child and the most common reason cited for their refusal was that they thought it was not safe (n=6). Government health facilities was the place of routine immunization for 60.5% (n=104) participants. Health care providers (n =79, 46%) were the major source of information regarding vaccines. Conclusions: Our study highlights the presence of very low prevalence of VH in Mangalore compared to similar studies from India and other parts of the world. The limited number of participants had refused vaccination due to concerns related to vaccine safety., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Thapar R et al.)

Background: Vaccine hesitancy (VH) has been identified by the World Health Organization as one among the top ten threats to global public health. There is limited literature regarding VH from developing countries like India. Methods: In this facility based cross-sectional study, 172 mothers of under-five children were assessed regarding VH using the parental attitude towards childhood vaccination questionnaire. Results: The prevalence of VH was 3.4% (n=6). Only 7.6% (n=13) of the study participants had refused vaccination for their child and the most common reason cited for vaccine refusal was that they thought it was not safe (n=6). Government health facilities was the place of routine immunization for 60.5% (n=104) participants. Health care providers (n =79, 46%) were the major source of information regarding vaccines. Conclusions: Our study highlights the presence of very low prevalence of VH in Mangalore compared to similar studies from India and other parts of the world. The limited number of participants had refused vaccination due to concerns related to vaccine safety., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Thapar R et al.)

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10 -10 ) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10 -8 ), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 -8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10 -8 ) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10 -3 ) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation., Competing Interests: Declaration of Interests Adam Butterworth has received grants (outside of this work) from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, and Sanofi; James Floyd has consulted for Shionogi; Qi Guo is a full-time employee of BenevolentAI; Joanna Howson is a full-time employee of Novo Nordisk. Parsa Akbari is a full-time employee of Regeneron Pharmaceuticals., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10 -9 , including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies., Competing Interests: Declaration of Interests Competing financial interests are declared in Table S1F., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A facile and eco-friendly hydrothermal method was used to prepare carbon quantum dots (CQDs) using orange waste peels. The synthesized CQDs were well dispersed and the average diameter was 2.9 ± 0.5 nm. Functional group identification of the CQDs was confirmed by Fourier transform infrared spectrum analysis. Fluorescence properties of the synthesized CQDs exhibited blue emission. The fluorescence quantum yield of the CQDs was around 11.37% at an excitation wavelength of 330 nm. The higher order nonlinear optical properties were examined using a Z-scan technique and a continuous wave laser that was operated at a wavelength of 532 nm. Results demonstrated that the synthesis of CQDs can be considered as promising for optical switching devices, bio-scanning, and bio-imaging for optoelectronic applications., (© 2019 John Wiley & Sons, Ltd.)

Summary: PhenoScanner is a curated database of publicly available results from large-scale genetic association studies in humans. This online tool facilitates 'phenome scans', where genetic variants are cross-referenced for association with many phenotypes of different types. Here we present a major update of PhenoScanner ('PhenoScanner V2'), including over 150 million genetic variants and more than 65 billion associations (compared to 350 million associations in PhenoScanner V1) with diseases and traits, gene expression, metabolite and protein levels, and epigenetic markers. The query options have been extended to include searches by genes, genomic regions and phenotypes, as well as for genetic variants. All variants are positionally annotated using the Variant Effect Predictor and the phenotypes are mapped to Experimental Factor Ontology terms. Linkage disequilibrium statistics from the 1000 Genomes project can be used to search for phenotype associations with proxy variants., Availability and Implementation: PhenoScanner V2 is available at www.phenoscanner.medschl.cam.ac.uk., (© The Author(s) 2019. Published by Oxford University Press.)

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.