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Background: Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways., Methods: To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses., Results: Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology., Conclusions: Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries., Competing Interests: Competing interests: Rebecca S. Fine: Rebecca S. Fine is currently employed by Vertex Pharmaceuticals Incorporated. Audrey Y Chu: Currently employed by GlaxoSmithkline. Dennis O. Mook-Kanamori: Dennis Mook-Kanamori is working as a part-time clinical research consultant for Metabolon, Inc. Paul W. Franks: PWF has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project. Mike A. Nalls: Dr. Mike A. Nalls is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. Dr. Nalls also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. Mark J. Caulfield: MJC is Chief Scientist for Genomics England, a UK government company. Joel N. Hirschhorn: JHN is on the scientific advisory board of Camp4 Therapeutics. Erik Ingelsson: Erik Ingelsson is now an employee of GlaxoSmithKline. Anubha Mahajan: Anubha Mahajan is an employee of Genentech since January 2020, and a holder of Roche stock. Mark I McCarthy: The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. MMcC has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, MMcC is an employee of Genentech, and a holder of Roche stock. Inês Barroso: IB and spouse declare stock ownership in GlaxoSmithkline and Incyte Ltd. James B. Meigs: JBM serves as an Academic Associate for Quest Diagnostics R&D Bruce M Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr. Sander W. van der Laan has received Roche funding for unrelated work. Matthias Blüher received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, Pfizer and Sanofi. Vinicius Tragante: VT became an employee of deCODE genetics/Amgen Inc. after the conclusion of this work Dr Franco is employed by ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.) and Metagenics., (Copyright: © 2023 Willems SM et al.)

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: Xpert MTB/RIF Ultra (Ultra) is a widely used rapid front-line tuberculosis and rifampicin-susceptibility testing. Mycobacterium Growth Indicator Tube (MGIT) 960 liquid culture is used as an adjunct but is vulnerable to contamination. We aimed to assess whether Ultra can be used on to-be-discarded contaminated cultures., Methods: We stored contaminated MGIT960 tubes (growth-positive, acid-fast bacilli [AFB]-negative) originally inoculated at a high-volume laboratory in Cape Town, South Africa, to diagnose patients with presumptive pulmonary tuberculosis. Patients who had no positive tuberculosis results (smear, Ultra, or culture) at contamination detection and had another, later specimen submitted within 3 months of the contaminated specimen were selected. We evaluated the sensitivity and specificity of Ultra on contaminated growth from the first culture for tuberculosis (next-available non-contaminated culture result reference standard) and rifampicin resistance (vs MTBDRplus on a later isolate). We calculated potential time-to-diagnosis improvements and also evaluated the immunochromatographic MPT64 TBc assay., Findings: Between June 1 and Aug 31, 2019, 36 684 specimens from 26 929 patients were processed for diagnostic culture. 2402 (7%) cultures from 2186 patients were contaminated. 1068 (49%) of 2186 patients had no other specimen submitted. After 319 exclusions, there were 799 people with at least one repeat specimen submitted; of these, we included in our study 246 patients (31%) with a culture-positive repeat specimen and 429 patients (54%) with a culture-negative repeat specimen. 124 patients (16%) with a culture-contaminated repeat specimen were excluded. When Ultra was done on the initial contaminated growth, sensitivity was 89% (95% CI 84-94) for tuberculosis and 95% (75-100) for rifampicin-resistance detection, and specificity was 95% (90-98) for tuberculosis and 98% (93-100) for rifampicin-resistance detection. If our approach were used the day after contamination detection, the time to tuberculosis detection would improve by a median of 23 days (IQR 13-45) and provide a result in many patients who had none. MPT64 TBc had a sensitivity of 5% (95% CI 0-25)., Interpretation: Ultra on AFB-negative growth from contaminated MGIT960 tubes had high sensitivity and specificity, approximating WHO criteria for sputum test target product performance and exceeding drug susceptibility testing. Our approach could mitigate negative effects of culture contamination, especially when repeat specimens are not submitted., Funding: The European & Developing Countries Clinical Trials Partnership, National Institutes of Health., Competing Interests: Declaration of interests GT reports funding from the EDCTP2 programme supported by the EU (RIA2018D-2509, PreFIT; RIA2018D-2493, SeroSelectTB; RIA2020I-3305, CAGE-TB) and the National Institutes of Health (D43TW010350; U01AI152087; U54EB027049; R01AI136894). RW reports funding from the South African Medical Research Council. All other authors report no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort., Methods: The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis., Results: We show that in the absence of a well powered trans-ethnic GWAS from which to derive marker SNPs and effect estimates for PRS, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred, by adjusting the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort., Conclusions: Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

