Risk Factors of Age-Related Macular Degeneration in a Population-Based Study: Results from SHIP-TREND-1 (Study of Health in Pomerania-TREND-1).

BACKGROUND Age-related macular degeneration (AMD) is the most common cause of visual impairment in the elderly population in industrialized countries. The Study of Health in Pomerania (SHIP) with its cohort SHIP-TREND was designed to investigate risk factors and clinical disorders in the general population of northeast Germany. This work focused on the first follow-up of SHIP-TREND and determined associated modifiable risk factors of AMD. Modifying risk factors is important to slow the progression of early AMD as there is currently no treatment for the late stage of geographic atrophy. Understanding AMD-associated risk factors also plays an important role in the development of therapeutic concepts. MATERIAL AND METHODS Between 2016 and 2019, data were collected from a total of 2507 initially randomly selected subjects from the general population aged 28 to 89 years. Non-mydriatic fundus photography of the right eye was performed in 2489 subjects. Grading of AMD was performed using the Rotterdam classification system. RESULTS We included 1418 gradable fundus photographs in the analysis. The risk of AMD changes increased with age and was positively correlated with HDL cholesterol, fT3, and low educational level. In men, BMI and cigarette smoking were also positively associated with AMD changes. CONCLUSIONS This study emphasizes the consideration of various metabolic pathways for the development of therapeutic concepts.

Body surface scan anthropometrics are associated with grip strength in the general population.

BACKGROUND AND AIM: Body shape and anthropometrics are well-known risk factors for cardiovascular diseases (CVD) and mortality. Hand-grip strength (HGS) is also a meaningful marker of health and a promising predictor of CVD and mortality. There is a lack of studies that have systematically investigated associations between body shape and anthropometrics with HGS. In a population-based study, we investigated if anthropometric markers derived from 3D body scanning are related to HGS. METHODS AND RESULTS: We used the data of 1,599 individuals aged 36 to 93 years, who participated in the Study of Health in Pomerania. A total of 87 anthropometric markers, determined by a 3D body scanner, were included in the analysis. Anthropometric measurements were standardized and used as exposure variables. HGS was measured with a hand dynamometer and used as outcome. Sex-stratified linear regression models adjusted for age and height were used to relate standardized anthropometrics and HGS. Anthropometric markers were ranked according to -log-p-values. In men, left and right forearm circumference, left arm length to neck (C7), left forearm length, and forearm-fingertip length were most strongly related to HGS. In women, right forearm circumference, forearm-fingertip length, shoulder breadth, left forearm circumference, and right wrist circumference showed the most significant associations with HGS. The final prediction models contained 13 anthropometric markers in males (R2=0.54) and eight anthropometric markers in females (R2=0.37). CONCLUSIONS: The identified parameters may help estimate HGS in the clinical setting. However, studies in clinical settings are essential to validating our findings.

Associations between 47 anthropometric markers derived from a body scanner and relative fat-free mass in a population-based study.

BACKGROUND: Low relative fat free mass (FFM) is associated with a greater risk of chronic diseases and mortality. Unfortunately, FFM is currently not being measured regularly to allow for individuals therapy. OBJECTIVE: One reason why FFM is not being used may be related to additional equipment and resources, thus we aimed to identify easily accessible anthropometric markers related with FFM. MATERIALS AND METHODS: We analyzed data of 1,593 individuals (784 women; 49.2%, age range 28-88 years) enrolled in the population-based Study of Health in Pomerania (SHIP-TREND 1). Forty-seven anthropometric markers were derived from a 3D optical body-scanner. FFM was assessed by bioelectrical impedance analysis (FFMBIA) or air displacement plethysmography (FFMADP). In sex-stratified linear regression models, FFM was regressed on anthropometric measurements adjusted for body height and age. Anthropometric markers were ranked according to the coefficient of determination (R2) derived from these regression models. RESULTS: Circumferences of high hip, belly, middle hip, waist and high waist showed the strongest inverse associations with FFM. These relations were stronger in females than in males. Associations of anthropometric markers with FFMAPD were greater compared to FFMBIA. CONCLUSION: Anthropometric measures were more strongly associated with FFMADP compared to FFMBIA. Anthropometric markers like circumferences of the high or middle hip, belly or waist may be appropriate surrogates for FFM to aid in individualized therapy. Given that the identified markers are representative of visceral adipose tissue, the connection between whole body strength as surrogate for FFM and fat mass should be explored in more detail.

