Facing the Center: Toward an Identity Poltiics of One-To-One Mentoring

In the diversity of their clients as well as their professional and student staff, writing centers present a complicated set of relationships that inevitably affect the instruction they offer. In Facing the Center, Harry Denny unpacks the identity matrices that enrich teachable moments, and he explores the pedagogical dynamics and implications of identity within the writing center. The face of the writing center, be it mainstream or marginal, majority or miority, orthodox or subversive, always has implications for teaching and learning. Facing the Center will extend current research in writing center theory to bring it in touch with theories now common in cultural studies curricula. Denny takes up issues of power, agency, language, and meaning, and pushes his readers to ask how they themselves, or the centers in which they work, might be perpetuating cultures that undermine inclusive, progressive education.https://digitalcommons.usu.edu/usupress_pubs/1167/thumbnail.jp

Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort:A phenome-wide mendelian randomization study

BACKGROUND: The role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; however, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance. METHODS AND FINDINGS: A phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic model (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 unrelated White British individuals (54% female) in the UK Biobank who were aged 40-69 years (mean age, 56.87; SD, 7.99) when recruited from 2006 to 2010. Mendelian randomization (MR) analyses were performed to replicate significant findings using various genome-wide association study (GWAS) consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for urate. PheWAS analysis, examining the association with 1,431 disease outcomes, identified 13 distinct phecodes representing 4 disease groups (inflammatory polyarthropathies, hypertensive disease, circulatory disease, and metabolic disorders) and 9 disease outcomes (gout, gouty arthropathy, pyogenic arthritis, essential hypertension, coronary atherosclerosis, ischemic heart disease, chronic ischemic heart disease, myocardial infarction, and hypercholesterolemia) that were associated with genetically determined serum urate levels after multiple testing correction (p < 3.35 × 10-4). TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases, and blood lipid levels but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with CVDs. The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and possible misclassification of cases for mild disease that did not require hospitalization. CONCLUSION: In this study, high serum urate levels were found to be associated with increased risk of different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a common mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Phenome-wide association study (PheWAS) on the genetic determinants of serum urate level and disease outcomes in UK Biobank

