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Abstract Following implementation of a national prevention program against iodine deficiency-related disorders in 1993 in Germany, the prevalence of thyroid disorders declined, but aggregated drug dispensation data suggested a recent increase in thyroid hormone use. We aimed to systematically investigate trends in the use of thyroid diagnostic and treatment measures between 2008 and 2019 in Germany. Using the GePaRD database (claims data from ~ 20% of the German population), we determined the annual age-specific and age-standardized prevalence of the use of thyroid diagnostics (thyroid-stimulating hormone (TSH) measurement, thyroid ultrasound, scintiscan, biopsy) and treatment (medication, surgery, radioiodine therapy) from 2008 to 2019 stratified by sex. Between 2008 and 2019, the age-standardized prevalence of TSH measurement increased by 44% in males (from 165 to 238 per 1,000 persons) and by 31% in females (from 134 to 176 per 1,000). The prevalence of thyroid ultrasound use showed no clear time trend, while there was a decrease in the prevalence of scintiscan use (males/females: decrease by 42/43%) and biopsy (males/females: decrease by 42/34%). The prevalence of levothyroxine use increased by ~ 31% both in males (from 36 to 47 per 1,000) and females (from 134 to 175 per 1,000), while the prevalence of thionamide use, iodine use, thyroidectomy, and radioiodine therapy decreased. Our study suggests a continued decline in the prevalence of clinically significant thyroid disorders between 2008 and 2019. The substantial increase in the prevalence of TSH measurement and levothyroxine use during this time period might indicate overuse of diagnostics and overtreatment, warranting further investigation.

Abstract Background Glenoid version is an important factor in the evaluation of shoulder stability and shoulder pathologies. However, there are neither established reference values nor known factors that influence the glenoid version, even though valid reference values are needed for diagnostic and orthopaedic surgery like corrective osteotomy and total or reverse shoulder arthroplasty (TSA/RSA). The aim of our population-based study was to identify factors influencing the glenoid version and to establish reference values from a large-scale population cohort. Results Our study explored the glenoid versions in a large sample representing the general adult population. We investigated 3004 participants in the population-based Study of Health in Pomerania (SHIP). Glenoid version was measured for both shoulders via magnetic resonance imaging (MRI). Associations with the glenoid version were calculated for sex, age, body height, body weight and BMI. The reference values for glenoid version in the central European population range between −9° and 7.5°, while multiple factors are associated with the glenoid version. Conclusion To achieve a reliable interpretation prior to orthopaedic surgery, sex- and age-adjusted reference values are proposed.

Abstract A close anatomical and physiological relationship is known between the senses of hearing and balance, while an additional pathophysiological interaction is supposed. The mechanisms underlying this association are not yet fully understood, especially in individuals without a known specific otologic disorder. In particular, only scarce information on the combined occurrence of audiovestibular sensory impairment is available so far. Therefore, this study aims to provide further insight into the prevalence and co-prevalence of the audiovestibular symptoms hearing loss, tinnitus and dizziness. Additionally, the influence of potential risk factors from lifestyle habits as well as cardiovascular and metabolic conditions on the development of those symptoms is studied. Data was analyzed from 8134 individuals from the population-based Study of Health in Pomerania (SHIP). SHIP pursues a broad and comprehensive examination program in chronologically separated cohorts with longitudinal follow-up. Cohorts are sampled from Western Pomerania, a rural region of north-eastern Germany. The study population represents a cross-sectional analysis from the cohorts SHIP-START (recruited 1997–2001) and SHIP-TREND (recruited 2008–2012), sampled for baseline investigations (SHIP-START-0 and SHIP-TREND-0) at the age of 20–79 years. Audiovestibular symptoms as outcome variables were assessed by structured questionnaires. Additionally, individuals were comprehensively characterized regarding modifiable lifestyle factors as well as cardiovascular and metabolic disorders, allowing the assessment of their role as exposure variables. We calculated a weighted prevalence of 14.2% for hearing loss, 9.7% for tinnitus, and 13.5% for dizziness in the population. Prevalence increased with age and differed among the sexes. A considerable share of 28.0% of the investigated individuals reported more than one symptom at once. The prevalence of hearing loss as well as tinnitus increased between the two cohorts. A moderate positive correlation was found between the occurrence of hearing loss and tinnitus (phi-coefficient 0.318). In multivariable regression analyses, education was identified as a significant protective factor while only smoking was significantly associated with all three symptoms. Furthermore, several cardiovascular risk factors contributed to both hearing loss and dizziness. In conclusion, audiovestibular symptoms are highly prevalent in the investigated population. A considerable but complex influence of risk factors points towards a relation with neuronal as well as cardiovascular disease processes. To clarify the underlying mechanisms, the interaction between the senses of hearing and balance as well as the mode of action of the risk factors should be evaluated in more detail in the future.

Abstract Background To identify factors associated with non-alcoholic fatty liver disease over a 5-year period. Methods Three hundred seven participants, including 165 women, with a mean age of 55.6 ± 12.0 years underwent continuous quantitative MRI of the liver using the proton-density fat fraction (PDFF). The liver’s fat fractions were determined at baseline and 5 years later, and the frequency of participants who developed fatty liver disease and potential influencing factors were explored. Based on significant factors, a model was generated to predict the development of fatty liver disease. Results After excluding participants with pre-existing fatty liver, the baseline PDFF of 3.1 ± 0.9% (n = 190) significantly increased to 7.67 ± 3.39% within 5 years (p

Background and aim: As the spleen plays a significant role in immunity, the aim was to investigate the associations of different body composition markers derived from various sources with spleen volume in a general population sample. Materials and methods: Cross-sectional data of 1095 individuals (570 women; 52%) aged between 30 and 90 years were collected in the Study of Health in Pomerania (SHIP-START-2). We measured spleen volume by magnetic resonance imaging (MRI).Body composition markers were derived from classic anthropometry, bioelectrical impedance analysis, including absolute fat mass (FM) and fat-free mass (FFM), as well as from MRI, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat content. Sex-stratified-adjusted linear regression models were used to analyze the associations of body composition markers with spleen volumes. Results: We observed positive associations of body mass index, body weight, waist circumference, hip circumference, waist-to-height ratio, absolute FM, absolute FFM, and VAT and SAT with spleen volume in men and women. An 8.12 kg higher absolute FFM was associated with a 38.4 mL (95% confidence interval [CI]: 26.7–50.1) higher spleen volume in men and a 5.21 kg higher absolute FFM with a 42.6 mL (95% CI: 26.2–59.0) higher spleen volume in women. Conclusion: Our findings indicate that obesity-related body composition markers and FFM are associated with a higher spleen volume. Particularly, higher absolute FFM showed a strong association with a larger spleen volume in both men and women. Further studies are warranted to understand the clinical significance of body composition markers on large spleen volume.

Abstract 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.

Abstract 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).

Abstract 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

Abstract 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

Abstract 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.

