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Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12-/-) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases. The role of coagulation factor FXII in diabetic kidney disease (DKD) remains unknown. Here, the authors show that zymogen FXII induces kidney injury via receptor (uPAR)-mediated signaling by inducing oxidative DNA damage and senescence, identifying new potential therapeutic targets for DKD. [ABSTRACT FROM AUTHOR]

Background: Physiological changes of blood amino acids and acylcarnitines during healthy child development are poorly studied. The LIFE (Leipziger Forschungszentrum für Zivilisationserkrankungen) Child study offers a platform with a large cohort of healthy children to investigate these dynamics. We aimed to assess the intra-person variability of 28 blood metabolites and their associations with anthropometric parameters related to growth and excess body fat. Methods: Concentrations of 22 amino acids (AA), 5 acylcarnitines (AC) and free carnitine of 2213 children aged between 3 months and 19 years were analyzed using liquid chromatography/tandem mass spectrometry. Values were transformed into standard deviation scores (SDS) to account for sex- and age-related variations. The stability of metabolites was assessed through the coefficient of determination. Associations with parameters for body composition and insulin-like growth factor-I (IGF-I) SDS were determined by the Pearson correlation and linear regression. Results: Our research revealed substantial within-person variation in metabolite concentrations during childhood and adolescence. Most metabolites showed a positive correlation with body composition parameters, with a notable influence of sex, pubertal status and weight group. Glycine exhibited negative associations with parameters of body fat distribution, especially in normal weight girls, overweight/obese boys and during puberty. Conclusion: Blood AA and AC measurements may contribute to elucidating pathogenesis pathways of adiposity-related comorbidities, but the specific timings and conditions of development during childhood and adolescence need to be taken into consideration. [ABSTRACT FROM AUTHOR]

It is assumed that bilirubin is hormonally regulated and influences weight development by preventing weight gain. However, studies in healthy infants are limited. The present study established reference values for bilirubin and investigated whether bilirubin levels are significantly associated with body weight, levels of ferritin and transferrin as well as steroid hormone levels in a study population of three- and six-month-old healthy infants. Data from a total of 411 study visits from the LIFE Child study (Leipzig, Germany) were analyzed. Associations were examined using linear regression analyses. Besides laboratory parameters, anthropometric data were gathered. We found statistically significant associations between body weight and bilirubin levels. In girls, we observed additional associations between bilirubin levels and both ferritin and transferrin concentrations at three months of age. At six months, steroid hormone levels were significantly associated with concentrations of total and indirect bilirubin, with effects differing by sex. Our study thus confirms associations already reported from animal studies and studies in adult populations. Furthermore, we showed that these associations already exist in the first year of life, are influenced by sex and age and, further, depend on the bilirubin type. Our results provide reference values for bilirubin and assist, therefore, in interpreting bilirubin levels in infancy. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) prognosis is determined by the disease stage with low survival rates for advanced stages. Current CRC screening programs are mainly using colonoscopy, limited by its invasiveness and high cost. Therefore, non-invasive, cost-effective, and accurate alternatives are urgently needed. Objective and design: This retrospective multi-center plasma proteomics study was performed to identify potential blood-based biomarkers in 36 CRC patients and 26 healthy volunteers by high-resolution mass spectrometry proteomics followed by the validation in an independent CRC cohort (60 CRC patients and 44 healthy subjects) of identified selected biomarkers. Results: Among the 322 identified plasma proteins, 37 were changed between CRC patients and healthy volunteers and were associated with the complement cascade, cholesterol metabolism, and SERPIN family members. Increased levels in CRC patients of the complement proteins C1QB, C4B, and C5 as well as pro-inflammatory proteins, lipopolysaccharide-binding protein (LBP) and serum amyloid A4, constitutive (SAA4) were revealed for first time. Importantly, increased level of C5 was verified in an independent validation CRC cohort. Increased C4B and C8A levels were correlated with cancer-associated inflammation and CRC progression, while cancer-associated inflammation was linked to the acute-phase reactant leucine-rich alpha-2-glycoprotein 1 (LRG1) and ceruloplasmin. Moreover, a 4-protein signature including C4B, C8A, apolipoprotein C2 (APO) C2, and immunoglobulin heavy constant gamma 2 was changed between early and late CRC stages. Conclusion: Our results suggest that C5 could be a potential biomarker for CRC diagnosis. Further validation studies will aid the application of these new potential biomarkers to improve CRC diagnosis and patient care. [ABSTRACT FROM AUTHOR]

Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity‐related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. Methods: A meta‐analysis of genome‐wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype‐Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. Results: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10−8, explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low‐density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. Conclusions: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism. [ABSTRACT FROM AUTHOR]

