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CMH Lahore Medical College and Institute of Dentistry CMH Lahore Medical College and Institute of Dentistry The Aga Khan University CMH Lahore Medical College and Institute of Dentistry The Aga Khan University CMH Lahore Medical College and Institute of Dentistry King Khaled Hospital Hail King Khaled Hospital Hail Mediciti Institute of Medical Sciences Health Promotion Bureau, Minstry of Health, Sri Lanka Queen Elizabeth Hospital King's Lynn Barnsley Hospital NHS Foundation Trust English Division of Medical University of Łódź Queen Alexandra Hospital Portsmouth Royal Hampshire County Hospital Winchester Children Hospital & The Institute of Child Health, Lahore Abstract Background Incidence of stroke is persistently increasing followed by effective medical treatment resulting in high number of stroke survivors. Post stroke recovery is critical necessitating sufficient knowledge, effective prevention and control of chronic diseases, pre-existing complications, and potential risk factors. Objective This study aimed to identify and evaluate potential risks and prognostic factors that can negatively influence post stroke rehabilitation in order to prevent, readily diagnose, and promptly manage the most common manifestations of stroke. Study Design Cross-sectional observational study conducted at Stroke Rehabilitation Center, Lahore, Pakistan with the sample size of 120 patients, selected by using convenient sampling. Results One hundred and twenty stroke survivors admitted in neurorehabilitation center (Age Mean±SD 56.9±12.2) were classified into 4 groups based on Modified Rankin scale: Mild (17.5%), Moderate (26.6%), Moderate to severe (39.1%), and severe impairment (16.6%). The major modifiable post stroke complications included depression (91%) and anxiety (84%). Acute infections (RTI n=69, 58%, UTI n=78, 65%) and poorly managed chronic disorders such as DM (n=59, 49.1%, 95% CI 0.5-2.5), HTN (n=34, 28%, 95% CI 1.7-2.5), and Kidney failure (n=12, 10%, 95% CI 0.4-3.5) were strongly associated with poor prognosis. Conclusion Incidence of stroke was found to be more common in adults (Age: Range=44-69 years, Mean=56.9) with no gender predominance. Most common post stroke complications were depression and anxiety, significantly influencing the recovery process. The severity of the post stroke neurological deficit was positively associated with the frequency of complications and poor neurorehabilitation. Knowledge of post stroke recovery process and effects of various factors on it is essential for the implication of effective clinical and rehabilitation interventions to minimize morbidity and subsequent post stroke disability. Keywords: brain injury. stroke recovery, neurorehabilitation, disability, stroke management

Additional file 10 Review history

SummaryPolygenic risk scores (PRS) aim to quantify the contribution of multiple genetic loci to an individual’s likelihood of a complex trait or disease. However, existing PRS estimate genetic liability using common genetic variants, excluding the impact of rare variants. We identified rare, large-effect variants in individuals with outlier gene expression from the GTEx project and then assessed their impact on PRS predictions in the UK Biobank (UKB). We observed large deviations from the PRS-predicted phenotypes for carriers of multiple outlier rare variants; for example, individuals classified as “low-risk” but in the top 1% of outlier rare variant burden had a 6-fold higher rate of severe obesity. We replicated these findings using data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) biobank and the Million Veteran Program, and demonstrated that PRS across multiple traits will significantly benefit from the inclusion of rare genetic variants.