Prednisolone Versus Colchicine for Acute Gout in Primary Care: statistical analysis plan for the pragmatic, multicenter, randomized, and double-blinded COPAGO non-inferiority trial.

BACKGROUND: To date, colchicine and prednisolone are two effective therapies for the treatment of acute gout but have never been compared directly in a randomized clinical trial. In addition, in previous trials of treating acute gout patients with concomitant comorbidities were often excluded due to contraindications to naproxen. STUDY DESIGN: This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial compares prednisolone with colchicine in terms of non-inferiority in patients with acute gout. Patients presenting to their general practitioner with acute gout can be included if the gout attack has occurred within the last 2 days. A total of 60 practices in the vicinity of three university medical centers (Greifswald, Göttingen, and Würzburg) participate in the study. The intervention group receives 30 mg prednisolone for 5 days, while the group of standard care receives low-dose colchicine (day 1: 1.5 mg; days 2-5: 1 mg). The first dose of treatment is provided at day 0 when patients present to the general practitioner due to an acute gout attack. From day 0 to day 6, patients will be asked to complete a study diary on daily basis regarding pain quantification. For safety reasons, potential side effects and the course of systolic blood pressure are also assessed. STATISTICAL ANALYSIS PLAN: N = 314 patients have to be recruited to compensate for 10% of dropout and to allow for showing non-inferiority of prednisolone compared to colchicine with a power of 90%. We use permuted block randomization with block sizes of 2, 4, and 6 to avoid imbalanced treatment arms in this multi-center study; patients are randomized in a 1:1 ratio. The absolute level of pain on day 3 (in the last 24 h) is the primary outcome and measured on a numerical rating scale (NRS: 0-10). Using a multiple linear regression model adjusted for age, sex, and pain at baseline, prednisolone is considered non-inferior if the effect estimate including the confidence intervals is lower than a margin of 1 unit on the NRS. Average response to treatment, joint swelling and tenderness, physical function of the joint, and patients' global assessment of treatment success are secondary outcomes. DISCUSSION: The trial will provide evidence from a direct comparison of colchicine and prednisolone regarding their efficacy of pain reduction in acute gout patients of primary care and to indicate possible safety signals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered).

Metabolic cost of unloading pedalling in different groups of patients with pulmonary hypertension and volunteers.

Recently, the parameter internal work (IW) has been introduced as change in oxygen uptake (VO2) between resting and unloading workload in cardiopulmonary exercise testing (CPET). The proportional IW (PIW) was defined as IW divided by VO2 at peak exercise. A second option is to calculate the PIW based on the workload [PIW (Watt)] by considering the aerobic efficiency. The aim of our study was to investigate whether IW and PIW differ between patients with and without pulmonary hypertension and healthy controls. Our study population consisted of 580 patients and 354 healthy controls derived from the Study of Health in Pomerania. The PIW was slightly lower in patients (14.2%) than in healthy controls (14.9%; p = 0.030), but the PIW (Watt) was higher in patients (18.0%) than in the healthy controls (15.9%; p = 0.001). Such a difference was also observed, when considering only the submaximal workload up to the VAT (19.8% in patients and 15.1% in healthy controls; p < 0.001). Since the PIW (Watt) values were higher in patients with pulmonary hypertension, this marker may serve as a useful CPET parameter in clinical practice. In contrast to most of the currently used CPET parameters, the PIW does not require a maximal workload for the patient. Further studies are needed to validate the prognostic significance of the PIW.

Sex-specific associations of childhood maltreatment with obesity-related traits - The Study of Health in Pomerania (SHIP).

