Low Serum Testosterone Is Associated with Increased Mortality in Men with Stage 3 or Greater Nephropathy

Background: Chronic kidney disease (CKD) and low serum total testosterone (TT) concentrations are independent predictors of mortality risk in the general population, but their combined potential for improved mortality risk stratification is unknown. Methods: We used data of 1,822 men from the population-based Study of Health in Pomerania followed- up for 9.9 years (median). The direct effects of kidney dysfunction (estimated glomerular filtration rate 2), albuminuria (urinary albumin-creatinine ratio ≧2.5 mg/mmol) and their combination (CKD) on all-cause and cardiovascular mortality were analyzed using multivariable Cox regression models. Serum TT concentrations below the age-specific 10th percentile (by decades) were considered low and were used for further risk stratification. Results: Kidney dysfunction (hazard ratio, HR, 1.40; 95% confidence interval, CI, 1.02–1.92), albuminuria (HR, 1.38; 95% CI, 1.06–1.79), and CKD (HR, 1.42; 95% CI, 1.09–1.84) were associated with increased all-cause mortality risk, while only kidney dysfunction (HR, 2.01; 95% CI, 1.21–3.34) was associated with increased cardiovascular mortality risk after multivariable adjustment. Men with kidney dysfunction and low TT concentrations were identified as high-risk individuals showing a more than 2-fold increased all-cause mortality risk (HR, 2.52; 95% CI, 1.08–5.85). Added to multivariable models, nonsignificant interaction terms suggest that kidney dysfunction and low TT are primarily additive rather than synergistic mortality risk factors. Conclusion: In the case of early loss of kidney function, measured TT concentrations might help to detect high-risk individuals for potential therapeutic interventions and to improve mortality risk assessment and outcome

The Composition of the Modernist Book: Ulysses, A Draft of XXX Cantos and The Making of Americans.

This is a study of the composition of three Modernist first editions: Ulysses (1922), The Making of Americans (1925) and A Draft of XXX Cantos (1930). The bibliographical and figurative commitments made to being in print by Ulysses, A Draft of XXX Cantos and The Making of Americans set a coherent program for reading Modernist texts in their perfected form: in print. The editorial reception of the Modernist book has proceeded, however, with reference to the editorial and bibliographical principles established by the New Bibliographers. In deferring to the authors and manuscripts of Modernist books as the highest source of textual authority, the vital significance of being in print to literary Modernism is obscured. The figure of the ideal Book concentrates the central aesthetic, intellectual and bibliographic problem posed the Modernist book: the making of literature. The rhyme with The Making of Americans is appropriate: this book intensifies and consolidates the propositions made about objective and autonomous composition made more hesitantly by Ulysses and A Draft of XXX Cantos. These three books display a gradual refusal to equate inscription and intention; their composition effaces all traces of a sovereign creative subjectivity. The vision of the book guides Modernist composition, and requires a critical distinction be drawn between manuscripts and printed letters. Modernism must be read in print. The vestigial nostalgia for Romantic modes of textual production and creation in Ulysses is repeated on the placards and proof-pages for the book. Printed drafts are revised and reformed by the pen of the author. The finality asserted by the printed letter is only reluctantly ceded on the publication of Ulysses. The composition of A Draft of XXX Cantos represents a further transition away from the script economy of Romanticism. The interplay between authorial typescripts, early publications and the first edition of A Draft of XXX Cantos assert an intermediate order of Modernist textuality which takes the printed page as its foundation. The Making of Americans relies on the absolute objectivity and anonymity of its composition for the effect of its narrative. Objectivity is the intellectual and aesthetic strategy which produces literature rather than the personality and memory of the author. The impersonality of the apparently automatically written manuscripts and scarcely revised typescripts for The Making of Americans severs the visible links between the writing author and her page. In their unwillingness to corroborate the modes of textual generation described by the New Bibliographers, these three books thematise their own composition as the exemplary Modernist and modern mode of textual generation. The Modernist book attenuates or denies a Romantic connection between the creative hand of the author and the surface image of the page: the mechanisms of print deliberately detach the author from the literary text. The distance of the author from the scene of textual reproduction is measured by the printed book. The composition of this analytical object is not a fallacy but an actuality, commemorated in the archive, enacted by the book. Modernism is the literature of the imprimatur rather than of authorial inscription and accordingly it is towards the first editions of Modernist texts that the attentions of editors and textual scholars must be directed