The Genotype-Tissue Expression (GTEx) project dissects how genetic variation affects gene expression and splicing. Some human genetic variants affect the amount of RNA produced and the splicing of gene transcripts, crucial steps in development and maintaining a healthy individual. However, some of these changes only occur in a small number of tissues within the body. The Genotype-Tissue Expression (GTEx) project has been expanded over time, and, looking at the final data in version 8, Aguet et al. present a deep characterization of genetic associations and gene expression and splicing in 838 individuals over 49 tissues (see the Perspective by Wilson). This large study was able to characterize the details underlying many aspects of gene expression and provides a resource with which to better understand the fundamental molecular mechanisms of how genetic variants affect gene regulation and complex traits in humans. Science, this issue p. 1318; see also p. 1298 The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues. We thank the donors and their families for their generous gifts of organ donation for transplantation and tissue donations for the GTEx research project; the Genomics Platform at the Broad Institute for data generation; J. Struewing for support and leadership of the GTEx project; M. Khan and C. Stolte for the illustrations in Fig. 1; and R. Do, D. Jordan, and M. Verbanck for providing GWAS pleiotropy scores. Funding: This work was supported by the Common Fund of the Office of the Director, U.S. National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, NIA, NIAID, and NINDS through NIH contracts HHSN261200800001E (Leidos Prime contract with NCI: A.M.S., D.E.T., N.V.R., J.A.M., L.S., M.E.B., L.Q., T.K., D.B., K.R., and A.U.), 10XS170 (NDRI: W.F.L., J.A.T., G.K., A.M., S.S., R.H., G.Wa., M.J., M.Wa., L.E.B., C.J., J.W., B.R., M.Hu., K.M., L.A.S., H.M.G., M.Mo., and L.K.B.), 10XS171 (Roswell Park Cancer Institute: B.A.F., M.T.M., E.K., B.M.G., K.D.R., and J.B.), 10X172 (Science Care Inc.), 12ST1039 (IDOX), 10ST1035 (Van Andel Institute: S.D.J., D.C.R., and D.R.V.), HHSN268201000029C (Broad Institute: F.A., G.G., K.G.A., A.V.S., X.Li., E.T., S.G., A.G., S.A., K.H.H., D.T.N., K.H., S.R.M., and J.L.N.), 5U41HG009494 (F.A., G.G., and K.G.A.), and through NIH grants R01 DA006227-17 (University of Miami Brain Bank: D.C.M. and D.A.D.), Supplement to University of Miami grant DA006227 (D.C.M. and D.A.D.), R01 MH090941 (University of Geneva), R01 MH090951 and R01 MH090937 (University of Chicago), R01 MH090936 (University of North Carolina–Chapel Hill), R01MH101814 (M.M.-A., V.W., S.B.M., R.G., E.T.D., D.G.-M., and A.V.), U01HG007593 (S.B.M.), R01MH101822 (C.D.B.), U01HG007598 (M.O. and B.E.S.), U01MH104393 (A.P.F.), extension H002371 to 5U41HG002371 (W.J.K.), as well as other funding sources: R01MH106842 (T.L., P.M., E.F., and P.J.H.), R01HL142028 (T.L., Si.Ka., and P.J.H.), R01GM122924 (T.L. and S.E.C.), R01MH107666 (H.K.I.), P30DK020595 (H.K.I.), UM1HG008901 (T.L.), R01GM124486 (T.L.), R01HG010067 (Y.Pa.), R01HG002585 (G.Wa. and M.St.), Gordon and Betty Moore Foundation GBMF 4559 (G.Wa. and M.St.), 1K99HG009916-01 (S.E.C.), R01HG006855 (Se.Ka. and R.E.H.), BIO2015-70777-P, Ministerio de Economia y Competitividad and FEDER funds (M.M.-A., V.W., R.G., and D.G.-M.), la Caixa Foundation ID 100010434 under agreement LCF/BQ/SO15/52260001 (D.G.-M.), NIH CTSA grant UL1TR002550-01 (P.M.), Marie-Skłodowska Curie fellowship H2020 Grant 706636 (S.K.-H.), R35HG010718 (E.R.G.), FPU15/03635, Ministerio de Educación, Cultura y Deporte (M.M.-A.),R01MH109905, 1R01HG010480 (A.Ba.), Searle Scholar Program (A.Ba.), R01HG008150 (S.B.M.), 5T32HG000044-22, NHGRI Institutional Training Grant in Genome Science (N.R.G.), EU IMI program (UE7-DIRECT-115317-1) (E.T.D. and A.V.), FNS funded project RNA1 (31003A_149984) (E.T.D. and A.V.), DK110919 (F.H.), F32HG009987 (F.H.), Massachusetts Lions Eye Research Fund Grant (A.R.H.), Wellcome grant WT108749/Z/15/Z (P.F.), and European Molecular Biology Laboratory (P.F. and D.Z.). Peer Reviewed "Article signat per 1 autors/es del BSC membres del THE GTEX CONSORTIUM: Marta Mele Messeguer"

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of “dedifferentiated” vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don’t eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.

Allele expression (AE) analysis robustly measures cis-regulatory effects. Here, we present and demonstrate the utility of a vast AE resource generated from the GTEx v8 release, containing 15,253 samples spanning 54 human tissues for a total of 431 million measurements of AE at the SNP level and 153 million measurements at the haplotype level. In addition, we develop an extension of our tool phASER that allows effect sizes of cis-regulatory variants to be estimated using haplotype-level AE data. This AE resource is the largest to date, and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution., Genetic variants in the FAM13A locus have been associated with anthropometric and glycemic traits. Here, using fine-mapping, in vitro knockdown studies in pre-adipocytes and in vivo knockout in mice, the authors show that FAM13A is involved in regulating fat distribution and metabolic traits.