BACKGROUND: Child maltreatment (CM) is linked to obesity in adulthood. However, sex-differences and direct measurements of body fat have previously been insufficiently considered in this context. OBJECTIVE: To assess sex-specific associations of CM with anthropometric markers of overweight/obesity and direct measures of body fat. PARTICIPANTS AND SETTING: Analyses were conducted in 4006 adults from a population-based cohort in Northeastern Germany (SHIP-TREND-0). METHODS: CM was assessed using the Childhood Trauma Questionnaire (CTQ). Obesity-related traits included anthropometric indicators (i.e., height, weight, body mass index [BMI], waist [WC] and hip circumference [HC], waist-to-hip ratio [WHR], waist-to-height ratio [WHtR]), fat mass (FM) and fat-free mass (FFM) derived from bioelectrical impedance analysis (BIA), and subcutaneous (SAT) and visceral adipose tissue (VAT) ascertained using magnetic resonance imaging (MRI). Sex-stratified linear regression models predicting obesity-related traits from total CTQ scores were adjusted for age and education. Exploratory analyses investigated effects of CTQ subscales on obesity-related traits. RESULTS: In men, CM was positively associated with WHtR (ß = 0.04; p = .030) and VAT (ß = 0.02; p = .031) and inversely with body height (ß = -0.05; p = .010). In women, CM-exposure was positively associated with body weight (ß = 0.07; p = .018), BMI (ß = 0.03; p = .013), WC (ß = 0.07; p = .005), HC (ß = 0.05; p = .046), WHR (ß = 0.03; p = .015), WHtR (ß = 0.04; p = .006), FM (ß = 0.04; p = .006), and SAT (ß = 0.06; p = .041). In both sexes, effects were mainly driven by exposure to emotional and physical abuse. CONCLUSIONS: Results suggest that associations between CM-exposure and obesity-related traits in adulthood are primarily present in women. This may have implications for sex-specific obesity-related cardiometabolic risk after CM.

Nutritional status in patients with chronic pancreatitis and liver cirrhosis is related to disease conditions and not dietary habits.

Malnutrition is a common complication of chronic pancreatitis (CP) and liver cirrhosis (LC). Inadequate food intake is considered a relevant driver of malnutrition in both entities. However, the contribution of habitual diet to impaired nutritional status is unclear. In a prospective, multicenter cross-sectional study, we recruited patients with confirmed CP or LC and healthy volunteers as a control group. Malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition criteria. We comprehensively investigated habitual dietary intake on nutrient, food group, and dietary pattern level applying two validated food frequency questionnaires. We included 144 patients (CP: n = 66; LC: n = 78) and 94 control subjects. Malnutrition was prevalent in 64% and 62% of patients with CP or LC, respectively. In both CP and LC, despite slightly altered food group consumption in malnourished and non-malnourished patients there were no differences in energy or nutrient intake as well as dietary quality. Compared to controls patients showed distinct dietary food group habits. Patients consumed less alcohol but also lower quantities of fruits and vegetables as well as whole grain products (p < 0.001, respectively). Nevertheless, overall dietary quality was comparable between patients and healthy controls. Nutritional status in CP and LC patients is rather related to disease than habitual dietary intake supporting the relevance of other etiologic factors for malnutrition such as malassimilation or chronic inflammation. Despite distinct disease-related differences, overall dietary quality in patients with CP or LC was comparable to healthy subjects, which suggests susceptibility to dietary counselling and the benefits of nutrition therapy in these entities.

Higher Parametric Thyroid Feedback Quantile-based Index is a predictor of type 2 diabetes in a German population sample.

BACKGROUND: Type 2 diabetes has been described to be associated with hypothyroidism but we recently found that a decrease in pituitary sensitivity to thyroid hormone is associated with diabetes, obesity, and the metabolic syndrome.We aim to assess the longitudinal nature of this association in the population-based Study of Health in Pomerania(SHIP) in Germany. MATERIALS AND METHODS: 77% of a population-based sample of 4308 participants between 20 and 79 years was followed for 5 years. We studied 2542 participants without diabetes or thyroid medication at baseline and complete data in the variables of interest. Data of baseline thyroxine(fT4) and thyrotropin(TSH) were used to calculate the Parametric Thyroid Feedback Quantile-based Index(PTFQI), which measures whether TSH remains elevated despite fT4 being high. It uses the average population response as reference. PTFQI association with incidence of type 2 diabetes over 5 years was estimated with Poisson regression models adjusted for age, sex, and body mass index(BMI). RESULTS: Compared with the 1st PTFQI quartile, Incidence Rate Ratios (IRR) for diabetes were 1.54(95% CI 0.97 to 2.46), 1.55(0.94 to 2.57), and 1.97(1.27 to 3.10) for the upper quartiles (p-trend=0.004) after adjusting for age and sex. The association remained statistically significant after additionally adjusting for BMI: 1.64(1.05 to 2.59) for the 4th vs the 1st quartile (p-trend=0.043). CONCLUSIONS: An elevation of the pituitary TSH-inhibition threshold is associated with incident type 2 diabetes independently of BMI. The PTFQI might have clinical potential for prognosis and metabolic status monitoring.