Abstract Parameters of cardiopulmonary exercise testing significantly discriminate between healthy subjects and patients with pulmonary hypertension (PH), also according to the new 2022 definition of pulmonary hypertension (mean pulmonary arterial pressure mPAP > 20 mmHg). The cut‐offs indicating on PH were peakVO2 ≤ 16.7 mL/min/kg (Youden‐Index YI = 0.79), petCO2@AT ≤ 34 mmHg (YI = 0.67), and VE/VCO2@AT ≤ 30 (YI = 0.76).

Background: The aim of our study was to investigate associations of spleen volume with blood count markers and lipid profile in the general population. Materials & methods: Cross-sectional data from 1,106 individuals aged 30–90 years from the population-based Study of Health in Pomerania (SHIP-START-2) were analyzed. Blood count markers included red blood cell (RBC) counts, hemoglobin, platelet count, and white blood cell (WBC) counts. Lipid profile included total-cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) as well as triglycerides. Linear regression models adjusted for age, sex, body height, and weight were used to associate standardized spleen volume with blood counts and lipid profile markers. Results: Spleen volume was positively associated with RBC (β = 0.05; 95% confidence interval [CI] = 0.03 to 0.08) and hemoglobin (β = 0.05; 95% CI = 0.01 to 0.09) but inversely with platelet count (β = −16.3; 95% CI = –20.5 to −12.1) and WBC (β = −0.25; 95% CI = −0.37 to −0.14). Furthermore, spleen volume showed inverse associations with total cholesterol (β = −0.17; 95% CI = −0.24 to −0.09), HDL-C (β = −0.08; 95% CI = −0.10 to −0.05), and LDL-C (β = −0.12; 95% CI = −0.17 to −0.06). There was no significant association of spleen volume with triglycerides. Conclusion: Our study showed that the spleen volume is associated with markers of the blood count and lipid profile in the general population.

Intrauterine growth restriction leads to an altered lipid and amino acid profile in the cord blood at the end of pregnancy. Pre-pregnancy underweight is an early risk factor for impaired fetal growth. The aim of this study was to investigate whether a pre-pregnancy body mass index (ppBMI) of 2, as early as at the beginning of pregnancy, is associated with changes in the umbilical cord metabolome. In a sample of the Survey of Neonates in Pomerania (SNIP) birth cohort, the cord blood metabolome of n = 240 newborns of mothers with a ppBMI of 2 with n = 208 controls (ppBMI of 18.5–24.9 kg/m2) was measured by NMR spectrometry. A maternal ppBMI of 2 was associated with increased concentrations of HDL4 cholesterol, HDL4 phospholipids, VLDL5 cholesterol, HDL 2, and HDL4 Apo-A1, as well as decreased VLDL triglycerides and HDL2 free cholesterol. A ppBMI of 2 combined with poor intrauterine growth (a gestational weight gain (GWG) < 25th percentile) was associated with decreased concentrations of total cholesterol; cholesterol transporting lipoproteins (LDL4, LDL6, LDL free cholesterol, and HDL2 free cholesterol); LDL4 Apo-B; total Apo-A2; and HDL3 Apo-A2. In conclusion, maternal underweight at the beginning of pregnancy already results in metabolic changes in the lipid profile in the cord blood, but the pattern changes when poor GWG is followed by pre-pregnancy underweight.

Abstract Background and aims Prevention measures for cardiovascular diseases (CVD) have shifted their focus from lipoproteins to the immune system. However, low-grade inflammation and dyslipidemia are tightly entangled. The objective of this study was to assess the relations between a broad panel of inflammatory biomarkers and lipoprotein subclass parameters. Methods We utilized data from the population-based Study of Health in Pomerania (SHIP-TREND, n = 403). Plasma concentrations of 37 inflammatory markers were measured by a bead-based assay. Furthermore, we employed nuclear magnetic resonance spectroscopy to measure total cholesterol, total triglycerides, total phospholipids as well as the fractional concentrations of cholesterol, triglycerides, phospholipids, ApoA1, ApoA2 and ApoB in all major lipoprotein subclasses. Associations between inflammatory biomarkers and lipoprotein subclasses were analyzed by adjusted linear regression models. Results APRIL, BAFF, TWEAK, sCD30, Pentraxin-3, sTNFR1, sTNFR2, Osteocalcin, Chitinase 3-like 1, IFN-alpha2, IFN-gamma, IL-11, IL-12p40, IL-29, IL-32, IL-35, TSLP, MMP1 and MMP2 were related with lipoprotein subclass components, forming two distinct clusters. APRIL had inverse relations to HDL-C (total and subclasses) and HDL Apo-A1 and Apo-A2 content. MMP-2 was inversely related to VLDL-C (total and subclasses), IDL-C as well as LDL5/6-C and VLDL-TG, IDL-TG, total triglycerides as well as LDL5/5-TG and HDL4-TG. Additionally, we identified a cluster of cytokines linked to the Th1-immune response, which were associated with an atherogenic lipoprotein profile. Conclusion Our findings expand the existing knowledge of inflammation-lipoprotein interactions, many of which are suggested to be involved in the pathogeneses of chronic non-communicable diseases. The results of our study support the use of immunomodulatory substances for the treatment and possibly prevention of CVD.

Abstract Background Obesity-related cardiometabolic comorbidity is common in major depressive disorder (MDD). However, sex differences and MDD recurrence may modify the MDD-obesity-link. Methods Sex-specific associations of MDD recurrence (single [MDDS] or recurrent episodes [MDDR]) and obesity-related traits were analyzed in 4.100 adults (51.6% women) from a cross-sectional population-based cohort in Germany (SHIP-Trend-0). DSM-IV-based lifetime MDD diagnoses and MDD recurrence status were obtained through diagnostic interviews. Obesity-related outcomes included anthropometrics (weight, body mass index, waist- and hip-circumference, waist-to-hip ratio, waist-to-height ratio), bioelectrical impedance analysis of body fat mass and fat-free mass, and subcutaneous (SAT) and visceral adipose tissue (VAT) from abdominal magnetic resonance imaging. Sex-stratified linear regression models predicting obesity-related traits from MDD recurrence status were adjusted for age, education, and current depressive symptoms. Results 790 participants (19.3%) fulfilled lifetime MDD criteria (23.8% women vs. 14.5% men, p