IntroductionElevated serum uric acid (SUA) concentration, known as hyperuricaemia, is a common abnormity in individuals with metabolic disorders. There is increasing evidence supporting the link between high SUA level and the increased risk of a wide range of clinical disorders, including hypertension, cardiovascular diseases (CVD), chronic renal diseases and metabolic syndrome. Although there are considerable research efforts in understanding the pathogenic pathways of high SUA level and the related clinical consequences, their causal relationships have not been established except for gout. Like other complex traits, genetic determinants play a substantial role (an estimated heritability of 40-70%) in the regulation of SUA level. Investigating the role of genetic variants related to SUA in various diseases might provide evidence for the above hypothesis which links uric acid to clinical disorders. Method Umbrella review was carried out first to provide a comprehensive overview on the range of health outcomes in relation to SUA level by incorporating evidence from systematic reviews and meta-analyses of observational studies, meta-analyses of randomised controlled trials (RCTs), and Mendelian randomisation (MR) studies. The umbrella review summarised the range of related health outcomes, the magnitude, direction and significance of identified associations and effects, and classified the evidence into four categories (class I [convincing], II [highly suggestive], III [suggestive], and IV [weak]) with assessment of multiple sources of biases. Then, a MR-PheWAS (Phenome-wide association study incorporated with Mendelian randomisation [MR]) was performed to investigate the associations between the 31 SUA genetic risk variants and a very wide range of disease outcomes by using the interim release data of UK Biobank (n=120,091). The SUA genetic risk loci were employed as instruments individually. The framework of phenome was defined by the PheCODE schema using the International Classification of Diseases (ICD) diagnosis codes documented in the health records of UK Biobank. Phenome-wide association test was performed first to identify any association across the SUA genetic risk loci and the phenome; MR design and HEIDI (heterogeneity in dependent instruments) tests were then applied to distinguish the PheWAS associations that were due to causality, pleiotropy or genetic linkage.To validate the MR-PheWAS findings, an enlarged Phenome-wide Mendelian randomisation (PWMR) analysis were performed by using data from the full UK Biobank cohort (n=339,256). A weighted polygenic risk score (GRS), incorporating effect estimates of multiple genetic risk loci, was employed as a proxy of the SUA level. The framework of phenome was defined by both the PheCODE schema and an alternative Tree-structured phenotypic model (TreeWAS) for analysis. Significant associations from these analyses were taken forward for replication in different populations by analysing data from various GWAS consortia documented in the MR-base database. Sensitivity analyses examining the pleiotropic effects of urate genetic risk loci on a set of metabolic traits were performed to explore any causal effects and pleiotropic associations.ResultsThe umbrella review included 101 articles and comprised 144 meta-analyses of observational studies, 31 meta-analyses of randomised controlled trials and 107 Mendelian randomisation studies. This remarkable assembly of evidence explored 136 unique health outcomes and reported convincing (class I) evidence for the causal role of SUA in gout and nephrolithiasis. Furthermore, highly suggestive (class II) evidence was reported for five health outcomes, in which high SUA level was associated with increased risk of heart failure, hypertension, impaired fasting glucose or diabetes, chronic kidney disease, and coronary heart disease mortality in the general population. The remaining 129 associations were classified as either suggestive or weak. The MR-PheWAS (using the interim release cohort) identified 25 disease groups/ outcomes to be associated with SUA genetic risk loci after multiple testing correction (p<8.6 ×10-5). The MR IVW (inverse variance weighted) analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI: 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI: 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI: 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI: 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI: 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI: 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI: 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. The analysis also highlighted a locus (ATXN2/S2HB3) that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy.The PWMR analysis, using data from the full UK Biobank cohort (n=339,256), examining the association with 1,431 disease outcomes, identified 13 phecodes that were associated with the weighted GRS of SUA level with the p value passing the significance threshold of PheWAS (p<3.4×10-4). These phecodes represent 4 disease groups: inflammatory polyarthropathies (OR=1.28; 95% CI: 1.21 to 1.35; p=4.97×10-19), hypertensive disease (OR=1.08; 95% CI: 1.05 to 1.11; p=6.02×10-7), circulatory disease (OR=1.05; 95% CI: 1.02 to 1.07; p=3.29×10-4) and metabolic disorders (OR=1.07; 95% CI: 1.03 to 1.11; p= 3.33×10-4), and 9 disease outcomes: gout (OR=5.37; 95% CI: 4.67 to 6.18; p= 4.27×10-123), gouty arthropathy (OR=5.11; 95% CI: 2.45 to 10.66; p=1.39×10-5), pyogenic arthritis (OR=2.10; 95% CI: 1.41 to 3.14; p=2.87×10-4), essential hypertension (OR=1.08; 95% CI: 1.05 to 1.11; p=6.62×10-7), coronary atherosclerosis (OR=1.10; 95% CI: 1.05 to 1.15; p=1.17×10-5), ischaemic heart disease (OR=1.10, 95% CI: 1.05 to 1.15; p=1.73×10-5), chronic ischaemic heart disease (OR=1.10, 95% CI: 1.05 to 1.15; p=1.52×10-5), myocardial infarction (OR=1.15, 95% CI=1.07 to 1.23, p=5.23×10-5), and hypercholesterolaemia (OR=1.08, 95% CI: 1.04 to 1.13, p=3.34×10-4). Findings from the TreeWAS analysis were generally consistent with that of PheWAS, with a number of more sub-phenotypes being identified. Results from IVW MR suggested that genetically determined high serum urate level was associated with increased risk of gout (OR=4.53, 95%CI: 3.64-5.64, p=9.66×10-42), CHD (OR=1.10, 95%CI: 1.02 to 1.19, p=0.009), myocardial infarction (OR=1.11, 95%CI:1.02 to 1.20, p=0.011) and decreased level of HDL-c (OR=0.93, 95%CI:0.88 to 0.98, p=0.004), but had no effect on RA (OR=0.92, 95%CI: 0.84 to 1.01, p=0.085) and ischaemic stroke (OR=1.03, 95%CI: 0.93 to 1.14, P= 0.582). Egger MR indicated pleiotropic effects on the causal estimates of DBP (P_pleiotropy=0.014), SBP (P_pleiotropy=0.003), CHD (P_pleiotropy=0.008), myocardial infarction (P_pleiotropy=0.008) and HDL-c (P_pleiotropy=0.016). When balancing out the potential pleiotropic effects in Egger MR, a causal effect can only be verified for gout (OR=4.17, 95%CI: 3.03 to 5.74, P_effect=1.27×〖10〗^(-9); P_pleiotropy=0.485). Sensitivity analyses on the GRSs of different groups of pleiotropic loci support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observed associations with cardiovascular/metabolic diseases. ConclusionsThis thesis presents a comprehensive investigation on the health outcomes in relation to SUA level. The causal relationship between high SUA level and gout is robustly verified in this thesis with consistent evidence from the umbrella review, the MR-PheWAS and the PWMR. The association of high SUA level with hypertension and heart diseases is supported by both the evidence from umbrella review and analyses conducted in this thesis, however, given the caveat of pleiotropy in the causal inference, a conclusion of causality on hypertension and heart diseases is not robust enough based on the current findings. Furthermore, the epidemiological evidence from the umbrella review indicated that high SUA level was associated with several components of metabolic disorders, and the analyses of the UK Biobank data identified a significant association with metabolic disorders and a sub-phenotype (hypercholesterolaemia). The causal inference in this study is limited by the common difficulty of pleiotropy caused by the use of multiple genetic instruments. Although we have performed sensitivity analysis by excluding the key pleiotropic locus, unmeasured pleiotropy and biases are still possible. In particular, unbalanced pleiotropy is recognised as an issue for the causal connections on the association between SUA level and hypertension. Other potential causal relevance of SUA level with respiratory diseases and ocular diseases is also worthy of further investigation. Overall, when taken together the findings from umbrella review, MR-PheWAS, PheWAS/TreeWAS analysis, MR replication and sensitivity analysis conducted in this thesis, I conclude that there are robust associations between urate and several disease groups, including gout, hypertensive diseases, heart diseases and metabolic disorders, but the causal role of urate only exists in gout. This study indicates that the observed associations between urate and cardiovascular/metabolic diseases are probably derived from the pleiotropic effects of genetic variants on urate and metabolic traits. Further investigation of therapies targeting the shared biological pathways between urate and metabolic traits may be beneficial for the treatment of gout and the primary prevention of cardiovascular/metabolic diseases