Steroid Metabolomic Signature in Term and Preterm Infants.

Adrenal function is essential for survival and well-being of preterm babies. In addition to glucocorticoids, it has been hypothesized that C19-steroids (DHEA-metabolites) from the fetal zone of the adrenal gland may play a role as endogenous neuroprotective steroids. In 39 term-born (≥37 weeks gestational age), 42 preterm (30-36 weeks) and 51 early preterm (<30 weeks) infants 38 steroid metabolites were quantified by GC-MS in 24-h urinary samples. In each gestational age group, three distinctive cluster were identified by pattern analysis (k-means clustering). Individual steroidal fingerprints and clinical phenotype were analyzed at the 3rd day of life. Overall, the excretion rates of C21-steroids (glucocorticoid precursors, cortisol, and cortisone metabolites) were low (<99 µg/kg body weight/d) whereas the excretion rates of C19-steroids were up to 10 times higher. There was a shift to higher excretion rates of C19-steroids in both preterm groups compared to term infants but only minor differences in the distribution of C21-steroids. Comparable metabolic patterns were found between gestational age groups: Cluster 1 showed mild elevation of C21- and C19-steroids with the highest incidence of neonatal morbidities in term and severe intraventricular hemorrhage in early preterm infants. In cluster 2 lowest excretion in general was noted but no clinically unique phenotype. Cluster 3 showed highest elevation of C21-steroids and C19-steroids but no clinically unique phenotype. Significant differences in steroid metabolism between clusters are only partly reflected by gestational age and disease severity. In early preterm infants, higher excretion rates of glucocorticoids and their precursors were associated with severe cerebral hemorrhage. High excretion rates of C19-steroids in preterm infants may indicate a biological significance.

Body composition markers are associated with changes in inflammatory markers but not vice versa: A bi-directional longitudinal analysis in a population-based sample.