Abstract Homoarginine (hArg) is a non-essential cationic amino acid which inhibits hepatic alkaline phosphatases to exert inhibitory effects on bile secretion by targeting intrahepatic biliary epithelium. We analyzed (1) the relationship between hArg and liver biomarkers in two large population-based studies and (2) the impact of hArg supplementation on liver biomarkers. We assessed the relationship between alanine transaminase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), alkaline phosphatases (AP), albumin, total bilirubin, cholinesterase, Quick’s value, liver fat, and Model for End-stage Liver Disease (MELD) and hArg in appropriately adjusted linear regression models. We analyzed the effect of L-hArg supplemention (125 mg L-hArg daily for 4 weeks) on these liver biomarkers. We included 7638 individuals (men: 3705; premenopausal women: 1866, postmenopausal women: 2067). We found positive associations for hArg and ALT (β 0.38 µkatal/L 95% confidence interval (CI): 0.29; 0.48), AST (β 0.29 µkatal/L 95% CI 0.17; 0.41), GGT (β 0.033 µkatal/L 95% CI 0.014; 0.053), Fib-4 score (β 0.08 95% CI 0.03; 0.13), liver fat content (β 0.016% 95% CI 0.006; 0.026), albumin (β 0.030 g/L 95% CI 0.019; 0.040), and cholinesterase (β 0.003 µkatal/L 95% CI 0.002; 0.004) in males. In premenopausal women hArg was positively related with liver fat content (β 0.047% 95%CI 0.013; 0.080) and inversely with albumin (β − 0.057 g/L 95% CI − 0.073; − 0.041). In postmenopausal women hARG was positively associated with AST (β 0.26 µkatal/L 95% CI 0.11; 0.42). hArg supplementation did not affect liver biomarkers. We summarize that hArg may be a marker of liver dysfunction and should be explored further.

Objective: Thyroid dysfunction is associated with relevant disturbances in glucose metabolism. Moreover, thyroid function undergoes important changes with ageing. The objective of this study was to investigate the association of thyroid function with insulin resistance with particular consideration of possible age-related effect modifications. Design: A sample of 4193 participants from two independent epidemiological studies, the Study of Health in Pomerania-TREND-0 and the Berlin Aging Study II, was included in this cross-sectional analysis. Methods: Insulin resistance was estimated by homeostasis model of insulin resistance (HOMA-IR) and the insulin sensitivity index (ISI). Associations of thyroid biomarkers (thyroid-stimulating hormone, free thyroxine, and free triiodothyronine (fT3)) with parameters of glucose metabolism were analysed by regression models adjusted for age, sex, smoking status, and study site. Results: A higher fT3 was significantly associated with higher fasting g lucose and higher fasting and 2-h postload insulin levels, a higher HOMA-IR, and lower ISI. A higher fT3 was also associated with a higher risk for impaired fasting glucose (RR 1.09, 95 CI 1.02; 1.18; P = 0.017). Many of these associations between thyroid markers and parameters of glucose metabolism were significant in young and middle-aged participants but not in older individuals. Conclusions: The main finding of this study was a consistent association of fT3 with almost all markers of insulin resistance. However, this effect s eems to be wearing off in higher age highlighting a potential age-related modification of the interaction between thyroid function and glucose metabolism. Further studies are needed to clarify causal relationships.

Objective: Aging, physical inactivity, and chronic disease can decrease strength and muscle mass and affect mobility and autonomy in older adults. This study aimed to analyze the prevalence and associated factors of low physical functional performance among older adults in the city of Pomerode, in southern Brazil. Methods: This is a cross-sectional population-based study with data on 733 older adults from the Study of Health in Pomerode – SHIP-Brazil. Low functional physical performance was defined as handgrip strength ≤ 32 kg for men or ≤ 20 kg for women and/or a Timed Up and Go test ≥ 11 seconds for men or ≥ 13 seconds for women. Associations were analysed by multiple logistic regression. Results: The prevalence of low physical functional performance was 43.7% (42.2% among women and 45.5% among men). Low physical functional performance was associated with the 70-79 years age group (odds ratio [OR] = 2.07) and insufficient physical activity (OR = 2.73) in men, and with the 70-79 years age group (OR = 2.09) and multimorbidity (OR = 1.87) in women. In general, older age, insufficient physical activity, and multimorbidity were associated with low physical functional performance in older adults. Conclusion: Our findings suggest that while insufficient physical activity is crucial for physical functional performance in older men, multimorbidity appears to be crucial for older women.

Abstract The assessment of cardiorespiratory fitness (CRF) is an important tool for prognosis evaluation of cardiovascular events. The gold standard to measure CRF is cardiopulmonary exercise testing (CPET) to determine peak oxygen uptake (VO2peak). However, CPET is not only time consuming but also expensive and is therefore not widely applicable in daily practice. The aim of our study was to analyze, whether and which anthropometric markers derived from a 3D body scanner were related to VO2peak in a general population-based study. We analyzed data (SHIP-START-3) from 3D body scanner and CPET of 1035 subjects (529 women; 51.1%, age range 36–93). A total of 164 anthropometric markers were detected with the 3D body scanner VITUS Smart XXL using the software AnthroScan Professional. Anthropometric measurements were standardized and associated with CRF by sex-stratified linear regression models adjusted for age and height. Anthropometric markers were ranked according to the − log- p values derived from these regression models. In men a greater left and right thigh-knee-ratio, a longer forearm-fingertip length, a greater left thigh circumference and greater left upper arm circumference were most strongly associated with a higher VO2peak. In women a greater left and right thigh circumference, left calf circumference, thigh thickness and right calf circumference were most strongly associated with a higher VO2peak. The detected VO2peak-related anthropometric markers could be helpful in assessing CRF in clinical routine. Commonly used anthropometric markers, e.g. waist and hip circumference, were not among the markers associated with VO2peak.

Abstract Background Missing data are ubiquitous in randomised controlled trials. Although sensitivity analyses for different missing data mechanisms (missing at random vs. missing not at random) are widely recommended, they are rarely conducted in practice. The aim of the present study was to demonstrate sensitivity analyses for different assumptions regarding the missing data mechanism for randomised controlled trials using latent growth modelling (LGM). Methods Data from a randomised controlled brief alcohol intervention trial was used. The sample included 1646 adults (56% female; mean age = 31.0 years) from the general population who had received up to three individualized alcohol feedback letters or assessment-only. Follow-up interviews were conducted after 12 and 36 months via telephone. The main outcome for the analysis was change in alcohol use over time. A three-step LGM approach was used. First, evidence about the process that generated the missing data was accumulated by analysing the extent of missing values in both study conditions, missing data patterns, and baseline variables that predicted participation in the two follow-up assessments using logistic regression. Second, growth models were calculated to analyse intervention effects over time. These models assumed that data were missing at random and applied full-information maximum likelihood estimation. Third, the findings were safeguarded by incorporating model components to account for the possibility that data were missing not at random. For that purpose, Diggle-Kenward selection, Wu-Carroll shared parameter and pattern mixture models were implemented. Results Although the true data generating process remained unknown, the evidence was unequivocal: both the intervention and control group reduced their alcohol use over time, but no significant group differences emerged. There was no clear evidence for intervention efficacy, neither in the growth models that assumed the missing data to be at random nor those that assumed the missing data to be not at random. Conclusion The illustrated approach allows the assessment of how sensitive conclusions about the efficacy of an intervention are to different assumptions regarding the missing data mechanism. For researchers familiar with LGM, it is a valuable statistical supplement to safeguard their findings against the possibility of nonignorable missingness. Trial registration The PRINT trial was prospectively registered at the German Clinical Trials Register (DRKS00014274, date of registration: 12th March 2018).