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.)

Background: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort., Methods: The PRS model was developed trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis., Results: We show that in the absence of a well powered trans-ethnic GWAS from which to derive SNPs and effect estimates, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred to adjust the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort., Conclusions: Widespread use of PRS in the clinic is hampered by a lack of genotyping data in individuals of non-European ancestry for the vast majority of traits. Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians.

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).)

Background and Aims: Condensed tannins, responsible for berry and wine astringency, may have been selected during grapevine domestication. This work examines the phylogenetic distribution of condensed tannins throughout the Vitaceae phylogenetic tree., Methods: Green berries and mature leaves of representative true-to-type members of the Vitaceae were collected before 'véraison', freeze-dried and pulverized, and condensed tannins were measured following depolymerization by nucleophilic addition of 2-mercaptoethanol to the C4 of the flavan-3-ol units in an organic acidic medium. Reaction products were separated and quantified by ultrahigh pressure liquid chromatography/diode array detection/mass spectrometry., Key Results and Conclusions: The original ability to incorporate epigallocatechin (EGC) into grapevine condensed tannins was lost independently in both the American and Eurasian/Asian branches of the Vitaceae, with exceptional cases of reversion to the ancestral EGC phenotype. This is particularly true in the genus Vitis, where we now find two radically distinct groups differing with respect to EGC content. While Vitis species from Asia are void of EGC, 50 % of the New World Vitis harbour EGC. Interestingly, the presence of EGC is tightly coupled with the degree of leaf margin serration. Noticeably, the rare Asian EGC-forming species are phylogenetically close to Vitis vinifera, the only remnant representative of Vitis in Eurasia. Both the wild ancestral V. vinifera subsp. sylvestris as well as the domesticated V. vinifera subsp. sativa can accumulate EGC and activate galloylation biosynthesis that compete for photoassimilates and reductive power., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Importance: Falls among older people occur frequently and are a leading cause of Emergency department (ED) admissions, disability, death and rising health care costs. Multifactorial fall prevention programs that are aimed to target the population at risk have shown to effectively reduce the rate of falling and fall-related injuries in community-dwelling older people. However, the participation of and adherence to these programs in real life situation is generally low., Objective: To test the feasibility of a transitionally organized fall prevention assessment with accompanying personalized intervention initiated at the ED., Design, Settings and Participants: A process evaluation, of a non-randomized controlled pilot trial for implementing a transitionally organized multifactorial fall prevention intervention, was performed using the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework to gain insight into the barriers and facilitators of implementation. Older fallers (>70yrs) presenting at the ED were selected based on ZIP-code and after obtaining informed consent, data for the evaluation was collected through questionnaires and interviews. Furthermore, feedback was collected from the healthcare providers., Main Results: The consent was obtained by 24 (70%) of the patients approached directly at the ED and 17 (26%) of the patients approached later by phone. Adherence to the protocol by the participants, clinical assessors and family practice were all more than 90%. After three months, nine (26%) of the participants had at least one recurrent fall: three (20%) patients in the intervention group and six (32%) in the control group., Conclusion: ED presentation due to a fall in older persons provides a window of opportunity for optimizing adherence to a multifactorial fall prevention program as willingness to participate was higher when the patients were approached at the ED during their stay. Implementing a transitionally organized multidisciplinary fall prevention program was successful with a high protocol adherence., The Netherlands Trial Register: NTR NL8142, November 8, 2019., Competing Interests: The authors declare that they have no competing interests.