BACKGROUND AND AIM: Growing body of evidence consistently link obesity and inflammation, Although the direction of the association is still unclear. We aimed to investigate longitudinal associations of body anthropometric, composition and fat distribution parameters with inflammatory markers and vice versa. METHOD AND RESULTS: We used data from 2464 individuals of the SHIP-TREND cohort with a median follow-up of 7 years. Linear regression models adjusted for confounders were used to analyze associations of standardized body composition markers derived from classic anthropometry, bioelectrical impedance analysis (BIA) and magnetic resonance imaging (MRI) at baseline with changes in inflammatory markers (C-reactive protein (CRP), white blood cell (WBC), fibrinogen) and vice versa. Higher level of anthropometric markers at baseline were associated with an increase in the change of inflammatory markers. A 13.5 cm higher waist circumference (WC), 16.0 kg body weight and 7.76 % relative fat mass (FM) at baseline was associated with a change in CRP of 0.52 mg/L (95 % confidence interval [CI]: 0.29 to 0.74), 0.51 mg/L (95 % CI: 0.29; 0.74) and 0.58 mg/L (95 % CI: 0.34; 0.82) respectively. Absolute FM showed the strongest association with changes in serum fibrinogen levels (ß for 8.69 kg higher FM: 0.07 g/L; 95 % CI: 0.05; 0.09). Baseline inflammatory markers were only associated with changes in hip circumference. CONCLUSION: Our study indicates the importance of anthropometric, body composition and fat distribution markers as a risk factor for the development of inflammation. To prevent inflammatory-related complications, important is to take measures against the development of obesity.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Cardiac remodelling in non-alcoholic fatty liver disease in the general population.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk for cardiovascular disease. Our study investigates the contribution of NAFLD to changes in cardiac structure and function in a general population. METHODS: One thousand ninety-six adults (49.3% female) from the Study of Health in Pomerania underwent magnetic resonance imaging including cardiac and liver imaging. The presence of NAFLD by proton density fat fraction was related to left cardiac structure and function. Results were adjusted for clinical confounders using multivariable linear regression model. RESULTS: The prevalence for NAFLD was 35.9%. In adjusted multivariable linear regression models, NAFLD was positively associated with higher left ventricular mass index (ß = 0.95; 95% confidence interval (CI): 0.45; 1.45), left ventricular concentricity (ß = 0.043; 95% CI: 0.031; 0.056), left ventricular end-diastolic wall thickness (ß = 0.29; 95% CI: 0.20; 0.38), left atrial end-diastolic volume index (ß = 0.67; 95% CI: 0.01; 1.32) and inversely associated with left ventricular end-diastolic volume index (ß = -0.78; 95% CI: -1.51; -0.05). When stratified by sex, we only found significant positive associations of NAFLD with left ventricular mass index, left atrial end-diastolic volume index, left ventricular cardiac output and an inverse association with global longitudinal strain in women. In contrast, men had an inverse association with left ventricular end-diastolic volume index and left ventricular stroke volume. Higher liver fat content was stronger associated with higher left ventricular mass index, left ventricular concentricity and left ventricular end-diastolic wall thickness. CONCLUSION: NAFLD is associated with cardiac remodelling in the general population showing sex specific patterns in cardiac structure and function.

Establishing Normative Values for Acromion Anatomy: A Comprehensive MRI-Based Study in a Healthy Population of 996 Participants.

Shoulder pain is a common issue often linked to conditions such as subacromial impingement or rotator cuff lesions. The role of the acromion in these symptoms remains a subject of debate. This study aims to establish standardized values for commonly used acromion dimensions based on whole-body MRI scans of a large and healthy population and to investigate potential correlations between acromion shape and influencing factors such as sex, age, BMI, dominant hand, and shoulder pain. The study used whole-body MRI scans from the Study of Health in Pomerania, a German population-based study. Acromion index, acromion tilt, and acromion slope were measured. Interrater variability was tested with two independent, trained viewers on 100 MRI sequences before actual measurements started. Descriptive statistics and logistic regression were used to evaluate the results. We could define reference values based on a shoulder-healthy population for each acromion parameter within the 2.5 to 97.5 percentile. No significant differences were found in acromion slope, tilt, and index between male and female participants. No significant correlations were observed between acromion morphology and anthropometric parameters such as height, weight, or BMI. No significant differences were observed in acromion parameters between dominant and non-dominant hands or stated pain intensity. This study provides valuable reference values for acromion-related parameters, offering insight into the anatomy of a healthy shoulder. The findings indicate no significant differences in acromion morphology based on sex, weight, BMI, or dominant hand. Further research is necessary to ascertain the clinical implications of these reference values. The establishment of standardized reference values opens new possibilities for enhancing clinical decision making regarding surgical interventions, such as acromioplasty.

Association between maternal pre-pregnancy body mass index and offspring's outcomes at 9 to 15 years of age.

OBJECTIVE: Maternal pre-pregnancy underweight, overweight and obesity might increase the risk for worse short- and long-term outcome in the offspring. There is a need for further study into the relationship between maternal pre-pregnancy body mass index (BMI) and the combined outcome of physical development, state of health and social behavior in children. QUESTION: Is maternal pre-pregnancy BMI associated with the child outcome in terms of physical development, state of health and social behavior (school and leisure time behavior) at the age of 9 to 15 years? METHODS: In the population-based birth cohort study Survey of Neonates in Pomerania (SNIP) children at the age 9-15 years and their families were re-examined by questionnaire-based follow-up. 5725 mother-child pairs were invited to SNiP-follow-up. This analysis is based on the recall fraction of 24.1% (n = 1379). Based on the maternal pre-pregnancy BMI (ppBMI), 4 groups were formed: underweight (ppBMI < 19 kg/m2, n = 117), normal weight (ppBMI 19-24.99 kg/m2, n = 913, reference), overweight (ppBMI 25-30 kg). /m2, n = 237) and obesity (ppBMI > 30 kg/m2, n = 109). RESULTS: In the multiple regression model, the BMI-z-score for children of mothers in the underweight group was -0.50 lower, and 0.50/1.07 higher in the overweight/obese group (p < 0.001) compared to reference at median age of 12 years. No differences were found in children of underweight mothers with regard to social behavior (interaction with friends and family), school and sports performance (coded from "very good" to "poor"), other leisure activities (watching television, using mobile phones, gaming), and health (occurrence of illnesses) compared to children of normal weight mothers. In contrast, maternal pre-pregnancy overweight and obesity were associated with lower school and sports performance, and higher screen time (smart phone, gaming, television) compared to children of normal weight mothers. CONCLUSION: Maternal pre-pregnancy overweight and obesity but not underweight was negatively associated with school performance and leisure time behavior in the offspring at 9-15 years of age.

Are there associations between hip geometry and bone quality? An analysis on 3074 adults from a general population.

INTRODUCTION: Patients with reduced bone mineral density and altered hip geometry are susceptible for hip pathologies. Knowledge on associations between bone properties and hip geometric parameters might facilitate identification of patients at risk for hip pathologies. The aim of the present study was to identify associations of bone properties assessed by quantitative ultrasound (QUS) at the heel and hip geometric parameters like center-edge angle (CE), neck-shaft angle (NSA) and alpha angle. MATERIALS AND METHODS: Hip geometric parameters (CE, NSA and alpha angle) of 3074 participants from the population-based Study of Health in Pomerania were assessed on magnetic resonance imaging. QUS was performed on both calcanei providing broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness-index. Based on the stiffness-index the individual osteoporotic fracture risk (low, moderate or high) was determined. Associations between QUS-based and hip geometric parameters were calculated in linear regression models adjusted for age, sex, body height and weight. Interactions of QUS markers with age and sex on hip geometric parameters were tested. RESULTS: Significant inverse associations between BUA (ß = - 0.068), SOS (ß = - 0.024) as well as stiffness-index (ß = - 0.056) and CE were present, while fracture risk was positively associated with CE (ß for high = 1.28 and moderate = 2.54 vs. low fracture risk). Interactions between BUA and sex as well as between SOS and age were detected in the models for CE. Furthermore, there was an inverse relation between fracture risk and NSA that was restricted to the moderate risk (ß for moderate vs. low fracture risk = - 0.60). There were no significant associations between QUS parameters and alpha angle. CONCLUSIONS: In the general population, several associations between QUS-based bone properties or fracture risk and hip geometry are present. Less dysplastic hips had a lower stiffness-index and a higher fracture risk, whereas more valgus hips had a lower fracture risk.

Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross-Cohort Collaboration.

BACKGROUND AND PURPOSE: Prior studies reported conflicting findings regarding the association of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis with measures of brain health. We examined whether NAFLD and liver fibrosis are associated with structural brain imaging measures in middle- and old-age adults. METHODS: In this cross-sectional study among dementia- and stroke-free individuals, data were pooled from the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Study of Health in Pomerania. NAFLD was assessed through abdominal imaging. Transient hepatic elastography (FibroScan) was used to assess liver fibrosis in FHS and RS. Linear regression models were used to explore the relation of NAFLD and liver fibrosis with brain volumes, including total brain, gray matter, hippocampus, and white matter hyperintensities, adjusting for potential confounders. Results were combined using fixed effects meta-analysis. RESULTS: In total, 5660 and 3022 individuals were included for NAFLD and liver fibrosis analyses, respectively. NAFLD was associated with smaller volumes of total brain (ß = -3.5, 95% confidence interval [CI] = -5.4 to -1.7), total gray matter (ß = -1.9, 95% CI = -3.4 to -0.3), and total cortical gray matter (ß = -1.9, 95% CI = -3.7 to -0.01). In addition, liver fibrosis (defined as liver stiffness measure ≥8.2 kPa) was related to smaller total brain volumes (ß = -7.3, 95% CI = -11.1 to -3.5). Heterogeneity between studies was low. CONCLUSIONS: NAFLD and liver fibrosis may be directly related to brain aging. Larger and prospective studies are warranted to validate these findings and identify liver-related preventive strategies for neurodegeneration.

Pituitary gland volumes and stress: Results of a population-based adult sample.

Early and chronic stress was reported to alter the hypothalamic-pituitary-adrenal axis functioning which regulates the secretion of cortisol. Nevertheless, few studies mainly focused on specific study populations (e.g. adolescents, pregnant women, and psychiatric patients), and researched interactive associations of pituitary volumes and single stress markers. The present study used pituitary volumes of two adult general-population cohorts of the Study of Health in Pomerania (SHIP-START-2: N = 1026, 54% Men, 30-90 years; SHIP-TREND-0: N = 1868, 53% Men, 21-82 years). In linear regression models, main effects of the pituitary volumes as well as interaction effects with childhood abuse and neglect (Childhood Trauma Questionnaire) were estimated using depressive symptoms (Beck Depression Inventory-II), and serum cortisol concentrations as outcome variables. The results of both cohorts were integrated via meta-analyses. No main effect between pituitary volumes and depressive symptoms was observed (START-2: ß = -0.004 [-0.082; 0.075], p = .929; TREND-0: ß = 0.020 [-0.033; 0.073], p = .466; Meta-analysis: ß = 0.012 [-0.031; 0.056], p = .580). However, larger pituitary volumes were associated with more depressive symptoms in participants with more severe childhood neglect (START-2: ß = 0.051 [-0.024; 0.126], p = .183; TREND-0: ß = 0.083 [0.006; 0.159], p = .034; Meta-analysis: ß = 0.066 [0.013; 0.120], p = .015). Further, larger pituitary volumes were associated with lower serum cortisol concentrations in participants with more severe depressive symptoms (START-2: ß = -0.087 [-0.145; -0.030], p = .003; TREND-0: ß = -0.053 [-0.091; -0.015], p = .006; Meta-analysis: ß = -0.063 [-0.095; -0.032], p = 8.39e-05). Summarizing, larger pituitary volumes were associated with more severe psychopathological symptoms, particularly in participants reporting early life stress. This was supported by stronger associations between pituitary volumes and cortisol concentrations in participants with more severe depressive symptoms. Future studies are needed to transfer these results into developmental stages of high hormonal changes and patient samples.

Correction: Analysis of epidemiological association patterns of serum thyrotropin by combining random forests and Bayesian networks.

[This corrects the article DOI: 10.1371/journal.pone.0271610.].

Association of Asymmetric and Symmetric Dimethylarginine with Inflammation in the Population-Based Study of Health in Pomerania.

The amino acids arginine (Arg), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are related to nitric oxide (NO) metabolism and potential markers of two different disease entities: cardiovascular disease such as atherosclerosis and systemic inflammation in critically ill patients with sepsis. Although very different in their pathophysiological genesis, both entities involve the functional integrity of blood vessels. In this context, large population-based data associating NO metabolites with proinflammatory markers, e.g., white blood cell count (WBC), high-sensitivity C-reactive protein (hsCRP), and fibrinogen, or cytokines are sparse. We investigated the association of Arg, ADMA and SDMA with WBC, hsCRP, and fibrinogen in 3556 participants of the Study of Health in Pomerania (SHIP)-TREND study. Furthermore, in a subcohort of 456 subjects, 31 inflammatory markers and cytokines were analyzed. We identified Arg and SDMA to be positively associated with hsCRP (ß coefficient 0.010, standard error (SE) 0.002 and 0.298, 0.137, respectively) as well as fibrinogen (ß 5.23 × 10-3, SE 4.75 × 10-4 and 0.083, 0.031, respectively). ADMA was not associated with WBC, hsCRP, or fibrinogen. Furthermore, in the subcohort, Arg was inversely related to a proliferation-inducing ligand (APRIL). SDMA was positively associated with osteocalcin, tumor necrosis factor receptor 1 and 2, and soluble cluster of differentiation 30. Our findings provide new insights into the involvement of Arg, ADMA, and SDMA in subclinical inflammation in the general population.