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 (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 (19-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.

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.

Abstract Aims Available upper reference levels (URLs) in older adults for N‐terminal pro brain natriuretic peptide (NT‐proBNP), an established biomarker for heart failure, are mainly based on small samples. We aimed to identify NT‐proBNP URL in a population‐based reference sample of individuals aged ≥65 years. Methods and results We analysed established NT‐proBNP predictors using quantile regression among 2459 participants of two‐independent population‐based cohorts located in Germany, the Activity and Function in the Elderly Study (ActiFE, n = 1450) and the Study of Health in Pomerania (SHIP‐TREND‐0, n = 1009). Based on predictors a reference population of 441 subjects (ActiFE, n = 227; SHIP‐TREND‐0, n = 214) without history of diabetes, cardiovascular, or pulmonary diseases and with systolic blood pressure (BP) 125 ng/L in 165 participants (37.4%), with NT‐proBNP URL (97.5% quantiles) equal to 663, 824, 592, and 697 ng/L in men, and 343, 463, 2641, 1276 ng/L in women for ages 65–69, 70–74, 75–79, and 80+ years, respectively. In the secondary analysis with a LVEF ≥50 and no diastolic dysfunction (35 men and 62 women) NT‐proBNP levels >125 ng/L were still observed in 38 (39.2%) participants. Conclusions This reference sample of apparently healthy asymptomatic older adults showed an age‐related increment of NT‐proBNP levels with URL markedly higher than the European Society of Cardiology recommended cut‐off of 125 ng/L for the diagnosis of heart failure in ambulatory settings. Identifying URL in those ≥80 years remains complex. Our results attempt to provide a frame for the further investigation of age‐specific NT‐proBNP cut‐offs in older adults. Considering the demographic changes, further evaluation of NT‐proBNP URL in larger samples of older adults followed by the validation of age‐specific cut‐off values for the identification of heart failure in those 65 years or older are urgently needed.

Abstract Clinically relevant postoperative pancreatic fistula (CR-POPF) is a common severe surgical complication after pancreatic surgery. Current risk stratification systems mostly rely on intraoperatively assessed factors like manually determined gland texture or blood loss. We developed a preoperatively available image-based risk score predicting CR-POPF as a complication of pancreatic head resection. Frequency of CR-POPF and occurrence of salvage completion pancreatectomy during the hospital stay were associated with an intraoperative surgical (sFRS) and image-based preoperative CT-based (rFRS) fistula risk score, both considering pancreatic gland texture, pancreatic duct diameter and pathology, in 195 patients undergoing pancreatic head resection. Based on its association with fistula-related outcome, radiologically estimated pancreatic remnant volume was included in a preoperative (preFRS) score for POPF risk stratification. Intraoperatively assessed pancreatic duct diameter (p

Objective: Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries /regions with different iodine status and prevention programs. Design: Register-based cross-sectional study. Methods: National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex-and age-standardized rates were calculated. Results: Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medica tion, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroi d surgery for benign disease and lower rates of thyroid hormone therapy were found f or countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs. Conclusions: The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availabilit y and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated . This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.

Abstract The Apolipoprotein E (APOE) gene polymorphism (rs429358 and rs7412) shows a well-established association with lipid profiles, but its effect on cardiovascular disease is still conflicting. Therefore, we examined the association of different APOE alleles with common carotid artery intima-media thickness (CCA-IMT), carotid plaques, incident myocardial infarction (MI) and stroke. We analyzed data from 3327 participants aged 20–79 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 14.5 years. Linear, logistic, and Cox-regression models were used to assess the associations of the APOE polymorphism with CCA-IMT, carotid plaques, incident MI and stroke, respectively. In our study, the APOE E2 allele was associated with lower CCA-IMT at baseline compared to E3 homozygotes (β: − 0.02 [95% CI − 0.04, − 0.004]). Over the follow-up, 244 MI events and 218 stroke events were observed. APOE E2 and E4 allele were not associated with incident MI (E2 HR: 1.06 [95% CI 0.68, 1.66]; E4 HR: 1.03 [95% CI 0.73, 1.45]) and incident stroke (E2 HR: 0.79 [95% CI 0.48, 1.30]; E4 HR: 0.96 [95% CI 0.66, 1.38]) in any of the models adjusting for potential confounders. However, the positive association between CCA-IMT and incident MI was more pronounced in E2 carriers than E3 homozygotes. Thus, our study suggests that while APOE E2 allele may predispose individuals to lower CCA-IMT, E2 carriers may be more prone to MI than E3 homozygotes as the CCA-IMT increases. APOE E4 allele had no effect on CCA-IMT, plaques, MI or stroke.

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 (β coefficient 0.010, standard error (SE) 0.002 and 0.298, 0.137, respectively) as well as fibrinogen (β 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.

The associations of thyroid function parameters with non-alcoholic fatty liver disease (NAFLD) and hepatic iron overload are not entirely clear. We have cross-sectionally investigated these associations among 2734 participants of two population-based cross-sectional studies of the Study of Health in Pomerania. Serum levels of thyroid-stimulating hormone (TSH), free tri-iodothyronine (fT3), and free thyroxine (fT4) levels were measured. Liver fat content (by proton-density fat fraction) as well as hepatic iron content (by transverse relaxation rate; R2*) were assessed by quantitative MRI. Thyroid function parameters were associated with hepatic fat and iron contents by median and logistic regression models adjusted for confounding. There were no associations between serum TSH levels and liver fat content, NAFLD, or hepatic iron overload. Serum fT4 levels were inversely associated with liver fat content, NAFLD, hepatic iron contents, and hepatic iron overload. Serum fT3 levels as well as the fT3 to fT4 ratio were positively associated with hepatic fat, NAFLD, hepatic iron contents, but not with hepatic iron overload. Associations between fT3 levels and liver fat content were strongest in obese individuals, in which we also observed an inverse association between TSH levels and NAF LD. These findings might be the result of a higher conversion of fT4 to the biologically active form fT3. Our results suggest that a subclinical hyperthyroid state may be associated with NAFLD, particularly in obese individuals. Furthermore, thyroid hormone levels seem to be more strongly associated with increased liver fat content compared to hepatic iron content.