Background The prevalence of obesity and its comorbidities, including type 2 diabetes mellitus (T2DM), is dramatically increasing throughout the world; however, the underlying aetiology is incompletely understood. Genome-wide association studies (GWAS) have identified hundreds of genec susceptibility loci for obesity and T2DM, although the causal genes and mechanisms are largely unknown. SPRY2 is a candidate gene identified in GWAS of body fat percentage and T2DM, and has recently been linked to insulin production in pancreatic β-cells. In the present study, we aimed to further understand SPRY2 via functional characterisation in HepG2 cells, an in vitro model of human hepatocytes widely used to investigate T2DM and insulin resistance. Methods CRISPR-Cas9 genome editing was used to target SPRY2 in HepG2 cells, and the functional consequences of SPRY2 knockout (KO) and overexpression subsequently assessed using glucose uptake and lipid droplet assays, measurement of protein kinase phosphorylation and RNA sequencing. Results The major functional consequence of SPRY2 KO was a significant increase in glucose uptake, along with elevated lipid droplet accumulation. These changes were attenuated, but not reversed, in cells overexpressing SPRY2. Phosphorylation of protein kinases across key signalling pathways (including Akt and mitogen activated protein kinases) was not altered after SPRY2 KO. Transcriptome profiling in SPRY2 KO and mock (control) cells revealed a number of differentially expressed genes related to cholesterol biosynthesis, cell cycle regulation and cellular signalling pathways. Phospholipase A2 group IIA (PLA2G2A) mRNA level was subsequently validated as significantly upregulated following SPRY2 KO, highlighting this as a potential mediator downstream of SPRY2. Conclusion These findings suggest a role for SPRY2 in glucose and lipid metabolism in hepatocytes and contribute to clarifying the function of this gene in the context of metabolic diseases.

The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2,519 out of 5,385) of the GWAS loci examined. Our results demonstrate the translational relevance of the GTEx resources and highlight the need to increase their resolution and breadth to further our understanding of the genotype-phenotype link.

Long non-coding RNA (lncRNA) genes are known to have diverse impacts on gene regulation. However, it is still a major challenge to distinguish functional lncRNAs from those that are byproducts of surrounding transcriptional activity. To systematically identify hallmarks of biological function, we used the GTEx v8 data to profile the expression, regulation, network relationships and trait associations of lncRNA genes across 49 tissues encompassing 87 distinct traits. In addition to revealing widespread differences in regulatory patterns between lncRNA and protein-coding genes, we identified novel disease-associated lncRNAs, such asC6orf3for psoriasis andLINC01475/RP11-129J12.1for ulcerative colitis. This work provides a comprehensive resource to interrogate lncRNA genes of interest and annotate cell type and human trait relevance.One Sentence SummarylncRNA genes have distinctive regulatory patterns and unique trait associations compared to protein-coding genes.

Large genome-wide association studies (GWAS) have identified variants accounting for a substantial portion of the heritable risk for coronary artery disease (CAD). These studies have catalyzed drug discovery and generated the possibility of improved risk prediction and stratification. Here, we review the current state-of-the art in polygenic risk scores (PRSs) and look to the future, as these scores move towards clinical application.Over the last decade, multilocus PRSs for CAD have expanded to include millions of variants and demonstrated strong association with CAD outcomes, even when adjusted for traditional risk factors. Recently, PRSs have shown better prediction of CAD outcomes than any single traditional risk factor alone. Advances in statistical methods used to generate PRSs have improved their predictive ability and transferability between populations with varied ancestries. Initial clinical studies have also demonstrated the potential of genetic information to impact shared decision-making between patients and providers, leading to improved outcomes.PRSs can improve risk stratification for CAD especially in white/European populations and have the potential to alter routine clinical care. However, unlocking this potential will require additional research in PRSs in nonwhite populations and substantial investment in clinical implementation studies.