Background: Ghrelin and leptin are both peptide hormones and act as opposing players in the regulation of hunger, satiety and energy expenditure. Leptin reduces appetite and feelings of hunger and is secreted mainly by adipocytes, while ghrelin increases appetite and food intake and reduces metabolic rate. Both hormones have been implicated in addictive disorders. Ghrelin was shown to have proaddictive effects while leptin's role in addiction yields more conflicting results. Their involvement in the regulation of both food intake and addictive behaviors make them interesting candidates when investigating the regulation of food addiction. However, only few human studies have been performed and large-scale studies are lacking to date. We aimed to investigate the association between total ghrelin and leptin serum levels with scores in the Yale Food Addiction Scale (YFAS). Methods: Subjects were recruited in the LIFE Adult cohort. 909 subjects were included in the analysis and we performed univariate multiple linear regression models, adjusted for age, sex (in total group analyses only), alcohol consumption, smoking status, BMI scores, cortisol concentrations, Center for Epidemiological Studies Depression Scale (CES-D) and the 7-item Generalized Anxiety Disorder Scale (GAD-7) sum scores. The dependent variable was the YFAS score. Results: In men, leptin serum levels showed a significant positive association (standardized β = 0.146; p = 0.012) with the YFAS score. This finding was confirmed in an extreme-group comparison: men in the highest quartile of leptin levels had significantly higher YFAS sum scores than men in the lowest quartile (1.55 vs. 1.18; p = 0.00014). There was no association with YFAS sum score in the total group (standardized β = -0.002; p = 0.974) or in women (standardized β = -0.034; p = 0.674). Total serum ghrelin showed no association with YFAS sum score neither in the total group (standardized β = -0.043; p = 0.196) nor in men (n = 530; standardized β = -0.063; p = 0.135) or women (n = 379; standardized β = -0.035; p = 0.494). Conclusion: Our findings are in line with previous literature and suggest that total ghrelin serum levels are not associated with food addiction scores. Leptin had been previously shown to be associated with food addiction and we confirmed this finding for men in a large, population-based approach. [ABSTRACT FROM AUTHOR]

Objectives: To assess the stability of lipid profiles throughout childhood and evaluate their onset and dynamic. Materials and methods: Lipid markers were longitudinally measured in more than 1300 healthy children from the LIFE Child study (Germany) and categorized into normal, at-risk, or adverse. Year-to-year intra-person persistence of the categories during follow-ups was examined and Pearson's correlation coefficient was calculated. Results: We found strong positive correlations for TC, LDL-C and ApoB (r > 0.75, p < 0.001) from the age of four years. Correlations were lowest during the first two years of life. Most children with normal levels also had normal levels the following year. Children with at-risk levels showed a tendency towards normal levels at the follow-up visit. Adverse levels of TC, LDL-C, ApoB (all ages), and HDL-C (from age 15) persisted in more than half of the affected children. Age-dependent patterns of stability were most pronounced and similar for TC, LDL-C, and ApoB. Conclusions: Normal levels of serum lipids show high stability and adverse levels stabilized in early childhood for TC, LDL, and ApoB. At-risk and adverse levels of TC, LDL-C or ApoB may warrant further or repeated diagnostic measurements with regards to preventing CVD in the long run. [ABSTRACT FROM AUTHOR]

Transforming growth factor beta-1 (TGFβ1) is an adipokine secreted from adipose tissue, placental tissue and immune cells with a role in cell proliferation, cell apoptosis and angiogenic proliferation. The role of TGFβ1 in pregnancy and child growth and the source of cord TGFβ1 are yet unknown. In this study, we sought to clarify the correlation of TGFβ1 levels with parameters of intrauterine growth and child growth during the first year of life, and to determine whether their source is primarily of fetal or maternal origin. Serum samples and anthropometric measurements were obtained from the LIFE Child cohort of 79 healthy mother–child pairs. Measurements were conducted using enzyme-linked immunosorbent assays. Statistical analyses including Mann–Whitney U-test, correlation analyses and linear regression analyses were performed using GraphPad Prism and R. TGFβ1 levels were significantly higher in cord than in maternal serum, suggesting a fetal origin. Multivariate regression analyses revealed strong positive associations between cord TGFβ1 levels at birth and child weight at U6. Furthermore, cord TGFβ1 was significantly correlated with child weight at approximately one year of age. An increase of 10,000 pg/mL in cord TGFβ1 concentrations at birth was associated with a higher body weight of 201 g at roughly one year of age when adjusted for sex. [ABSTRACT FROM AUTHOR]