Comparison of genotyping using pooled DNA samples (allelotyping) and individual genotyping using the affymetrix genome-wide human SNP array 6.0

Background: Genome-wide association studies (GWAS) using array-based genotyping technology are widely used to identify genetic loci associated with complex diseases or other phenotypes. The costs of GWAS projects based on individual genotyping are still comparatively high and increase with the size of study populations. Genotyping using pooled DNA samples, as also being referred as to allelotyping approach, offers an alternative at affordable costs. In the

Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality

Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases

Gender differences in the association of individual social class and neighbourhood unemployment rate with prevalent type 2 diabetes mellitus: a cross-sectional study from the DIAB-CORE consortium

OBJECTIVE: To analyse gender differences in the relationship of individual social class, employment status and neighbourhood unemployment rate with present type 2 diabetes mellitus (T2DM). DESIGN: Five cross-sectional studies. SETTING: Studies were conducted in five regions of Germany from 1997 to 2006. PARTICIPANTS: The sample consisted of 8871 individuals residing in 226 neighbourhoods from five urban regions. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalent T2DM. RESULTS: We found significant multiplicative interactions between gender and the individual variables–—social class and employment status. Social class was statistically significantly associated with T2DM in men and women, whereby this association was stronger in women (lower vs higher social class: OR 2.68 (95% CIs 1.66 to 4.34)) than men (lower vs higher social class: OR 1.78 (95% CI 1.22 to 2.58)). Significant associations of employment status and T2DM were only found in women (unemployed vs employed: OR 1.73 (95% CI 1.02 to 2.92); retired vs employed: OR 1.77 (95% CI 1.10 to 2.84); others vs employed: OR 1.64 (95% CI 1.01 to 2.67)). Neighbourhood unemployment rate was associated with T2DM in men (high vs low tertile: OR 1.52 (95% CI 1.18 to 1.96)). Between-study and between-neighbourhood variations in T2DM prevalence were more pronounced in women. The considered covariates helped to explain statistically the variation in T2DM prevalence among men, but not among women. CONCLUSIONS: Social class was inversely associated with T2DM in both men and women, whereby the association was more pronounced in women. Employment status only affected T2DM in women. Neighbourhood unemployment rate is an important predictor of T2DM in men, but not in women

Investigating the genetic and environmental basis of head micromovements during MRI

Introduction Head motion during magnetic resonance imaging is heritable. Further, it shares phenotypical and genetic variance with body mass index (BMI) and impulsivity. Yet, to what extent this trait is related to single genetic variants and physiological or behavioral features is unknown. We investigated the genetic basis of head motion in a meta-analysis of genome-wide association studies. Further, we tested whether physiological or psychological measures, such as respiratory rate or impulsivity, mediated the relationship between BMI and head motion.Methods We conducted a genome-wide association meta-analysis for mean and maximal framewise head displacement (FD) in seven population neuroimaging cohorts (UK Biobank, LIFE-Adult, Rotterdam Study cohort 1-3, Austrian Stroke Prevention Family Study, Study of Health in Pomerania; total N = 35.109). We performed a pre-registered analysis to test whether respiratory rate, respiratory volume, self-reported impulsivity and heart rate mediated the relationship between BMI and mean FD in LIFE-Adult.Results No variant reached genome-wide significance for neither mean nor maximal FD. Neither physiological nor psychological measures mediated the relationship between BMI and head motion.Conclusion Based on these findings from a large meta-GWAS and pre-registered follow-up study, we conclude that the previously reported genetic correlation between BMI and head motion relies on polygenic variation, and that neither psychological nor simple physiological parameters explain a substantial amount of variance in the association of BMI and head motion. Future imaging studies should thus rigorously control for head motion at acquisition and during preprocessing

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research