Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma.

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.

Optimizing Recovery: A Systematic Scoping Review of Upper Extremity Exercise Immediately After Cardiac Implantable Electronic Device Implantation.

Background 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 five 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 Cochrane Risk of Bias Assessment Tool and Joanna Briggs Institute critical appraisal checklists. Results This review included six studies that used upper extremity pendular, range of motion, stretching and strengthening exercises. Initiation time varied from first post-operative day to second post-operative 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. Conclusions 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.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. 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.

Genetic influences on circulating retinol and its relationship to human health.

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.

Associations between genetically predicted plasma protein levels and Alzheimer's disease risk: a study using genetic prediction models.

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.

Carbon Encapsulation of Supported Metallic Iridium Nanoparticles: An in Situ Transmission Electron Microscopy Study and Implications for Hydrogen Evolution Reaction.

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.

Enhancing early functional independence following cardiac surgery: a quality improvement programme.

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).χ2 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.

Plasma proteomic associations with genetics and health in the UK Biobank.

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 therapeutics1.

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.

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.

Identification of blood protein biomarkers associated with prostate cancer risk using genetic prediction models: analysis of over 140,000 subjects.

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.

Developing and delivering a hybrid Cardiac Rehabilitation Phase II exercise program during the COVID-19 pandemic: a quality improvement program.

The COVID-19 pandemic resulted in the cessation of approximately 75% of cardiac rehabilitation (CR) programmes worldwide. In March 2020, CR phase II (CRP2) services were stopped in Qatar. Multiple studies had shown safety, effectiveness, reduced cost of delivery and improved participation with hybrid CR. A multidisciplinary team reviewed various alternative models for delivery and decided to implement a hybrid CRP2 exercise programme (HCRP2-EP) to ensure continuation of our patient care. Our aim was to enrol in the HCRP2-EP 70% of all eligible patients by 30 September 2020. Institute for Health Care Improvement's collaborative model was adopted. Multiple plan-do-study-act cycles were used to test change ideas. The outcomes of the project were analysed using standard run chart rules to detect the changes in outcomes over time. This project was implemented from March 2020, and the male patients enrolled between August 2020 and April 2021, with sustained monthly median enrolment above target of 70% throughout. As for our secondary outcome, 75.8% of the male patients who completed HCRP2-EP showed a meaningful change in peak exercise capacity of ≥10% (mean change 17%±6%). There were no major adverse events reported, and the median Patient Satisfaction Score was 96% well above the institutional target of 90%. This shows a well-designed quality improvement programme is an appropriate strategy for implementing HCRP2-EP in a clinical setting, and HCRP2-EP is a feasible, effective and safe intervention in eligible male patients with cardiovascular disease.

An atlas of genetic scores to predict multi-omic traits.

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-omics1. Here we examine a large cohort (the INTERVAL study2; 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 Biobank3 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.

Quality control and removal of technical variation of NMR metabolic biomarker data in ~120,000 UK Biobank participants.

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.

Rare and common genetic determinants of metabolic individuality and their effects on human health.

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.

Delivery of Acute Rehabilitation to a Postcoronary Artery Bypass Graft COVID-19 Patient in a Pandemic Environment.

During the first wave of the coronavirus disease (COVID-19) pandemic, a 57-year-old COVID-19 male patient was diagnosed with non-ST-elevation myocardial infarction and required urgent coronary artery bypass graft. In-patient cardiac rehabilitation following cardiac surgery was inevitable to limit or prevent various postoperative complications. A routine rehabilitation program was not feasible because of the strict COVID-19 isolation procedures, the high risk of cross infections, and the lack of various resources. Moreover, the detrimental effects of COVID-19 infection on multiple body systems reduced his exercise tolerance, limiting his engagement in physical activity. This case report highlights the various challenges encountered during the rehabilitation of these patients and strategies adopted to overcome them, illustrating the feasibility of a modified rehabilitation program to ensure early functional recovery.

Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke.

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.

Evidence of in-vivo myofascial force transfer in humans- a systematic scoping review.

BACKGROUND: The fascial system not only enables the body to operate in an integrated manner but modifies its tension in response to the stress on it. Recent animal, cadaveric and in-vitro trials have shown that "myofascial force transmission" (MFT) can play a major role in homeostasis, musculoskeletal function and pain. Human evidence for the in-vivo existence of MFT is scarce. OBJECTIVE: This scoping review attempts to gather and interpret the available evidence of the in-vivo existence of MFT in humans, its role in homeostasis, and musculoskeletal function. METHOD: A search of major databases using the keywords 'myofascial force transmission' and 'epimuscular force transmission' yielded 247 articles as of November 2021. For the final analysis, only original in-vivo human studies were considered. In-vitro human studies, cadaveric or animal studies, reviews, and similar studies were excluded. A qualitative analysis of the studies was conducted after rating it with the Oxford's Center for Evidence -based Medicine (CEBM) scale. RESULT: Twenty studies ranging from randomized controlled trials (RCTs) to case studies covering 405 patients have been included in this review. The analysed trials were highly heterogeneous and of lower methodological quality meddling with the quantitative analysis. The majority of the appraised studies demonstrated a higher probability of MFT existence, while two studies revealed a lower probability. CONCLUSION: Our search for proof of the in vivo existence of MFT in humans has led us to support such an existence, albeit prudently. Previous research on animals and human cadavers reinforces our finding. We are optimistic that the forthcoming studies on the topic will pave the way for the unraveling of several musculoskeletal riddles that are currently unknown or less well-known.

Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites.

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.

Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.

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.