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

Background: The global obesity epidemic is a major public health concern, and accurate diagnosis is essential for identifying at-risk individuals. Three-dimensional (3D) body scanning technology offers several advantages over the standard practice of tape measurements for diagnosing obesity. This study was conducted to validate body scan data from a German population-based cohort and explore clinical implications of this technology in the context of metabolic syndrome. Methods: We performed a cross-sectional analysis of 354 participants from the Study of Health in Pomerania that completed a 3D body scanning examination. The agreement of anthropometric data obtained from 3D body scanning with manual tape measurements was analyzed using correlation analysis and Bland–Altman plots. Classification agreement regarding abdominal obesity based on IDF guidelines was assessed using Cohen’s kappa. The association of body scan measures with metabolic syndrome components was explored using correlation analysis. Results: Three-dimensional body scanning showed excellent validity with slightly larger values that presumably reflect the true circumferences more accurately. Metabolic syndrome was highly prevalent in the sample (31%) and showed strong associations with central obesity. Using body scan vs. tape measurements of waist circumference for classification resulted in a 16% relative increase in the prevalence of abdominal obesity (61.3% vs. 52.8%). Conclusions: These results suggest that the prevalence of obesity may be underestimated using the standard method of tape measurements, highlighting the need for more accurate approaches.

Abstract Background Compared to individuals without type 2 diabetes mellitus, the relative increase in cardiovascular mortality is much higher in women than in men in individuals with type 2 diabetes mellitus. Methods We evaluated data from 7443 individuals (3792 women, 50.9%), aged 20 to 81 years, from two independent population-based investigations, SHIP-0 and MONICA/KORA S3. We analyzed the longitudinal sex-specific associations of lipoprotein(a) with cardiovascular mortality in individuals with and without type 2 diabetes mellitus using Cox regression. Results During a median follow-up of 20.5 years (136,802 person-years), 657 participants (404 men and 253 women) died of cardiovascular causes. Among individuals without type 2 diabetes mellitus, men had a significantly higher risk for cardiovascular mortality compared to women in unadjusted model and after adjustment. On the other hand, in participants with type 2 diabetes mellitus, the risk for cardiovascular mortality was not different between men and women in the unadjusted model and after adjustment for age, body mass index, low-density lipoprotein-cholesterol, fasting status and study sample (SHIP-0, MONICA/KORA S3). Further adjustment for lipoprotein(a) concentrations had no impact on the hazard ratio (HR) for cardiovascular mortality comparing men versus women in individuals without type 2 diabetes mellitus [HR: 1.94; 95% confidence interval (CI) 1.63 to 2.32; p

Abstract The aim of our study was to investigate the association of hepatic steatosis derived from quantitative ultrasound and magnetic resonance imaging (MRI) with prediabetes in a large population-based study conducted in Northeast Germany. Hepatic steatosis was assessed through transabdominal ultrasound and quantitative MRI. For analysis we included 1622 subjects with MRI who participated in an oral glucose tolerance test and reported no known type 2 diabetes mellitus (T2DM). We classified participants as proposed by the American Diabetes Association: isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT), and undiagnosed T2DM. Regression models were adjusted for age, sex body mass index and alcohol consumption. We observed positive associations of hepatic steatosis with glycated hemoglobin, fasting glucose and insulin, 2-h glucose and insulin, as well as homeostasis model assessment-insulin resistance index. Similarly, individuals having hepatic steatosis as defined by MRI had a higher relative risk ratio (RR) to be in the prediabetes groups i-IFG (RR = 1.6; 95% confidence interval (CI) 1.2; 2.2), i-IGT (RR = 3.3, 95% CI 2.0; 5.6) and IFG + IGT (RR = 2.5, 95% CI 1.6; 3.9) or to have undiagnosed T2DM (RR = 4.8, 95% CI 2.6; 9.0). All associations were attenuated when defining hepatic steatosis by ultrasound. Hepatic steatosis is associated with prediabetes and undiagnosed T2DM in the general population. Quantitative liver MRI revealed stronger associations with prediabetes and undiagnosed T2DM compared to ultrasound, which indicates the higher sensitivity and specificity of MRI to determine hepatic steatosis.

Abstract Previous studies on the association between thyroid function and body composition are conflicting and showed strong differences across age groups. Our aim was to clarify age-specific associations of serum thyroid-stimulating hormone (TSH) levels with markers of body composition including body mass index (BMI), waist circumference, fat mass (FM), fat-free mass (FFM) and body cell mass (BCM). We used data from two independent population-based cohorts within the framework of the Study of Health in Pomerania. The study population included 5656 individuals aged 20 to 90 years. Markers of body composition were measured by bioelectrical impedance analysis. Serum TSH levels were significantly positively associated with BMI (β = 0.16; 95% confidence interval [CI]: 0.06 to 0.27), waist circumference (β = 0.35; 95% CI: 0.08 to 0.62) and FM (β = 0.32; 95% CI: 0.12 to 0.52), but not with FFM and BCM. Interaction analysis revealed positive associations of serum TSH levels with BMI, waist circumference, FM, FFM and BCM in individuals older than 60 years, while no such associations were observed in younger individuals. We demonstrated that lower serum TSH levels were accompanied with lower values of BMI, waist circumference, FM, FFM, and BCM in the elderly, while no such associations were observed in younger individuals.

Background. The German maternity guidelines require regular medical checkup (MC) during pregnancy as a measure of prevention. Socioeconomic factors such as education, profession, income and origin, but also age and parity may influence the preventive and health behavior of pregnant women. The aim was to investigate the influence of these factors on the participation rate in MC of pregnant women. Method. The current analysis is based on the prospective population-based birth cohort study Survey of Neonates in Pomerania, which was conducted in Western Pomerania, Germany. The data of 4092 pregnant women from 2004 to 2008 were analyzed regarding the antenatal care and health behavior. Up to 12 MC were regularly offered; participation in 10 MC is defined as standard screening according to maternity guidelines. Results. Women participated in the first preventive MC on average in the 10th (±3.8 SD) week of pregnancy. 1343 (34.2%) women participated in standard screening and 2039 (51.9%) took a screening above standard. 547 (13.92%) women participated in less than the 10 standard MCs. In addition, about one-third of the pregnancies investigated in this study were unplanned. Bivariate analyses showed an association between better antenatal care behavior and higher maternal age, stabile partnerships and mother born in Germany, p < 0.05. On the contrary antenatal care below standard were more often found by women with unplanned pregnancies, less educational women and women with lower equivalent income, p < 0.001. Health behaviors also influenced antenatal care. Whereas the risk of antenatal care below standard increased by smoking during pregnancy (RRR 1.64; 95% CI 1.25, 2.14) and alcohol consumption (RRR 1.31; 95% CI 1.01, 1.69), supplementation intake was associated with decreased risk (iodine—RRR 0.66; 95% CI 0.53, 0.81; folic acid—RRR 0.56; 95% CI 0.44, 0.72). The health behavior of pregnant women also differs according to their social status. Higher maternal income was negatively correlated with smoking during pregnancy (OR 0.2; 95% CI 0.15, 0.24), but positively associated with alcohol consumption during pregnancy (OR 1.3; 95% CI 1.15, 1.48) and lower pre-pregnancy BMI (Coef. = 0.083, p < 0.001). Lower maternal education was positively correlated with smoking during pregnancy (OR 59.0; 95% CI 28.68, 121.23). Conclusions. Prenatal care according to maternity guidelines is well established with a high participation rate in MC during pregnancy of more than 85%. However, targeted preventive measures may address younger age, socioeconomic status and health-damaging behaviors (smoking, drinking) of the pregnant women because these factors were associated with antenatal care below standard.