Additional file 1: Supplementary Methods. Figure S1. Overview of the SPRY2 locus. Figure S2. Exon organisation of SPRY2 gene. Figure S3. Examples of DNA mutations generated following CRISPR-Cas9 genome editing for SPRY2 in HepG2 cells. Figure S4. SPRY2 KO increases glucose uptake in HepG2 cells. Figure S5. Increased lipid droplet accumulation following SPRY2 KO in HepG2 cells. Figure S6. SPRY2 KO does not alter protein kinase phosphorylation in HepG2 cells. Figure S7. Alterations in the expression of key genes involved in glucose transport, lipogenesis and glycolysis following SPRY2 KO in HepG2 cells. Figure S8. Confirmation of CRISPR-Cas9 genome editing for SPRY2. Table S1. Primer sequences for RT-qPCR.

Several epidemiological studies have shown an increased risk of atrial fibrillation in individuals with type 2 diabetes or milder forms of dysglycaemia. We aimed to assess whether this relation is causal using a Mendelian randomisation approach. Two-sample Mendelian randomisation was used to obtain estimates of the influence of type 2 diabetes, fasting blood glucose (FBG), and HbA1c on the risk of atrial fibrillation. Instrumental variables were constructed using available summary statistics from meta-analyses of genome-wide association studies (GWAS) for type 2 diabetes and associated phenotypes. Pleiotropic SNPs were excluded from the analyses. The most recent GWAS meta-analysis summary statistics for atrial fibrillation, which included over 1 million individuals (approximately 60,000 individuals with atrial fibrillation) was used for outcome analysis. Neither type 2 diabetes (OR 1.01 [95% CI 0.98, 1.03]; p = 0.37), nor FBG (OR 0.95 [95% CI 0.82, 1.09] per mmol/l; p = 0.49) or HbA1c (OR 1.01 [95% CI, 0.85, 1.17] per mmol/mol [%]; p = 0.88) were associated with atrial fibrillation in Mendelian randomisation analyses. We had >80% statistical power to detect ORs of 1.08, 1.06 and 1.09 or larger for type 2 diabetes, FBG and HbA1c, respectively, for associations with atrial fibrillation. This Mendelian randomisation analysis does not support a causal role of clinical significance between genetically programmed type 2 diabetes, FBG or HbA1c and development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective strategy for atrial fibrillation prevention. The datasets analysed during the current study are available from the following repository: Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al (2018) GWAS summary statistics for AF (N=60,620 AF cases and 970,216 controls). Center for Statistical Genetics: http://csg.sph.umich.edu/willer/public/afib2018/nielsen-thorolfsdottir-willer-NG2018-AFib-gwas-summary-statistics.tbl.gz

BACKGROUND: PCSK9 inhibition is a potent new therapy for hypercholesterolemia and cardiovascular disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. METHODS: We tested association of the PCSK9 missense variant rs11591147 with pre-defined phenotypes, and phenome-wide, in 337,536 individuals of British ancestry in the United Kingdom Biobank (UKB), with independent discovery and replication. Using a Bayesian statistical method, we leveraged phenotype correlations to evaluate the phenome-wide impact of PCSK9 inhibition with higher power at a finer resolution. RESULTS: The T allele of rs11591147 showed a protective effect on hyperlipidemia (OR = 0.63±0.04, p = 2.32×10(−38)), coronary heart disease (OR = 0.73±0.09, p = 1.05×10(−6)) and ischemic stroke (OR = 0.61±0.18, p = 2.40×10(−3)), and was associated with increased type 2 diabetes (T2D) risk adjusted for lipid-lowering medication status (OR = 1.24±0.10, p = 1.98×10(−7)). We did not observe associations with cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. Leveraging phenotype correlations, we observed evidence of a protective association with cerebral infarction and vascular occlusion. These results explore the effects of direct PCSK9 inhibition; off-target effects cannot be predicted using this approach. CONCLUSIONS: This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke, and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to low density lipoprotein cholesterol, atherosclerosis and T2D, suggesting that other effects are either small or absent.