Biobanked samples are becoming increasingly important for research outcomes. Most of the biobanking processes (from preparation to storage) are affected by temperature in a time-dependent manner and have a high impact on sample quality. We aimed to validate time and temperature sensitive processes such as sample preparation, transport, sorting, and storage, which have a high impact on sample quality. Temperature was measured using internal or external temperature data loggers. We analysed the temperature and present real data from our sample transport on dry ice and with the CryoPod, from our ultra-low temperature freezers (UTFs) of different manufacturers and cryostores. We also tested sample sorting on dry ice and in a cryogenic workbench. In the UTFs, we identified temperature zones with a temperature difference from 4.7 °C up to 20.8 °C across the whole UTF. For sample transport within approximately 30 min we observed temperatures of −80.2 °C ± 4.0 °C and −173.9 °C ± 16.9 °C for dry ice boxes and the CryoPod, respectively. Sorting on dry ice was best in a polystyrene box half-filled with dry ice pellets, although the temperature increased by 7.5 °C within the first 5 min, whereas the temperature in the cryogenic workbench remained stable below −100 °C for hours. Time and temperature play a crucial role in the entire biobanking process, with sometimes immense temperature fluctuations in some equipment. We recommend the validation or verification of all equipment and processes used to avoid pre-analytical errors in accordance with DIN EN ISO 20387. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH)-associated mutations increase the risk of atherosclerotic cardiovascular diseases. However, it is unclear whether the mutations detected in circulating blood cells can also be detected in tissues associated with atherosclerosis, where they could affect physiology locally. To address this, the presence of CH mutations in peripheral blood, atherosclerotic lesions and associated tissues was assessed in a pilot study of 31 consecutive patients with peripheral vascular disease (PAD) who underwent open surgical procedures. Next-generation sequencing was used to screen the most commonly mutated loci (DNMT3A, TET2, ASXL1 and JAK2). Twenty CH mutations were detected in peripheral blood of 14 (45%) patients, 5 of whom had more than one mutation. TET2 (11 mutations, 55%) and DNMT3A (8 mutations, 40%) were the most frequently affected genes. Altogether, 88% of the mutations detectable in peripheral blood were also present in the atherosclerotic lesions. Twelve patients also had mutations in perivascular fat or subcutaneous tissue. The presence of CH mutations in PAD-associated tissues as well as in blood suggests that CH mutations may make a previously unknown contribution to PAD disease biology. [ABSTRACT FROM AUTHOR]

Google Scholar Crossref Search ADS PubMed WorldCat 7 Quante M, Hesse M, Dohnert M et al.; LIFE Child Study Investigators. Google Scholar Crossref Search ADS PubMed WorldCat 9 Enzenbach C, Wicklein B, Wirkner K, Loeffler M. Evaluating selection bias in a population-based cohort study with low baseline participation: the LIFE-Adult-Study. Google Scholar Crossref Search ADS PubMed WorldCat 2 Holle R, Happich M, Lowel H, Wichmann HE; MONICA/KORA Study Group. Key Features The LIFE-Adult-Study is a population-based cohort study investigating the prevalence and incidence of common diseases and subclinical disease phenotypes, the complex interactions between genetic and lifestyle factors regarding the co-occurrence and development of subclinical phenotypes and diseases, and the role of biomarkers to predict disease initiation and progression. [Extracted from the article]

Background: There are socioeconomic inequalities in dementia risk. Underlying pathways are not well known. Objective: To investigate whether modifiable health and lifestyle factors for brain health mediate the association of socioeconomic status (SES) and cognitive functioning in a population without dementia. Methods: The "LIfestyle for BRAin health" (LIBRA) score was computed for 6,203 baseline participants of the LIFE-Adult-Study. LIBRA predicts dementia in midlife and early late life, based on 12 modifiable factors. Associations of SES (education, net equivalence income, and occupational status) and LIBRA with cognitive functioning (composite score) were investigated using adjusted linear regression models. Bootstrapped structural equation modelling (SEM) was used to investigate whether LIBRA mediated the association of SES and cognitive functioning. Results: Participants were M = 57.4 (SD = 10.6, range: 40-79) years old; 50.3% were female. Both, SES (Wald: F(2)=52.5, p < 0.001) and LIBRA (Wald: F(1)=5.9, p < 0.05) were independently associated with cognitive functioning; there was no interaction (Wald: F(2)=2.9, p = 0.060). Lower SES and higher LIBRA scores indicated lower cognitive functioning. LIBRA partially mediated the association of SES and cognitive functioning (IE: =0.02, 95% CI [0.02, 0.03], p < 0.001). The proportion mediated was 12.7%. Conclusion: Differences in cognitive functioning due to SES can be partially attributed to differences in modifiable health and lifestyle factors; but to a small extent. This suggests that lifestyle interventions could attenuate socioeconomic inequalities in cognitive functioning. However, directly intervening on the social determinants of health may yield greater benefits for dementia risk reduction. [ABSTRACT FROM AUTHOR]