Abstract Background Thyroid disorders are common in the adult German population. Little is known about guideline implementation in clinical practice and the prevalence of diagnostic procedures in ambulatory care. The study aims to investigate the use of thyroid hormone measurements, thyroid ultrasound, thyroid scintiscan and associated costs in ambulatory care at population level. Methods Data were derived from two independent population-based cohorts of the Study of Health In Pomerania (SHIP). Ambulatory billing data from the Association of Statutory Health Insurance Physicians Mecklenburg-Vorpommern were individually linked for the period 2002–2016 with SHIP data. The main outcomes were the frequency of outpatient ultrasound, scintiscan, serum TSH level measurement, free triiodothyronine (fT3) and free thyroxine (fT4) measurement, TSH-receptor-antibodies and microsomal antibodies measurement within 1 year and 3 years prior to the study entrance of the participants. Multinomial logistic regression models were used to assess the association of age, sex, thyroid medication intake and Charlson-Comorbidity-Index with frequency of TSH measurements and ultrasound examinations. Results A total of 5552 participants (47% male, median age 55) were included in the analysis. 25% (1409/5552) had a diagnosed thyroid disorder or treatment, 40% (2191/5552) had clinical findings based on ultrasound or laboratory testing in SHIP only and 35% (1952/5552) neither a coded thyroid disorder or clinical finding nor thyroid medication. In the total study population 30% (1626/5552) received at least one TSH measurement, 6.8% (378/5552) at least one thyroid ultrasound and 2.6% (146/5552) at least one scintiscan within the past year before the study examination. Tests were performed more frequently in patients with thyroid medication and coded thyroid disorders. Hence, this group caused the highest expenditures. Conclusions Given the high prevalence of thyroid disorders, diagnostic and monitoring tests should be used rationally with regard to costs. TSH levels should be monitored regularly in patients on thyroid medication. A consensus on monitoring frequency and iteration of monitoring of morphological thyroid disorders with TSH and ultrasound and specific guideline recommendations are needed. Trial registration Versorgungsforschung Deutschland (VfD_17_003880).

Background and purpose — The neck–shaft angle (NSA) is valuable for diagnostics and therapy of the hip, but current reference values derive mostly from studies on anatomic specimens, small cohorts, or are hospital-based. Moreover, associated factors such as age, sex, or anthropometric data have rarely been considered. Therefore, we determined associated factors for NSA and reassessed the historical reference values in a general adult population. Methods — NSAs on both sides of 3,226 volunteers from the population-based Study of Health in Pomerania (SHIP) were measured with MRI. SHIP drew a representative sample of the population of Pomerania (northeastern Germany). NSAs were compared with sex, age, and anthropometric data by bivariable linear regression models. Reference values were assessed by quantile regressions for 2.5th and 97.5th percentiles. Results — The mean NSA was 127° (SD 7), while men had a lower NSA than women (95% confidence interval [CI] 0.4°–1.4°). The reference range was 114°–140°. Age was inversely associated with NSA (CI –0.2 to –0.1). Body height was positively associated with the NSA, while BMI and waist circumference showed a negative association. There was no association between body weight and NSA. Interpretation — The historical lower limit of 120° might be too high, so the radiological prevalence of hip pathology might have been overestimated. The previously reported influence of age, sex, and body height on the NSA has been confirmed.

BackgroundApproaching epidemiological data with flexible machine learning algorithms is of great value for understanding disease-specific association patterns. However, it can be difficult to correctly extract and understand those patterns due to the lack of model interpretability.MethodWe here propose a machine learning workflow that combines random forests with Bayesian network surrogate models to allow for a deeper level of interpretation of complex association patterns. We first evaluate the proposed workflow on synthetic data. We then apply it to data from the large population-based Study of Health in Pomerania (SHIP). Based on this combination, we discover and interpret broad patterns of individual serum TSH concentrations, an important marker of thyroid functionality.ResultsEvaluations using simulated data show that feature associations can be correctly recovered by combining random forests and Bayesian networks. The presented model achieves predictive accuracy that is similar to state-of-the-art models (root mean square error of 0.66, mean absolute error of 0.55, coefficient of determination of R2 = 0.15). We identify 62 relevant features from the final random forest model, ranging from general health variables over dietary and genetic factors to physiological, hematological and hemostasis parameters. The Bayesian network model is used to put these features into context and make the black-box random forest model more understandable.ConclusionWe demonstrate that the combination of random forest and Bayesian network analysis is helpful to reveal and interpret broad association patterns of individual TSH concentrations. The discovered patterns are in line with state-of-the-art literature. They may be useful for future thyroid research and improved dosing of therapeutics.

Abstract Background Recent guidelines recommend a cranial ultrasound (CU) in neonates born at

Background Lower cardiorespiratory fitness (CRF) is associated with an increased risk for cardiovascular disease. However, very little information is available about the association between lower CRF and right ventricular (RV) remodeling. We investigated the relationship between CRF and RV structure and function in a large, aging, and largely sedentary adult population–based cohort. Methods and Results We used cross‐sectional data of 2844 subjects (1486 women; median age, 51 years; interquartile range, 40–62 years) from the population‐based cohort SHIP (Study of Health in Pomerania) with echocardiography, of which 941 also had cardiac magnetic resonance imaging. We analyzed the associations of peak oxygen uptake with RV parameters determined by both imaging techniques using multivariable‐adjusted linear regression models. In echocardiography, a 1 L/min lower peak oxygen uptake was associated with a 1.18 mm (95% CI, 0.66–1.71; P

Representative epidemiologic data on the average volume of the parotid gland in a large population-based MRI survey is non-existent. Within the Study of Health in Pomerania (SHIP), we examined the parotid gland in 1725 non-contrast MRI-scans in T1 weighted sequence of axial layers. Thus, a reliable standard operating procedure (Intraclass Correlation Coefficient > 0.8) could be established. In this study, we found an average, single sided parotid gland volume of 27.82 cm3 (95% confidence interval (CI) 27.15 to 28.50) in male and 21.60 cm3 (95% CI 21.16 to 22.05) in female subjects. We observed positive associations for age, body mass index (BMI), as well as male sex with parotid gland size in a multivariate model. The prevalence of incidental tumors within the parotid gland regardless of dignity was 3.94% in the Northeast German population, slightly higher than assumed. Further epidemiologic investigations regarding primary salivary gland diseases are necessary.