BackgroundUrine biomarkers, such as creatinine, microalbumin, potassium and sodium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease and diabetes mellitus. Knowledge about the genetic determinants of the levels of these biomarker may shed light on pathophysiological mechanisms underlying the development of these diseases.MethodsWe performed genome-wide association studies of urinary levels of creatinine, microalbumin, potassium, and sodium in up to 326,441 unrelated individuals of European ancestry from the UK Biobank, a large population-based cohort study of over 500,000 individuals recruited across the United Kingdom in 2006-2010. Further, we explored genetic correlations, tissue-specific gene expression and possible causal genes related to these biomarkers.ResultsWe identified 23 genome-wide significant independent loci associated with creatinine, 20 for microalbumin, 12 for potassium, and 38 for sodium. We confirmed several established associations including between the CUBN locus and microalbumin (rs141640975, p=3.11e-68). Variants associated with the levels of urinary creatinine, potassium, and sodium mapped to loci previously associated with obesity (GIPR, rs1800437, p=9.81e-10), caffeine metabolism (CYP1A1, rs2472297, p=1.61e-8) and triglycerides (GCKR, rs1260326, p=4.37e-16), respectively. We detected high pairwise genetic correlation between the levels of four urinary biomarkers, and significant genetic correlation between their levels and several anthropometric, cardiovascular, glycemic, lipid and kidney traits. We highlight GATM as causally implicated in the genetic control of urine creatinine, and GIPR, a potential diabetes drug target, as a plausible causal gene involved in regulation of urine creatinine and sodium.ConclusionWe report 78 novel genome-wide significant associations with urinary levels of creatinine, microalbumin, potassium and sodium in the UK Biobank, confirming several previously established associations and providing new insights into the genetic basis of these traits and their connection to chronic diseases.Author SummaryUrine biomarkers, such as creatinine, microalbumin, potassium and sodium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease and diabetes mellitus. Knowledge about the genetic determinants of the levels of these biomarker may shed light on pathophysiological mechanisms underlying the development of these diseases. Here, we performed genome-wide association studies of urinary levels of creatinine, microalbumin, potassium and sodium in up to 326,441 unrelated individuals of European ancestry from the UK Biobank. Further, we explored genetic correlations, tissue-specific gene expression and possible causal genes related to these biomarkers. We identified 78 novel genome-wide significant associations with urinary biomarkers, confirming several previously established associations and providing new insights into the genetic basis of these traits and their connection to chronic diseases. Further, we highlight GATM as causally implicated in the genetic control of urine creatinine, and GIPR, a potential diabetes drug target, as a plausible causal gene involved in regulation of urine creatinine and sodium. The knowledge arising from our work may improve the predictive utility of the respective biomarker and point to new therapeutic strategies to prevent common diseases.

Coronary artery disease (CAD) is the leading cause of death globally. Genome-wide association studies (GWAS) have identified more than 95 independent loci that influence CAD risk, most of which reside in non-coding regions of the genome. To interpret these loci, we generated transcriptome and whole-genome datasets using human coronary artery smooth muscle cells (HCASMC) from 52 unrelated donors, as well as epigenomic datasets using ATAC-seq on a subset of 8 donors. Through systematic comparison with publicly available datasets from GTEx and ENCODE projects, we identified transcriptomic, epigenetic, and genetic regulatory mechanisms specific to HCASMC. We assessed the relevance of HCASMC to CAD risk using transcriptomic and epigenomic level analyses. By jointly modeling eQTL and GWAS datasets, we identified five genes (SIPA1, TCF21, SMAD3, FES, and PDGFRA) that modulate CAD risk through HCASMC, all of which have relevant functional roles in vascular remodeling. Comparison with GTEx data suggests that SIPA1 and PDGFRA influence CAD risk predominantly through HCASMC, while other annotated genes may have multiple cell and tissue targets. Together, these results provide new tissue-specific and mechanistic insights into the regulation of a critical vascular cell type associated with CAD in human populations.

PCSK9 inhibitors are a potent new therapy for hypercholesterolemia and have been shown to decrease risk of coronary heart disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large well-phenotyped biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. We tested association of the PCSK9 loss-of-function variant rsll591147 (R46L) in a hypothesis-driven 11 phenotype set and a hypothesis-generating 278 phenotype set in 337,536 individuals of British ancestry in the United Kingdom Biobank (UKB), with independent discovery (n = 225K) and replication (n = 112K). In addition to the known association with lipid levels (OR 0.63) and coronary heart disease (OR 0.73), the T allele of rs11591147 showed a protective effect on ischemic stroke (OR 0.61, p = 0.002) but not hemorrhagic stroke in the hypothesis-driven screen. We did not observe an association with type 2 diabetes, cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. In the phenome-wide screen, the variant was associated with a reduction in metabolic disorders, ischemic heart disease, coronary artery bypass graft operations, percutaneous coronary interventions and history of angina. A single variant analysis of UKB data using TreeWAS, a Bayesian analysis framework to study genetic associations leveraging phenotype correlations, also showed evidence of association with cerebral infarction and vascular occlusion. This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke, and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to low density lipoprotein cholesterol and atherosclerosis, suggesting that other effects are either small or absent.