A major obstacle in diabetes is the metabolic or hyperglycemic memory, which lacks specific therapies. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, human samples and in vitro models. Tubular and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans. Mechanistically, sustained tubular p21 expression in DKD is linked to demethylation of its promoter and reduced DNMT1 expression. Two disease resolving agents, protease activated protein C (3K3A-aPC) and parmodulin-2, reversed sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence is a pathway contributing to the hyperglycemic memory, which can be therapeutically targeted. Persistent diabetic complications despite controlled blood glucose levels, known as hyperglycemic memory, remain a poorly understood phenomenon in diabetic kidney disease. Here the authors identify senescence-associated gene p21 as a regulator of hyperglycemic memory, the suppression of which improves hyperglycemic memory and renal function. [ABSTRACT FROM AUTHOR]

Substantial evidence indicates a huge potential for risk reduction of cognitive decline and dementia based on modifiable health and lifestyle factors. To maximize the chances for risk reduction, it is useful to investigate associations of social determinants and lifestyle for brain health. We computed the "LIfestyle for BRAin health" (LIBRA) score for baseline participants of the Leipzig Research Centre for Civilization Diseases (LIFE) Adult Study, a population-based urban cohort in Germany. LIBRA predicts dementia in midlife and early late life populations, comprising 12 modifiable risk factors (heart disease, kidney disease, diabetes, obesity, hypertension, hypercholesterolemia, alcohol consumption, smoking, physical inactivity, diet, depression, cognitive inactivity). Associations of social determinants (living situation, marital status, social isolation, education, net equivalence income, occupational status, socioeconomic status/SES, employment) with LIBRA were inspected using age- and sex-adjusted multivariable linear regression analysis. Z-standardization and sampling weights were applied. Participants (n = 6203) were M = 57.4 (SD = 10.6, range 40–79) years old and without dementia, 53.0% were women. Except for marital status, all considered social determinants were significantly associated with LIBRA. Beta coefficients for the association with higher LIBRA scores were most pronounced for low SES (β = 0.80, 95% CI [0.72–0.88]; p < 0.001) and middle SES (β = 0.55, 95% CI [0.47–0.62]; p < 0.001). Social determinants, particularly socioeconomic factors, are associated with lifestyle for brain health, and should thus be addressed in risk reduction strategies for cognitive decline and dementia. A social-ecological public health perspective on risk reduction might be more effective and equitable than focusing on individual lifestyle behaviors alone. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8–12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels. [ABSTRACT FROM AUTHOR]

Objective: Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects on blood DNA methylation in participants of the LIFE‐Adult study, a well‐characterised population‐based cohort from Germany. Research design and methods: Lifestyle scores (LS) based on diet, physical activity, smoking and alcohol intake were calculated in 4107 participants of the LIFE‐Adult study. Fifty subjects with an extremely healthy lifestyle and 50 with an extremely unhealthy lifestyle (5th and 95th percentiles LS) were selected for genome‐wide DNA methylation analysis in blood samples employing Illumina Infinium® Methylation EPIC BeadChip system technology. Results: Differences in DNA methylation patterns between body mass index groups (<25 vs. >30 kg/m2) were rather marginal compared to inter‐lifestyle differences (0 vs. 145 differentially methylated positions [DMPs]), which identified 4682 differentially methylated regions (DMRs; false discovery rate [FDR <5%) annotated to 4426 unique genes. A DMR annotated to the glutamine‐fructose‐6‐phosphate transaminase 2 (GFPT2) locus showed the strongest hypomethylation (∼6.9%), and one annotated to glutamate rich 1 (ERICH1) showed the strongest hypermethylation (∼5.4%) in healthy compared to unhealthy lifestyle individuals. Intersection analysis showed that diet, physical activity, smoking and alcohol intake equally contributed to the observed differences, which affected, among others, pathways related to glutamatergic synapses (adj. p <.01) and axon guidance (adj. p <.05). We showed that methylation age correlates with chronological age and waist‐to‐hip ratio with lower DNA methylation age (DNAmAge) acceleration distances in participants with healthy lifestyles. Finally, two identified top DMPs for the alanyl aminopeptidase (ANPEP) locus also showed the strongest expression quantitative trait methylation in blood. Conclusions: DNA methylation patterns help discriminate individuals with a healthy versus unhealthy lifestyle, which may mask subtle methylation differences derived from obesity. [ABSTRACT FROM AUTHOR]