Background: Following acute pulmonary embolism (PE), a relevant number of patients experience decreased exercise capacity which can be associated with disturbed pulmonary perfusion. Cardiopulmonary exercise testing (CPET) shows several patterns typical for disturbed pulmonary perfusion. Research question: We aimed to examine whether CPET can also provide prognostic information in chronic thromboembolic pulmonary hypertension (CTEPH). Study Design and Methods: We performed a multicenter retrospective chart review in Germany between 2002 and 2020. Patients with CTEPH were included if they had ≥6 months of follow-up and complete CPET and hemodynamic data. Symptom-limited CPET was performed using a cycle ergometer (ramp or Jones protocol). The association of anthropometric data, comorbidities, symptoms, lung function, and echocardiographic, hemodynamic, and CPET parameters with survival was examined. Mortality prediction models were calculated by Cox regression with backward selection. Results: 345 patients (1532 person-years) were included; 138 underwent surgical treatment (pulmonary endarterectomy or balloon pulmonary angioplasty) and 207 received only non-surgical treatment. During follow-up (median 3.5 years), 78 patients died. The death rate per 1000 person-years was 24.9 and 74.2 in the surgical and non-surgical groups, respectively (p < 0.001). In age- and sex-adjusted Cox regression analyses, CPET parameters including peak oxygen uptake (VO2peak, reflecting cardiopulmonary exercise capacity) were prognostic in the non-surgical group but not in the surgical group. In mortality prediction models, age, sex, VO2peak (% predicted), and carbon monoxide transfer coefficient (% predicted) showed significant prognostic relevance in both the overall cohort and the non-surgical group. In the non-surgical group, Kaplan–Meier analysis showed that patients with VO2peak below 53.4% predicted (threshold identified by receiver operating characteristic analysis) had increased mortality (p = 0.007). Interpretation: The additional measurement of cardiopulmonary exercise capacity by CPET allows a more precise prognostic evaluation in patients with CTEPH. CPET might therefore be helpful for risk-adapted treatment of CTEPH.

Abstract Background Systemic sclerosis (SSc) is a severe rheumatic disease of the interstitial tissue, in which heart and lung involvement can lead to disease-specific mortality. Our study tests the hypothesis that in addition to established prognostic factors, cardiopulmonary exercise testing (CPET) parameters, particularly peak oxygen uptake (peakVO2) and ventilation/carbon dioxide (VE/VCO2)-slope, can predict survival in patients with SSc. Subjects and methods We retrospectively assessed 210 patients (80.9% female) in 6 centres over 10 years with pulmonary testing and CPET. Survival was analysed with Cox regression analysis (adjusted for age and gender) by age, comorbidity (Charlson-Index), body weight, body-mass index, extensive interstitial lung disease, pulmonary artery pressure (measured by echocardiography and invasively), and haemodynamic, pulmonary and CPET parameters. Results Five- and ten-year survival of SSc patients was 93.8 and 86.9%, respectively. There was no difference in survival between patients with diffuse (dcSSc) and limited cutaneous manifestation (lcSSc; p = 0.3). Pulmonary and CPET parameters were significantly impaired. Prognosis was worst for patients with pulmonary hypertension (p = 0.007), 6-min walking distance 35. Age (hazard ratio HR = 1.23; 95% confidence interval CI: 1.14;1.41), VE/VCO2-slope (HR = 0.9; CI 0.82;0.98), diffusion capacity (Krogh factor, HR = 0.92; CI 0.86;0.98), forced vital capacity (FVC, HR = 0.91; CI 0.86;0.96), and peakVO2 (HR = 0.87; CI 0.81;0.94) were significantly linked to survival in multivariate analyses (Harrell’s C = 0.95). Summary This is the first large study with SSc patients that demonstrates the prognostic value of peakVO2 35.

Abstract Background Mortality attributable to heart failure remains high. The prevalence of heart failure in patients with diabetes mellitus ranges from 19 to 26%. It is estimated that up to 21.1 million adults in the United States have diagnosed diabetes mellitus and around 80.8 million have impaired fasting glucose. We investigated the associations of fasting glucose (FG) and fasting insulin (FI), the homeostasis model assessment-insulin resistance index (HOMA-IR) and 2-h postload glucose (2HG) and insulin (2HI) with parameters of left ventricular geometry and function and arterial stiffness determined by magnetic resonance imaging in individuals without diagnosed type 2 diabetes. Methods Cross-sectional analyses of 1001 individuals (453 women, 45.3%), aged 21 to 80 years, from two independent population-based studies, the Study of Health in Pomerania (SHIP-TREND-0) and KORA FF4 Study. FG, FI, HOMA-IR, 2HG and 2HI, as well as glucose tolerance categories, were analyzed for associations with heart and arterial parameters using multivariable-adjusted linear regression models. Results In total, 390 individuals (39%) had prediabetes (isolated impaired fasting glucose, isolated glucose tolerance or both), and 49 (4.9%) were found to have unknown type 2 diabetes. In the multivariable-adjusted analysis, positive linear associations of FG, FI, HOMA-IR, 2HG and 2HI with arterial stiffness index and left ventricular wall-thickness and concentricity and inverse linear associations with left ventricular end-diastolic volume were observed. A 1 mmol/l higher FG was associated with a 1.18 ml/m2.7 (1.80 to 0.57; p

Background Cardiopulmonary exercise testing (CPET) is a frequently used method for the evaluation of the cardiorespiratory system. The prognostic relevance of the measured parameters is commonly known. Longitudinal data on cardiorespiratory fitness in a large sample of well-characterised healthy volunteers are rare in the literature. Methods CPET data of 615 healthy individuals who voluntarily took part in the Study of Health in Pomerania (SHIP) at three different measurement times were analysed. The median observation time was 10.5 years. The age range was 25–85 years. Results Over the observed timeframe and with increasing age, a decline in maximum power, peak oxygen uptake (V′O2peak) and oxygen uptake at anaerobic threshold (V′O2@AT) was detectable. This decline was aggravated with increasing age. For the minute ventilation (V′E)/carbon dioxide production (V′CO2) slope, an increase was measured in individuals aged ≥50 years only. Conclusion The present study affirms the decrease in aerobic capacity with increasing age in a selected, well-characterised, healthy study sample, which seems to be less pronounced in females.