Mitral regurgitation (MR) is a common consequence of ventricular remodeling in heart failure (HF) patients with systolic dysfunction and is associated with diminished survival rates. Characterization of patient-specific anatomy and function of the regurgitant mitral valve (MV) can enhance surgical decision making in terms of medical device choice and deployment strategy for minimally invasive endovascular approaches for MV repair. As a first step toward pre-operative planning for MV repair, we examine the feasibility of using cardiac magnetic resonance (CMR) images acquired in multiple orientations to resolve leaflet function and timing. In this study, MV motion of a HF patient with ischemic heart disease exhibiting both adverse ventricular remodeling and MR was compared pre-operatively against a normal control from the Sunnybrook cardiac database, starting with manually segmented 2D MV contours from cine CMR images acquired in multiple orientations. We find that MV motion analysis from CMR imaging is feasible and anatomical reconstruction using oriented segmentations from a combination of imaging slices acquired in multiple orientations can help overcome inherent limitations of CMR image data in terms of resolving small anatomical features, owing to finite slice-thicknesses and partial volume effects.Copyright © 2014 by ASME

OBJECTIVES: The ideal vascular reconstruction strategy for anomalies associated with Tetralogy of Fallot (ToF) is often driven by observations made at the operating table. A method to conduct accurate studies to assess the virtues of a certain surgical technique to guide surgical decisions is found wanting. We hypothesize that patient-specific computed tomography (CT)-based morphometry followed by in silico reconstruction of viable surgical options with haemodynamic function assessment using computational fluid dynamics (CFD) can guide surgical decisions and help forecast functional outcomes without invasive measurements. METHODS: A ToF patient associated with additional left pulmonary artery (LPA) stenosis and a patent ductus arteriosus (PDA) who underwent a successful correction using a single pericardial patch (SPP) was selected as a reference for morphological characterization after 3D anatomical reconstruction from CT images. A second patient with morphological similarities established after scaled, co-registration with the reference patient was selected for virtual correction using the same strategy (i.e. SPP repair). CFD was employed for functional analysis of pulmonary artery (PA) pressure gradients in the baseline preoperative and virtually corrected models, using patient-specific cardiac output and Qp/Qs information. RESULTS: SPP repair was modelled in silico following surgical steps of PDA ligation, creation of an incision along the LPA and main PA (MPA) and finally suturing a rectangular SPP, effectively reducing MPA to LPA angle. Analysis of SPP repair revealed significant reduction in right ventricular outflow tract-LPA pressure gradient with improved left–right PA flow distribution in both patients. CONCLUSIONS: In silico surgery followed by CFD evaluation has the potential in augmenting morphology-guided decisions on surgical strategy and holds promise in preoperatively determining optimal intervention strategy. This is a paradigm-shifting concept to evaluate patient-specific anomalies in a manner more objective than mere visual inspection of anatomical traits from radiology images. Present studies are focused on an analysis with a larger patient cohort to establish a library of ToF patients’ successful surgical outcomes to inform morphology-based selection of surgical strategy.

Background Military personnel and civilians living in areas of armed conflict have increased risk of exposure to blast overpressures that can cause significant hearing loss and/or brain injury. The equipment used to simulate comparable blast overpressures in animal models within laboratory settings is typically very large and prohibitively expensive. New method To overcome the fiscal and space limitations introduced by previously reported blast wave generators, we developed a compact, low-cost blast wave generator to investigate the effects of blast exposures on the auditory system and brain. Results The blast wave generator was constructed largely from off the shelf components, and reliably produced blasts with peak sound pressures of up to 198 dB SPL (159.3 kPa) that were qualitatively similar to those produced from muzzle blasts or explosions. Exposure of adult rats to 3 blasts of 188 dB peak SPL (50.4 kPa) resulted in significant loss of cochlear hair cells, reduced outer hair cell function and a decrease in neurogenesis in the hippocampus. Comparison to existing methods Existing blast wave generators are typically large, expensive, and are not commercially available. The blast wave generator reported here provides a low-cost method of generating blast waves in a typical laboratory setting. Conclusions This compact blast wave generator provides scientists with a low cost device for investigating the biological mechanisms involved in blast wave injury to the rodent cochlea and brain that may model many of the damaging effects sustained by military personnel and civilians exposed to intense blasts.

[This corrects the article DOI: 10.7759/cureus.50541.]., Competing Interests: No competing interests declared., (Copyright © 2024, Gugnani et al.)