Purpose: Adipokines may play an important role in the complex etiology of human obesity and its metabolic complications. Here, we analyzed the relationship between 15 adipokines, eating behavior and body-mass index (BMI). Methods: The study included 557 participants of the Sorbs (62.1% women, 37.9% men) and 3101 participants of the population-based LIFE-Adult cohorts (53.4% women, 46.4% men) who completed the German version of the Three-Factor-Eating Questionnaire to assess the eating behavior types cognitive restraint, disinhibition and hunger. Serum levels of 15 adipokines, including adiponectin, adipocyte fatty acid-binding protein (AFABP), angiopoietin-related growth factor (AGF), chemerin, fibroblast growth factor (FGF)-19, FGF-21, FGF-23, insulin-like growth factor (IGF)-1, interleukin (IL) 10, irisin, progranulin, vaspin, pro-neurotensin (pro-NT), pro-enkephalin (PENK) and leptin were measured. Based on significant correlations between several adipokines with different eating behavior items and BMI, we conducted mediation analyses, considering the eating behavior items as potential mediation variable towards BMI. Results: Here, we found that the positive association between chemerin, AFABP or leptin and BMI in Sorbian women was mediated by higher restraint or disinhibited eating, respectively. Additionally, in Sorbian women, the negative relation between IGF-1 and BMI was mediated by higher disinhibition and the positive link between AGF and BMI by lower disinhibition. In Sorbian men, the negative relationship between PENK and BMI was mediated by lower disinhibition and hunger, whereas the negative relation between IGF-1 and BMI was mediated by higher hunger. In the LIFE-Adult women´s cohort, associations between chemerin and BMI were mediated by decreased hunger or disinhibition, respectively, whereas relations between PENK and BMI were fully mediated by decreased disinhibition. Conclusion: Our study suggests that adipokines such as PENK, IGF-1, chemerin, AGF, AFABP and leptin might affect the development of obesity by directly modifying individual eating behavior. Given the observational nature of the study, future experimental or mechanistic work is warranted. [ABSTRACT FROM AUTHOR]

ABIDE_MI is a complementary funded 18 months project within the German Medical Informatics Initiative (MII), which aims to align IT infrastructures and regulatory/governance structures between biobanks/biobanking IT and the MII data integration centres (DIC) at German university hospitals. A major task in 2021 was the systematic collection of all documents describing rules, as well as proposal/contract templates for data and biosample use and access at each of the participating 24 university hospitals and their comparison with MII-wide consented data sharing principles, documents and governance structures. This comparison revealed large heterogeneity across the ABIDE_MI sites and further, redundant structures/regulations currently established at the German university hospitals. A second task was the design and stepwise development of an IT network infrastructure with central components (data and biosample query portal) and decentralized standardized FHIR servers to capture the standardized FHIR-based core data set modules (resources) defined within the MII working group “Interoperability”. Subsequent steps in the project are the harmonization of the data and biosample sharing governance/regulation frameworks at each ABIDE_MI site, creating synergies for the research infrastructures at the German university hospitals and to link those resources to the German Portal for Medical Research Data and with the BBMRI-ERIC Directory and Negotiator tools. [ABSTRACT FROM AUTHOR]

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD. Physterols are cholesterol homologs derived from plants, which are found in humans through consumption of plant products. Here the authors have performed a genome-wide meta-analysis of 32 serum phytosterol traits, with evidence suggesting causality between sitosterol and coronary artery disease. [ABSTRACT FROM AUTHOR]

The quality of biospecimens stored in a biobank depends tremendously on the technical personnel responsible for processing, storage, and release of biospecimens. Adequate training of these biobank employees would allow harmonization of correct sample handling and thus ensure a high and comparable quality of samples across biobank locations. However, in Germany there are no specific training opportunities for technical biobank staff. To understand the educational needs of the technical personnel a web-based survey was sent to all national biobanks via established e-mail registers. In total, 79 biobank employees completed the survey, including 43 technicians. The majority of the participating technical personnel stated that they had worked in a biobank for less than three years and had never participated in an advanced training. Three-quarters of the technicians indicated that they were not able to understand English content instantly. Based on these results and the results of a workshop with 16 biobank technicians, 41 learning objectives were formulated. These learning objectives can be used as a basis for advanced training programs for technical personnel in biobanks. Setting up courses based on the identified learning objectives for this group of biobank staff could contribute to harmonization and sustainability of biospecimen quality. [ABSTRACT FROM AUTHOR]

As higher mental demands at work are associated with lower dementia risk and a key symptom of dementia is hippocampal atrophy, the study aimed at investigating the association between mental demands at work and hippocampal volume. We analyzed data from the population-based LIFE-Adult-Study in Leipzig, Germany (n = 1,409, age 40–80). Hippocampal volumes were measured via three-dimensional Magnetic resonance imaging (MRI; 3D MP-RAGE) and mental demands at work were classified via the O*NET database. Linear regression analyses adjusted for gender, age, education, APOE e4-allele, hypertension, and diabetes revealed associations between higher demands in "language and knowledge," "information processing," and "creativity" at work on larger white and gray matter volume and better cognitive functioning with "creativity" having stronger effects for people not yet retired. Among retired individuals, higher demands in "pattern detection" were associated with larger white matter volume as well as larger hippocampal subfields CA2/CA3, suggesting a retention effect later in life. There were no other relevant associations with hippocampal volume. Our findings do not support the idea that mental demands at work protect cognitive health via hippocampal volume or brain volume. Further research may clarify through what mechanism mentally demanding activities influence specifically dementia pathology in the brain. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-neurotensin (Pro-NT) was asso ciated with metabolic diseases and predicted incident CVD and mortality. However, Pro-NT regulation in CKD a nd its potential role linking CKD and mortality have not been investigated, so far. Methods: In a central lab, circulating Pro-NT was quantified in three in dependent cohorts comprising 4715 participants (cohort 1: patients with CKD; cohort 2: general population stud y; and cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. In a 4th independent cohort, serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-spec ific Nts expression was further investigated in two mouse models of diabetic CKD and compared to non-diabetic contr ol mice. Results: Pro-NT significantly increased with deteriorating renal functio n (P < 0.001). In meta-analysis of cohorts 1-3, Pro-NT was significantly and independently associated with estim ated glomerular filtration rate (P ≤ 0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-ca use mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, P = 0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals. Conclusions: Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD. [ABSTRACT FROM AUTHOR]

Biobanks are important infrastructures to support clinical research and developments in personalized medicine. Although biobanking is not a new invention it has gained importance in the last few years due to increased quality requirements for biological samples in biomedical research and new high resolution Omics-technologies. Moreover, quality-assured collection, processing and storage of biological samples with defined pre-analytical history plays a key role for reproducibility in scientific research and paves the path towards precision medicine. Due to the increasing need for large numbers of samples, both in basic as well as in translational research, particular attention must be paid to sample acquisition and preparation in order to guarantee the highest possible sample quality. This can be achieved by following best practices or implementation and operation of specific biobank quality management systems that are compliant with the new DIN EN ISO 20387. Moreover, automation of critical process steps in biobanking can help to reach the highest quality standard and consistent sample quality. The following article will present and discuss currently available solutions for process automation in biobanking. [ABSTRACT FROM AUTHOR]

Background: There is only limited information on serum reference ranges of calcitonin (CT) in infants, children and adolescents. This gap hampers valid diagnostics in patients with multiple endocrine neoplasia type 2 (MEN 2) and planned prophylactic thyroidectomy. In addition, age-dependent reference ranges for CT are necessary to define a cure in medullary thyroid carcinoma (MTC). We asked whether the reference ranges for CT levels were age- and gender-dependent in the serum of a pediatric cohort. Methods: A total of 6090 serum samples of 2639 subjects of the LIFE-Child cohort aged between 1 month and 17.9 years were analyzed by the CT electrochemiluminescence immunoassay (ECLIA). Reference intervals were estimated using the LMS method. For clinical validation the serum of 28 patients (61 samples) with MEN 2 and 106 patients (136 samples) with thyroid diseases were analyzed. Results: CT levels showed a clear age- and gender-dependence with significantly higher values in boys (p<0.01). An accelerated decline of CT levels from newborn to children at the age of 4 and 5 years was observed for both sexes. A cure for MTC was demonstrated in 71% of MEN 2 patients after thyroidectomy, whereas 5 patients remained suspicious for micrometastasis or relapse. Only 1.5% of our patients with thyroid diseases revealed increased CT levels. Conclusions: This is the largest study to establish novel pediatric reference ranges from the CT values of healthy subjects. It allows a precise laboratory monitoring of CT in pediatric patients with MEN 2. Thyroid diseases did not have a relevant influence on CT levels in our pediatric cohort. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate the associations between blood levels of stress-related hormones and early signs of periodontal disease in children and adolescents.Materials and methods: Within the LIFE (Leipzig research center for civilization diseases) Child study, 498 adolescents (10 to 18 years) were included. Early signs of periodontal inflammation were measured by probing depth (PD) at six index teeth (16, 11, 26, 36, 31, 46). Blood levels of stress-related hormones (cortisol, dehydroepiandosterone-sulfate [DHEA-S]) and, additionally interleukine-6 (IL-6) were measured. Socioeconomic status, oral hygiene, orthodontic appliances, and nutritional status, recorded by body-mass-index-standard-deviation-score (BMI-SDS), were considered as confounding factors. Additionally, in 98 participants, an oral chairside active matrix metalloproteinase-8 (aMMP-8) test was performed. Statistical tests are the Mann-Whitney U tests, chi-squared tests and multivariate logistic regression model.Results: IL-6, BMI-SDS as well as positive aMMP-8 test result were significantly associated with maximum PD > 3 mm (p < 0.05). However, no statistically significant associations between stress-related hormones (cortisol and DHEA-S) and presence of maximum PD > 3 mm were found (p > 0.05). Higher DHEA-S and BMI were associated with positive aMMP-8 result, even after adjusting for age and gender (p = 0.027, padj = 0.026).Conclusion: The results reveal no associations between PD and stress-related hormones cortisol and DHEA-S. aMMP-8 test result might be associated with DHEA-S level. Nutritional status seems to influence periodontal disease in adolescents.Clinical relevance: DHEA-S and BMI-SDS show associations with early signs of periodontal disease in adolescents aged 10 to 18 years. This association should be confirmed by the investigation of high-risk groups. [ABSTRACT FROM AUTHOR]

Background: PR interval prolongation is associated with increased risk for atrial fibrillation (AF). Different biomarkers are used to predict AF incidence and its outcomes. The aim of this study was to investigate the association between echocardiographic parameters and blood biomarkers in PR interval groups and AF. Methods: The LIFE-Adult-Study is a population-based cohort study of randomly selected participants from Leipzig, Germany. In this cross-sectional analysis, individuals ≥40 years with available echocardiographic (LA diameter, EF) and laboratory data (creatinine, Troponin, NT-proBNP) were included. Results: The study population comprised 1.429 individuals (median age 56 (IQR 48–66) years, 40% males) with complete ECG, echocardiographic and laboratory data. There were 48 (3.4%) individuals with AF, 177 (12.4%) with short, 138 (9.7%) with prolonged and 1.066 (74.5%) with normal PR interval. Individuals with PR interval prolongation had larger LA diameter, higher Troponin and NT-proBNP levels than individuals with normal PR interval, but lower than AF group (p<0.001). In contrast, eGFR was significantly higher in the group with PR interval prolongation than in AF, but lower than in individuals with normal PR interval (p<0.001). In the multivariate analysis, PR interval prolongation and AF shared similar characteristics, the only parameter different between both groups was NT-proBNP. Conclusions: Individuals with PR interval prolongation and AF showed similarities in echocardiographic parameters, renal function and blood biomarker levels. Longitudinal studies are necessary to prove whether the PR interval prolongation may be considered as preliminary stage for AF. [ABSTRACT FROM AUTHOR]

The LIFE Child study is a large population-based longitudinal childhood cohort study conducted in the city of Leipzig, Germany. As a part of LIFE, a research project conducted at the Leipzig Research Center for Civilization Diseases, it aims to monitor healthy child development from birth to adulthood and to understand the development of lifestyle diseases such as obesity. The study consists of three interrelated cohorts; the birth cohort, the health cohort, and the obesity cohort. Depending on age and cohort, the comprehensive study program comprises different medical, psychological, and sociodemographic assessments as well as the collection of biological samples. Optimal data acquisition, process management, and data analysis are guaranteed by a professional team of physicians, certified study assistants, quality managers, scientists and statisticians. Due to the high popularity of the study, more than 3000 children have already participated until the end of 2015, and two-thirds of them participate continuously. The large quantity of acquired data allows LIFE Child to gain profound knowledge on the development of children growing up in the twenty-first century. This article reports the number of available and analyzable data and demonstrates the high relevance and potential of the study. [ABSTRACT FROM AUTHOR]

Background: The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies. Methods/design: The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography. Discussion: The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016. [ABSTRACT FROM AUTHOR]

Background: The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies. Methods/design: The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography. Discussion: The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016. [ABSTRACT FROM AUTHOR]

Background: Liquid biobanking is an important tool for laboratory diagnostics in routine settings and clinical studies. However, the current knowledge about adequate storage conditions for different classes of biomarkers is incomplete and, in part, contradictory. Here, we performed a comprehensive study on the effects of different storage conditions on the stability of various biomarkers in human serum and plasma. Methods: Serum and citrated plasma were aliquoted and stored at 4 °C, -20 °C, -80 °C, and <-130 °C for 0, 7, 30, and 90 days, respectively (5-10 pools/condition). Additionally, frozen aliquots were temporarily exposed to higher temperatures during storage to simulate removing individual samples. Stability was tested for 32 biomarkers from 10 different parameter classes (electrolytes, enzymes, metabolites, inert proteins, complement factors, ketone bodies, hormones, cytokines, coagulation factors, and sterols). Results: Biobanking at -80 °C and <-130 °C for up to 90 days did not lead to substantial changes (defined as >3 interassay coefficients of variation and p<0.01) of any biomarker concentration. In contrast, storage at 4 °C and -20 °C induced substantial changes in single biomarker concentrations in most classes. Such substantial changes were increases (<20%) in electrolytes, metabolites, and proteins, and decreases (<96%) in enzymes, ketone bodies, cytokines, and coagulation factors. Biomarker stability was minimally affected by occasional short-term thermal exposure. Conclusions: Based on these results, we provide recommendations for storage conditions of up to 90 days for several biomarkers. Generally, storage at ≤-80 °C for at least 90 days including occasional short-term thermal exposure is an excellent storage condition for most biomarkers. [ABSTRACT FROM AUTHOR]

In this article the affiliation details for Helena Gylling were incorrectly given as Department of Internal Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland but this should have been Heart and Lung Center, Cardiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. The original article can be found online at https://doi.org/10.1038/s41467-021-27706-6. [Extracted from the article]

Depression and vitamin D deficiency are major public health problems. The existing literature indicates the complex relationship between depression and vitamin D. The purpose of this study was to examine whether this relationship is moderated or mediated by inflammation. A community sample (n = 7162) from the LIFE-Adult-Study was investigated, for whom depressive symptoms were assessed via the German version of CES-D scale and serum 25-hydroxyvitamin D (25(OH)D) levels and inflammatory markers (IL-6 and CRP levels, WBC count) were quantified. Mediation analyses were performed using Hayes' PROCESS macro and regression analyses were conducted to test moderation effects. There was a significant negative correlation between CES-D and 25(OH)D, and positive associations between inflammatory markers and CES-D scores. Only WBC partially mediated the association between 25(OH)D levels and depressive symptoms both in a simple mediation model (ab: −0.0042) and a model including covariates (ab: −0.0011). None of the inflammatory markers showed a moderation effect on the association between 25(OH)D levels and depressive symptoms. This present work highlighted the complex relationship between vitamin D, depressive symptoms and inflammation. Future studies are needed to examine the effect of vitamin D supplementation on inflammation and depressive symptomatology for causality assessment. [ABSTRACT FROM AUTHOR]

This study proposes age- and sex-specific percentiles for serum cobalamin and folate, and analyzes the effects of sex, age, body mass index (BMI), and socioeconomic status (SES) on cobalamin and folate concentrations in healthy children and adolescents. In total, 4478 serum samples provided by healthy participants (2 months–18.0 years) in the LIFE (Leipzig Research Centre for Civilization Diseases) Child population-based cohort study between 2011 and 2015 were analyzed by electrochemiluminescence immunoassay (ECLIA). Continuous age-and sex-related percentiles (2.5th, 10th, 50th, 90th, 97.5th) were estimated, applying Cole's LMS method. In both sexes, folate concentrations decreased continuously with age, whereas cobalamin concentration peaked between three and seven years of age and declined thereafter. Female sex was associated with higher concentrations of both vitamins in 13- to 18-year-olds and with higher folate levels in one- to five-year-olds. BMI was inversely correlated with concentrations of both vitamins, whilst SES positively affected folate but not cobalamin concentrations. To conclude, in the assessment of cobalamin and folate status, the age- and sex-dependent dynamic of the respective serum concentrations must be considered. While BMI is a determinant of both vitamin concentrations, SES is only associated with folate concentrations. [ABSTRACT FROM AUTHOR]

Background: Changes in the metabolic fingerprint of blood during child growth and development are a largely under-investigated area of research. The examination of such aspects requires a cohort of healthy children and adolescents who have been subjected to deep phenotyping, including collection of biospecimens for metabolomic analysis. The present study considered whether amino acid (AA) and acylcarnitine (AC) concentrations are associated with age, sex, body mass index (BMI), and puberty during childhood and adolescence. It also investigated whether there are associations between amino acids (AAs) and acylcarnitines (ACs) and laboratory parameters of glucose and lipid metabolism, as well as liver, kidney, and thyroid parameters. Methods: A total of 3989 dried whole blood samples collected from 2191 healthy participants, aged 3 months to 18 years, from the LIFE Child cohort (Leipzig, Germany) were analyzed using liquid chromatography tandem mass spectrometry to detect levels of 23 AAs, 6 ACs, and free carnitine (C0). Age- and sex-related percentiles were estimated for each metabolite. In addition, correlations between laboratory parameters and levels of the selected AAs and ACs were calculated using hierarchical models. Results: Four different age-dependent profile types were identified for AAs and ACs. Investigating the association with puberty, we mainly identified peak metabolite levels at Tanner stages 2 to 3 in girls and stages 3 to 5 in boys. Significant correlations were observed between BMI standard deviation score (BMI-SDS) and certain metabolites, among them, branched-chain (leucine/isoleucine, valine) and aromatic (phenylalanine, tyrosine) amino acids. Most of the metabolites correlated significantly with absolute concentrations of glucose, glycated hemoglobin (HbA1c), triglycerides, cystatin C (CysC), and creatinine. After age adjustment, significant correlations were observed between most metabolites and CysC, as well as HbA1c. Conclusions: During childhood, several AA and AC levels are related to age, sex, BMI, and puberty. Moreover, our data verified known associations but also revealed new correlations between AAs/ACs and specific key markers of metabolic function. [ABSTRACT FROM AUTHOR]