BackgroundAs healthcare-related data proliferate, there is need to annotate them expertly for the purposes of personalized medicine. Crowdworking is an alternative to expensive expert labour. Annotation corresponds to diagnosis, so comparing unlabeled records to labeled ones seems more appropriate for crowdworkers without medical expertise. We modeled the comparison of a record to two other records as a triplet annotation task, and we conducted an experiment to investigate to what extend sensor-measured stress, task duration, uncertainty of the annotators and agreement among the annotators could predict annotation correctness.Materials and methodsWe conducted an annotation experiment on health data from a population-based study. The triplet annotation task was to decide whether an individual was more similar to a healthy one or to one with a given disorder. We used hepatic steatosis as example disorder, and described the individuals with 10 pre-selected characteristics related to this disorder. We recorded task duration, electro-dermal activity as stress indicator, and uncertainty as stated by the experiment participants (n = 29 non-experts and three experts) for 30 triplets. We built an Artificial Similarity-Based Annotator (ASBA) and compared its correctness and uncertainty to that of the experiment participants.ResultsWe found no correlation between correctness and either of stated uncertainty, stress and task duration. Annotator agreement has not been predictive either. Notably, for some tasks, annotators agreed unanimously on an incorrect annotation. When controlling for Triplet ID, we identified significant correlations, indicating that correctness, stress levels and annotation duration depend on the task itself. Average correctness among the experiment participants was slightly lower than achieved by ASBA. Triplet annotation turned to be similarly difficult for experts as for non-experts.ConclusionOur lab experiment indicates that the task of triplet annotation must be prepared cautiously if delegated to crowdworkers. Neither certainty nor agreement among annotators should be assumed to imply correct annotation, because annotators may misjudge difficult tasks as easy and agree on incorrect annotations. Further research is needed to improve visualizations for complex tasks, to judiciously decide how much information to provide, Out-of-the-lab experiments in crowdworker setting are needed to identify appropriate designs of a human-annotation task, and to assess under what circumstances non-human annotation should be preferred.

Background Common carotid intima–media thickness (cIMT) is a biomarker for subclinical atherosclerosis and is associated with all‐cause as well as cardiovascular mortality. Higher cIMT is accompanied by a compensatory increase in lumen diameter (LD) of the common carotid arteries. Whether cIMT or LD carry more information with regard to mortality is unclear. Methods and Results A total of 2751 subjects (median age 53 years; 52% female) were included. During a median follow‐up of 14.9 years (range: 12.8–16.5) a total of 506 subjects died. At baseline, cIMT and LD were assessed by carotid ultrasound scans. Multivariable Cox regression models were used to relate cIMT, LD, LD adjusted for cIMT (LD+cIMT), and LD/cIMT ratio with all‐cause, cardiovascular, and noncardiovascular mortality. All models were ranked using Akaike's information criterion. Harrel's c statistic was used to compare the models' predictive power for mortality. A 1‐mm increase in LD was related to a higher risk for all‐cause mortality (hazard ratio [HR], 1.29; 95% CI, 1.14–1.45, P

Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.

Abstract Background Gestational diabetes mellitus (GDM) is the most frequent complication during pregnancy. Untreated GDM is a severe threat to maternal and neonatal health. Based on recent evidence, up to 15% of all pregnancies may be affected by GDM. We hypothesized that in a rural birth cohort, higher maternal BMI and adverse socioeconomic conditions would promote GDM, which in turn would lead to adverse effects on pregnancy outcomes. Methods The current study is a part of a population-based cohort study examining the health and socioeconomic information from 5801 mothers and their children. The study, titled the Survey of Neonates in Pomerania (SNiP), was based in northeastern Pomerania, Germany (2002–2008). Results The cumulative incidence of GDM was 5.1%. Multiple logistic regression revealed prepregnancy overweight (OR 1.84 (95% CI 1.27–2.68)), prepregnancy obesity (OR 3.67 (2.48–5.44)) and maternal age (OR 1.06 (1.03–1.08)) as risk factors for GDM (p = 0.001). Alcohol use during pregnancy (OR 0.61 (0.41–0.90), a higher monthly income (OR 0.62 (0.46–0.83)), and the highest level of education (OR 0.44 (0.46–0.83)) decreased the risk of GDM. Newborns of GDM mothers had an increased risk of hypoglycaemia (OR 11.71 (7.49–18.30)) or macrosomia (OR 2.43 (1.41–4.18)) and were more often delivered by primary (OR 1.76 (1.21–2.60)) or secondary C-section (OR 2.00 (1.35–2.97)). Moreover, they were born 0.78 weeks (95% CI -1.09 – -0.48 weeks) earlier than infants of mothers without diabetes, resulting in higher percentage of late preterm infants with a gestational age of 32–36 weeks (11.1% vs. 6.96%). Conclusions Age and BMI before pregnancy were the predominant mediators of the increased risk of GDM, whereas a higher income and educational level were protective. GDM affected relevant perinatal and neonatal outcomes based on its association with an increased risk of delivery by C-section, preterm birth, macrosomia at birth and neonatal hypoglycaemia.

Abstract Background To investigate the association between the structural quality of care and patient satisfaction with care in individuals with disorders/ differences of sex development (DSD). Methods A multicenter cross-sectional comparative study was conducted in 14 clinics in six European countries. We assessed the level of structural quality of care in each center using a self-constructed measure (Center Score) and the level of participant satisfaction with care using the customer satisfaction questionnaire (CSQ-4) and an adopted version of the Youth Health Care – Satisfaction, Utilization & Needs (YHC-SUN-SF). Data were obtained from individuals with Turner Syndrome (261), Klinefelter Syndrome (173), 46, XX congenital adrenal hyperplasia (190) and XY-DSD (257). Results We found large variations between the scores for structural quality of care both within a diagnostic group and within a country; the overall association between participant satisfaction with the center score was significant. Conclusions Comparative effectiveness research across Europe can lead to more insight on beneficial structures and processes and the overall strategy to care for people with rare diseases in general and specific conditions such as disorders/ differences of sex development. Appreciation of higher levels of structural quality of the centers in this study supports the concept of comprehensive care. Trial registration German Clinical Trials Register: Registration identification number: DRKS00006072, date of registration April 17th, 2014. DRKS00006072 (German Clinical Trials Register).

Abstract Background This review aims to (1) consolidate evidence regarding the association between socioeconomic status (SES) and cardiorespiratory fitness (CRF), (2) conduct a meta-analysis of the association between SES and CRF using methodologically comparable data, stratified by sex, and (3) test whether the association varies after adjustment for physical activity (PA). Methods A systematic review of studies from MEDLINE, EMBASE, Latin American and Caribbean Health Sciences (LILACS), Scientific Electronic Library Online (ScIELO), and Cochrane Library without time or language restrictions, which investigated associations between SES and CRF. Risk of bias within studies was assessed using a customized quality assessment tool. Results were summarized in table format and methodologically similar studies were synthesized using meta-analysis of Hedges’ g effect sizes. Synthesized results were appraised for cross-study bias. Results were tested for the impact of PA adjustment using meta-regression. Results Compared to individuals with low education, both men and women showed higher CRF among individuals with high education (men 0.12 [0.04–0.20], women 0.19 [0.02–0.36]), while participants with medium education showed no significant difference in CRF (men 0.03 [− 0.04–0.11], women 0.09 [− 0.03–0.21]). Adjustment for PA did not significantly impact the association between education and CRF. Conclusions There is fair evidence for an association between high levels of education and increased CRF. This could have implications for monitoring, of health target compliance and of chronic disease risk among higher risk populations, to detect and prevent non-communicable diseases (NCDs) and to diminish social health inequalities. Trial Registration PROSPERO, CRD42017055456