Administration of Thimerosal to Infant Rats Increases Overflow of Glutamate and Aspartate in the Prefrontal Cortex: Protective Role of Dehydroepiandrosterone Sulfate

Thimerosal, a mercury-containing vaccine preservative, is a suspected factor in the etiology of neurodevelopmental disorders. We previously showed that its administration to infant rats causes behavioral, neurochemical and neuropathological abnormalities similar to those present in autism. Here we examined, using microdialysis, the effect of thimerosal on extracellular levels of neuroactive amino acids in the rat prefrontal cortex (PFC). Thimerosal administration (4 injections, i.m., 240 μg Hg/kg on postnatal days 7, 9, 11, 15) induced lasting changes in amino acid overflow: an increase of glutamate and aspartate accompanied by a decrease of glycine and alanine; measured 10–14 weeks after the injections. Four injections of thimerosal at a dose of 12.5 μg Hg/kg did not alter glutamate and aspartate concentrations at microdialysis time (but based on thimerosal pharmacokinetics, could have been effective soon after its injection). Application of thimerosal to the PFC in perfusion fluid evoked a rapid increase of glutamate overflow. Coadministration of the neurosteroid, dehydroepiandrosterone sulfate (DHEAS; 80 mg/kg; i.p.) prevented the thimerosal effect on glutamate and aspartate; the steroid alone had no influence on these amino acids. Coapplication of DHEAS with thimerosal in perfusion fluid also blocked the acute action of thimerosal on glutamate. In contrast, DHEAS alone reduced overflow of glycine and alanine, somewhat potentiating the thimerosal effect on these amino acids. Since excessive accumulation of extracellular glutamate is linked with excitotoxicity, our data imply that neonatal exposure to thimerosal-containing vaccines might induce excitotoxic brain injuries, leading to neurodevelopmental disorders. DHEAS may partially protect against mercurials-induced neurotoxicity

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Abstract: Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate