Showing papers by "Winfried März published in 2018"
Gregory A. Roth1, Gregory A. Roth2, Degu Abate3, Kalkidan Hassen Abate4 +1025 more•Institutions (333)
TL;DR: Non-communicable diseases comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5–74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional causes accounted for 18·6% (17·9–19·6), and injuries 8·0% (7·7–8·2).
5,211 citations
Jeffrey D. Stanaway1, Ashkan Afshin1, Emmanuela Gakidou1, Stephen S Lim1 +1050 more•Institutions (346)
TL;DR: This study estimated levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs) by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017 and explored the relationship between development and risk exposure.
2,910 citations
Christopher J L Murray1, Charlton S K H Callender1, Xie Rachel Kulikoff1, Vinay Srinivasan1 +1092 more•Institutions (424)
TL;DR: This work estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods and used the cohort-component method of population projection, with inputs of fertility, mortality, population, and migration data.
287 citations
Harvard University1, Karolinska Institutet2, King's College London3, Pasteur Institute4, Massachusetts Institute of Technology5, National Institutes of Health6, Boston University7, Uppsala University8, Stanford University9, Medical University of Graz10, University College London11, University of Cambridge12, University of Maryland, Baltimore13, University of Minnesota14, Indiana University – Purdue University Indianapolis15, Greifswald University Hospital16, University of South Australia17, University of Oxford18, Johns Hopkins University19, University of Texas Health Science Center at Houston20, University of Amsterdam21, Erasmus University Rotterdam22, Wageningen University and Research Centre23, Tufts University24, University of Helsinki25, University of Gothenburg26, Wake Forest University27, Leiden University28, Max Planck Society29, Heidelberg University30, Synlab Group31, University of Washington32, United States Department of Agriculture33, University of California, Los Angeles34, University of Virginia35, Vanderbilt University36, University of Oulu37, Imperial College London38, Queen Mary University of London39, University of Edinburgh40, Trinity College, Dublin41, University of Nottingham42, University of Turku43, Academy of Finland44, Analytical Services45, Wellcome Trust Sanger Institute46
TL;DR: In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
256 citations
Geneva College1, Imperial College London2, Sahlgrenska University Hospital3, University of Gothenburg4, University of Milan5, National Institutes of Health6, University of Western Ontario7, Emory University8, Children's Hospital Oakland Research Institute9, Leipzig University10, University of Toronto11, University of Graz12, Heidelberg University13, Copenhagen University Hospital14, University of Copenhagen15, University of the Witwatersrand16, University of Düsseldorf17, University of São Paulo18, Hartford Hospital19, Hacettepe University20, State University of New York System21, Columbia University22
TL;DR: Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above, and the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.
Abstract: Aims
To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract.
228 citations
Karolinska Institutet1, Harvard University2, King's College London3, Pasteur Institute4, Massachusetts Institute of Technology5, Boston University6, National Institutes of Health7, Uppsala University8, Stanford University9, Medical University of Graz10, University College London11, University of Cambridge12, University of Maryland, Baltimore13, University of Minnesota14, Indiana University – Purdue University Indianapolis15, Greifswald University Hospital16, University of South Australia17, University of Oxford18, Johns Hopkins University19, University of Texas Health Science Center at Houston20, University of Amsterdam21, Erasmus University Rotterdam22, Wageningen University and Research Centre23, Tufts University24, University of Helsinki25, University of Gothenburg26, Wake Forest University27, Leiden University28, Max Planck Society29, Heidelberg University30, Synlab Group31, University of Washington32, United States Department of Agriculture33, University of California, Los Angeles34, University of Virginia35, Vanderbilt University36, Imperial College London37, University of Oulu38, Queen Mary University of London39, University of Edinburgh40, Trinity College, Dublin41, University of Nottingham42, University of Turku43, Academy of Finland44, Analytical Services45, Wellcome Trust Sanger Institute46
TL;DR: The SUNLIGHT Consortium GWAS of serum 25-hydroxyvitamin D concentrations has identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, and CYP24A1) as mentioned in this paper.
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
202 citations
Imperial College London1, Central European Institute of Technology2, University of the Witwatersrand3, University of São Paulo4, University of Manchester5, University of Western Australia6, Saint Joseph's University7, Hamad Medical Corporation8, Sultan Qaboos University9, Medical University of Vienna10, Oslo University Hospital11, Institute of Chartered Accountants of Nigeria12, Gdańsk Medical University13, Hebrew University of Jerusalem14, Ljubljana University Medical Centre15, McGill University Health Centre16, Ege University17, University of Belgrade18, National University of Singapore19, University of Latvia20, University of Ioannina21, Capital Medical University22, National Health Laboratory Service23, Heidelberg University24, Kyrgyz State Medical Academy25, University of Basel26, Academy of Medical Sciences, United Kingdom27, Universiti Teknologi MARA28, University of Copenhagen29, University of Debrecen30, Vilnius University31, Sofia Medical University32, University of Zagreb33, University of Benin34, Mashhad University of Medical Sciences35, United Arab Emirates University36, National Taiwan University37, Khoo Teck Puat Hospital38, University of Malta39, The Chinese University of Hong Kong40, National Institutes of Health41, Universidad Autónoma de Guadalajara42, Tallinn University of Technology43, Slovak Medical University44, University of Helsinki45, Osaka University46, Medical University of Łódź47, Linköping University48, University of the Philippines49, Technische Universität München50, Hacettepe University51, Nanyang Technological University52, University of Milan53
TL;DR: FH is a recognised public health concern, with overall suboptimal identification and under-treatment, and efforts and initiatives to improve FH knowledge and management are underway, but support from health authorities and better funding are greatly needed.
161 citations
TL;DR: The majority of studies did not find significant associations between LTL, bone mineral density (BMD) and osteoporosis and reviews existing knowledge regarding the relationship between telomere length and age-related diseases.
Abstract: Telomeres are the protective end caps of chromosomes and shorten with every cell division. Telomere length has been proposed as a biomarker of biological age and a risk factor for age-related diseases. Epidemiologic studies show an association between leukocyte telomere length (LTL) and mortality. There is solid evidence that links LTL with cardiovascular disease. Short telomeres promote atherosclerosis and impair the repair of vascular lesions. Alzheimer's disease patients have also a reduced LTL. Telomeres measured in tumor tissue from breast, colon and prostate are shorter than in healthy tissue from the same organ and the same patient. In healthy tissue directly adjacent to these tumors, telomeres are also shorter than in cells that are more distant from the cancerous lesion. A reduced telomere length in cancer tissue from breast, colon and prostate is associated with an advanced disease state at diagnosis, faster disease progression and poorer survival. By contrast, results regarding LTL and cancer are inconsistent. Furthermore, the majority of studies did not find significant associations between LTL, bone mineral density (BMD) and osteoporosis. The present manuscript gives an overview about our current understanding of telomere biology and reviews existing knowledge regarding the relationship between telomere length and age-related diseases.
118 citations
TL;DR: It is still not clear whether vitamin D supplementation improves fertility or decreases the risk of adverse pregnancy outcomes such as low birth weight, pre-eclampsia and neonatal mortality, or reduces wheeze/asthma in the infants.
Abstract: Vitamin D deficiency is common and there exists a huge gap between recommended dietary vitamin D intakes and the poor vitamin D supply in the general population. While vitamin D is important for musculoskeletal health, there are accumulating data suggesting that vitamin D may also be important for fertility, pregnancy outcomes and lactation. Significant changes in vitamin D metabolism during pregnancy such as increased production of the “active vitamin D hormone” calcitriol support the important role of vitamin D in this setting. Observational studies show that vitamin D deficiency is a risk marker for reduced fertility and various adverse pregnancy outcomes and is associated with a low vitamin D content of breast milk. Meta-analyses of randomized controlled trials (RCTs) document that physiological vitamin D supplementation during pregnancy is safe and improves vitamin D and calcium status, thereby protecting skeletal health. Although certain RCTs and/or meta-analyses reported some other beneficial effects, it is still not clear whether vitamin D supplementation improves fertility or decreases the risk of adverse pregnancy outcomes such as low birth weight, pre-eclampsia and neonatal mortality, or reduces wheeze/asthma in the infants. Nevertheless, vitamin D supplementation in pregnant women is frequently required to achieve a sufficient vitamin D status as recommended by nutritional vitamin D guidelines. In this review, we provide an overview of systematic reviews, meta-analyses and large trials reporting clinical data on the role of vitamin D for fertility, pregnancy and lactation.
92 citations
TL;DR: In this article, the Cegedim Longitudinal practice database in Germany was used to assess LLT treatment patterns and LDL-C threshold attainment in Germany in a large, real-world cohort of patients.
57 citations
TL;DR: It is of concern that significant sections of the general population do not meet recommended vitamin D levels, and definitely requires action from a public health perspective.
Abstract: Vitamin D is of public health interest because its deficiency is common and is associated with musculoskeletal diseases, as well as extraskeletal diseases, such as cancer, cardiovascular diseases, and infections. Several health authorities have reviewed the existing literature and published nutritional vitamin D guidelines for the general population. There was a wide consensus that serum 25-hydroxyvitamin D [25(OH)D] concentration should be used to assess vitamin D status and intake, and that musculoskeletal, and not extraskeletal, effects of vitamin D should be the basis for nutritional vitamin D guidelines. Recommended target levels for 25(OH)D range from 25 to 50 nmol/l (10 to 20 ng/ml), corresponding to a vitamin D intake of 400 to 800 International Units (10 to 20 μg) per day. It is of concern that significant sections of the general population do not meet these recommended vitamin D levels. This definitely requires action from a public health perspective.
TL;DR: The effects of vitamin D on lipid metabolism are potentially unfavorable and require further investigation in view of the wide use ofitamin D testing and treatment.
TL;DR: The hypothesis that short telomere length increases the risk of all-cause and CVD mortality is supported, although additional adjustment for age attenuated this effect.
Abstract: Introduction Short telomeres have been associated with adverse lifestyle factors, cardiovascular risk factors and age-related diseases, including cardiovascular disease (CVD), myocardial infarction, atherosclerosis, hypertension, diabetes, and also with mortality. However, previous studies report conflicting results. Objectives The aim of the present study has been to investigate the involvement of telomere length in all-cause and CVD mortality in subjects hospitalized for diagnostic coronary angiography of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Methods Relative telomere length (RTL) was measured with a Q-PCR based method in 3,316 participants of the LURIC study. Age-corrected RTL was calculated as the ratio between RTL and age. Median follow-up was 9.9 years. Cox regression and Kaplan-Maier analyses were performed to evaluate the role of RTL for all-cause and cardiovascular mortality. Results RTL correlated negatively with age (r = -0.09; p<0.001). In surviving patients the correlation between age and RTL was statistically significant (r = -0.088; p<0.001), but not in patients who died during follow-up (r = -0.043; p = 0.20). Patients in quartiles 2–4 of RTL had a lower hazard ratio for all-cause mortality (HR:0.822; 95%CI 0.712–0.915; p = 0.008) and CVD-mortality (HR:0.836; 95%CI 0.722–0.969; p = 0.017) when compared to those in the 1st quartile. Adjustment for major cardiovascular risk factors did not change this result, however additional adjustment for age attenuated this effect. Patients in the 4th quartile of age-corrected RTL compared to those in the 1st quartile had a lower hazard ratio for all-cause mortality, even with adjustment for major cardiovascular risk factors. Conclusions The present study supports the hypothesis that short telomere length increases the risk of all-cause and CVD mortality. Age appears to be an important co-variate that explains a substantial fraction of this effect. It remains unclear whether short telomeres contribute directly to the increase in mortality or if they are simply a surrogate marker for other adverse processes of aging.
TL;DR: PCSK9i treatment in addition to standard therapy allows attainment of target values in many patients with initially very high LDL-C, as well as in patients with pre-existing CVD.
TL;DR: There is no convincing evidence that moderate/responsible solarium use increases melanoma risk and current scientific knowledge is mainly based on observational studies with poor quality data, which report associations but do not prove causality.
Abstract: © 2018 International Institute of Anticancer Research. All rights reserved. Background: There is an ongoing debate whether solarium use (indoor tanning/artificial UV) may increase the risk for primary cutaneous malignant melanoma. Aim: A systematic literature search was conducted using MEDLINE and ISI Web of Science. Included studies were critically assessed regarding their risk of bias, and methodological shortcomings. Levels of evidence and grades of recommendation were determined according to guidelines of the Oxford Centre for Evidence-Based Medicine. Summary risk estimates and 95% confidence intervals for four different outcomes (ever exposure, exposure at younger age, high/low exposure vs. non-exposure) were derived from random-effects meta-analyses to account for possible heterogeneity across studies. Results: Two cohort and twenty-nine case-controlstudies were eligible. Overall, quality of included studies was poor as a result of severe limitations, including possible recall and selection bias, and due to lack of interventional trials. Summary risk estimates suggested a weak association (odds ratio (OR)=1.19, 95% confidence interval (CI)=1.04- 1.35, p=0.009) for ever-exposure to UV radiation from a solarium with melanoma risk. However, sensitivity analyses did not show an association for studies from Europe (OR=1.10; 95%CI=0.95-1.27, p=0.218), studies with low risk of bias (OR=1.15; 95%CI=0.94-1.41, p=0.179), and studies conducted after 1990 (OR 1.09; 95%CI=0.93-1.29, p=0.295). Moreover, moderate associations were found for first exposure to UV radiation from a solarium at younger age ( 10 sessions in lifetime) with melanoma risk. However, for all outcomes analyzed, overall study quality and resulting levels of evidence (3a-) and grades of recommendation (D) were low due to lack of interventional studies and severe limitations including unobserved or unrecorded confounding. Conclusion: Current scientific knowledge is mainly based on observational studies with poor quality data, which report associations but do not prove causality. At present, there is no convincing evidence that moderate/responsible solarium use increases melanoma risk.
TL;DR: The data provide the first evidence that a functional variant of VWF plays a role in arterial thromboembolism and emphasize the functional effect of the VWF C4 domain for VWF-mediated platelet aggregation in a shear-dependent manner.
TL;DR: A sex-specific inverse association of T change, but not baseline T, with increased depressive symptom burden in men is observed and future studies should assess longitudinal changes in sex hormone status as predictor of adverse health outcomes related to low T.
Greifswald University Hospital1, Catholic University of the Sacred Heart2, University of Lausanne3, Heidelberg University4, Medical University of Graz5, University of Graz6, Synlab Group7, University of Edinburgh8, Western General Hospital9, University Medical Center Groningen10, University of Freiburg11, Johns Hopkins University12
TL;DR: This study suggests that circulating vitamin D metabolite levels are negatively associated with eGFR, and further studies are needed to elucidate the underlying mechanisms.
Abstract: Background. The kidney plays a central role in the regulation of vitamin D metabolism. It is not clear, however, whether vitamin D influences kidney function. Previous studies have reported conflicting results, which may have been influenced by reverse causation and residual confounding. We conducted a Mendelian randomization (MR) study to obtain unconfounded estimates of the association between genetically instrumented vitamin D metabolites and estimated glomerular filtration rate (eGFR) as well as the urinary albumin: creatinine ratio (UACR). Methods. We performed a two-sample MR study based on three single nucleotide variants associated with 25(OH)D levels: rs2282679, rs10741657 and rs12785878, related to the genes GC, CYP2R1 and DHCR7, respectively. Estimates of the allele-dependent effects on serum 25(OH)D and eGFR/UACR were obtained from summary statistics of published genome-wide association meta-analyses. Additionally, we performed a one-sample MR analysis for both 25(OH)D and 1,25(OH)2D using individual-level data from six cohorts. Results. The combined MR estimate supported a negative causal effect of log transformed 25(OH)D on log transformed eGFR (beta = -0.013, P = 0.003). The analysis of individual-level data confirmed the main findings and also revealed a significant association of 1,25(OH)2D on eGFR (beta = -0.094, P = 0.008). These results show that a 10% increase in serum 25(OH)D levels causes a 0.3% decrease in eGFR. There was no effect of 25(OH)D on UACR (beta = 0.032, P = 0.265). Conclusion. Our study suggests that circulating vitamin D metabolite levels are negatively associated with eGFR. Further studies are needed to elucidate the underlying mechanisms.
TL;DR: The UGT1A1*28 gene variant is associated with lower mortality rates and likely includes mechanism other than bilirubin metabolism, which is in line with previous studies investigating the role of UGT2A1 genotypes in mortality.
Abstract: BACKGROUND Uridine diphosphate glycosyltransferases 1A1 (UGT1A1) plays an essential role in detoxification and excretion of several endogenous and exogenous compounds. A functional polymorphism in the promoter of the UGT1A1 gene (TA repeat insertion, UGT1A1*28, rs3064744) has been associated with reduced UGT1A1 enzyme activity. The purpose of the present study was to investigate the role of UGT1A1 genotypes in mortality. METHODS UGT1A1 genotypes as well as baseline plasma bilirubin levels were analyzed in participants of the Ludwigshafen Risk and Cardiovascular Health study (n=3316). UGT1A1*28 genotypes were determined on an ABI PRISM 3730 genetic analyzer. RESULTS As expected, UGT1A1 genotypes were associated with baseline bilirubin levels (*1/*1 genotype: 9.1±4.6 µmol/L; *1/*28 genotype: 10.8±5.3; *28/*28: 16.9±9.2; p<0.001). During a median follow-up of 10.4 years, 995 subjects (30.0%) died. In a multivariate regression analysis adjusting for age, sex, smoking, type 2 diabetes, dyslipidemia, alanine aminotransferase (ALT) levels and bilirubin levels, the UGT1A1*28 variant predicted lower overall mortality (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.78-0.95; p=0.003). Contrary to expected, higher baseline bilirubin levels predicted increased mortality (HR, 1.014; 95% CI, 1.002-1.025; p=0.019). CONCLUSIONS The UGT1A1*28 gene variant is associated with lower mortality rates. The protective effect of the UGT1A1*28 variant likely includes mechanism other than bilirubin metabolism.
TL;DR: The case of a 10-year-old boy suffering from homozygous familial hypercholesterolemia with generalized atherosclerosis and large xanthomas impressively demonstrates the potential of low-density lipoprotein cholesterol lowering to rapidly regress pathologic cutaneous manifestations of hypercholesterololemia.
TL;DR: Fixed-dose combination drugs (polypills) could increase the medication adherence of patients, reduce risks and prevent cardiovascular events, and fixed-dose combinations showed a superior control of risk factors.
Abstract: Die multifaktorielle Genese kardiovaskularer Erkrankungen hat in der Primar- und Sekundarprophylaxe zur Polypharmazie mit evidenzbasierten Therapeutika wie Statinen, Antihypertensiva und Thrombozytenhemmern gefuhrt. Die Anzahl verschriebener Phamaka korreliert umgekehrt mit der Adharenz, was die Effektivitat der Therapie beeintrachtigen kann. Fixe Kombinationspraparate („Polypill“) konnten die Adharenz der Patienten steigern und damit kardiovaskularen Ereignissen vorbeugen. Literaturrecherche in Medline (via PubMed) und The Cochrane Library sowie der Studiendatenbank ClinicalTrials.gov. In den bisher durchgefuhrten Studien zur kardiovaskularen Primarpravention zeigt die Polypill eine uberlegene Kontrolle der Risikofaktoren (Hypertonie, „Low-density-lipoprotein“-Cholesterin [LDL-C]) gegenuber Placebo und gegenuber einer Standardtherapie aus Einzelpraparaten mindestens eine Nichtunterlegenheit. In der Sekundarpravention zeigen Kombinationspraparate vorwiegend Vorteile bei nichtadharenten Patienten bezuglich Blutdruckkontrolle und Reduktion der LDL-C-Konzentration. Der Nachweis, dass die Polypill die kardiovaskulare Morbiditat und Mortalitat gegenuber einer Standardtherapie absenkt, steht aus. Kombinationspraparate sind nach Risiko-Nutzen-Einschatzung als Alternative zur Polypharmazie, insbesondere bei nichtadharenten Patienten in Erwagung zu ziehen. Inwieweit durch die erwiesene Senkung der Risikofaktoren kardiovaskulare Ereignisse verhindert werden konnen, ist Gegenstand laufender Untersuchungen. Limitiert sind die gegenwartigen Polypills durch eine zu geringe Auswahl an Dosierungen der Einzelwirkstoffe, um eine Uber- und Untertherapie in der individuellen Behandlung zu vermeiden.
TL;DR: The BTP/creatinine ratio was more predictive for all-cause and cardiovascular mortality in haemodialysis patients and individuals referred for angiography compared with BTP as single marker.
Abstract: Background Beta-trace protein (BTP) is a low-molecular-weight glycoprotein, which may serve as an endogenous biomarker of kidney function and cardiovascular risk. Methods We examined cardiovascular and all-cause mortality according to BTP concentrations in 2962 individuals referred for coronary angiography from the Ludwigshafen Risk and Cardiovascular Health study and in 907 patients with Type 2 diabetes mellitus undergoing haemodialysis from the German Diabetes and Dialysis (4D) study. Results Haemodialysis patients had considerably higher median (interquartile range) BTP concentrations [6.00 (4.49-7.96) mg/L] and experienced a 4-fold increased mortality rate compared with coronary angiography patients [BTP concentration: 0.55 (0.44-0.67) mg/L]. After adjustment for age, sex, cardiovascular risk factors and creatinine, 4D patients in the highest quartile (>7.96 mg/L) had a 1.6-fold increased rate of all-cause mortality [hazard ratio (HR) 1.62, 95% confidence interval (CI) 1.19-2.20] compared with the lowest quartile ( 0.67 mg/L) compared with the lowest (<0.44 mg/L) quartile (P = 0.043 and 0.062). In both cohorts, the BTP/creatinine ratio was a stronger predictor of all-cause and cardiovascular mortality compared with BTP. Conclusion BTP was associated with all-cause mortality independently of renal function in haemodialysis patients. The BTP/creatinine ratio was more predictive for all-cause and cardiovascular mortality in haemodialysis patients and individuals referred for angiography compared with BTP as single marker.
TL;DR: The present observational study of a large-scale prospective sample showed no association of T with optimism or pessimism, and further experimental and interventional evidence from alternative methodological approaches would strengthen this conclusion and establish stronger evidence about the potential hormonal basis of psychological traits.
Abstract: Background: Previous experimental research on testosterone (T) and psychological traits is inconclusive. Thus, we performed the first large-scale observational study of the association between T and dispositional optimism / pessimism.
Methods: We used prospective data from 6,493 primary-care patients (3,840 women) of the DETECT study (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment), including repeated immunoassay-based measurement of serum T and optimism / pessimism assessed by the revised Life-Orientation Test (LOT-R). Cross-sectional and longitudinal associations of baseline T and one-year change in T with optimism and pessimism were investigated using age- and multivariable-adjusted regression models.
Results: Cross-sectional analyses showed no association of T with optimism or pessimism in both sexes. Longitudinal analyses also showed no association of baseline T with optimism or pessimism at four-year follow-up. Multivariable analyses of total LOT-R score yielded similarly non-significant results (β-coefficient per unit change in T for men: -0.01 (95% CI: -0.24–0.22), women: 0.08 (-0.03–0.20)). Furthermore, change in T was not related to optimism or pessimism at four-year follow-up.
Conclusions: The present observational study of a large-scale prospective sample showed no association of T with optimism or pessimism. Integrating further experimental and interventional evidence from alternative methodological approaches would strengthen this conclusion and establish stronger evidence about the potential hormonal basis of psychological traits.
01 Sep 2018
10 Dec 2018
TL;DR: PCSK9-Inhibitoren vermögen den LDL-Cholesterin-Spiegel effektiv zu senken und können eingesetzt werden, wenn die Lipidzielwerte mittels Statinen und/oder Ezetimib nicht erreicht werde könten.
Abstract: PCSK9-Inhibitoren vermogen den LDL-Cholesterin-Spiegel effektiv zu senken und konnen eingesetzt werden, wenn die Lipidzielwerte mittels Statinen und/oder Ezetimib nicht erreicht werden konnen. Doch wie kann der Einsatz der PCSK9-Inhibitoren kosteneffektiv gestaltet werden?
Erasmus University Medical Center1, University of Texas Health Science Center at Houston2, University of Washington3, National Institutes of Health4, Johns Hopkins University School of Medicine5, University of Michigan6, Brigham and Women's Hospital7, UCLA Medical Center8, Heidelberg University9, University of Jena10, University of Greifswald11, Greifswald University Hospital12, University of Bristol13, Universidade Federal de Pelotas14, Ludwig Maximilian University of Munich15, University of Ulm16, Technische Universität München17, University of Minnesota18, Human Genome Sequencing Center19, Mayo Clinic20, University of Vermont21, Leiden University Medical Center22, Medical University of Graz23, Synlab Group24, Imperial College London25, Group Health Research Institute26, Veterans Health Administration27
TL;DR: An important update to initial Mendelian Randomization analyses of the causal effect of fibrinogen on coronary heart disease (CHD) utilized single variants and did not take advantage of modern, multivariant approaches is provided.
Abstract: Background Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. Methods and Findings We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score incorporated data from 11 European-ancestry prospective cohorts to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. Conclusions A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies. Author Summary Initial Mendelian Randomization (MR) analyses of the causal effect of fibrinogen on coronary heart disease (CHD) utilized single variants and did not take advantage of modern, multivariant approaches. This manuscript provides an important update to these initial analyses by incorporating larger sample sizes and employing multiple, modern multi-variant MR approaches to account for pleiotropy. We used incident cases to perform a MR study of the causal effect of fibrinogen on incident CHD and the nested outcome of myocardial infarction (MI) using an allele score approach. Then using data from a case-control genome-wide association study for CHD and MI we performed two sample MR analyses with multiple, pleiotropy robust approaches. Overall, the results indicated that associations between fibrinogen and CHD in observational studies are likely upwardly biased from any underlying causal effect. Single variant MR approaches show little evidence of a causal effect of fibrinogen on CHD or MI. Multi-variant MR analyses of fibrinogen on CHD indicate there may be a small positive effect, however this result needs to be interpreted carefully as the 95% confidence intervals were still consistent with a null effect. Multi-variant MR approaches did not suggest evidence of even a small causal effect of fibrinogen on MI.