Childhood and adolescence factors and multiple sclerosis: results from the German National Cohort (NAKO).

BACKGROUND: Multiple Sclerosis (MS) represents the most common inflammatory neurological disease causing disability in early adulthood. Childhood and adolescence factors might be of relevance in the development of MS. We aimed to investigate the association between various factors (e.g., prematurity, breastfeeding, daycare attendance, weight history) and MS risk. METHODS: Data from the baseline assessment of the German National Cohort (NAKO) were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between childhood and adolescence factors and risk of MS. Analyses stratified by sex were conducted. RESULTS: Among a total of 204,273 participants, 858 reported an MS diagnosis. Male sex was associated with a decreased MS risk (HR 0.48; 95% CI 0.41-0.56), while overweight (HR 2.03; 95% CI 1.41-2.94) and obesity (HR 1.89; 95% CI 1.02-3.48) at 18 years of age compared to normal weight were associated with increased MS risk. Having been breastfed for ≤ 4 months was associated with a decreased MS risk in men (HR 0.59; 95% CI 0.40-0.86) compared to no breastfeeding. No association with MS risk was observed for the remaining factors. CONCLUSIONS: Apart from overweight and obesity at the age of 18 years, we did not observe considerable associations with MS risk. The proportion of cases that can be explained by childhood and adolescence factors examined in this study was low. Further investigations of the association between the onset of overweight and obesity in childhood and adolescence and its interaction with physical activity and MS risk seem worthwhile.

Large-scale assessment of physical activity in a population using high-resolution hip-worn accelerometry: the German National Cohort (NAKO).

Large population-based cohort studies utilizing device-based measures of physical activity are crucial to close important research gaps regarding the potential protective effects of physical activity on chronic diseases. The present study details the quality control processes and the derivation of physical activity metrics from 100 Hz accelerometer data collected in the German National Cohort (NAKO). During the 2014 to 2019 baseline assessment, a subsample of NAKO participants wore a triaxial ActiGraph accelerometer on their right hip for seven consecutive days. Auto-calibration, signal feature calculations including Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD), identification of non-wear time, and imputation, were conducted using the R package GGIR version 2.10-3. A total of 73,334 participants contributed data for accelerometry analysis, of whom 63,236 provided valid data. The average ENMO was 11.7 ± 3.7 mg (milli gravitational acceleration) and the average MAD was 19.9 ± 6.1 mg. Notably, acceleration summary metrics were higher in men than women and diminished with increasing age. Work generated in the present study will facilitate harmonized analysis, reproducibility, and utilization of NAKO accelerometry data. The NAKO accelerometry dataset represents a valuable asset for physical activity research and will be accessible through a specified application process.

Longitudinal impact of intracerebral low-grade glioma disease on health-related quality of life.

BACKGROUND: The aim of this study was to assess health-related quality of life (HRQOL) before and after treatment for intracerebral low-grade glioma. METHODS: Patients with low-grade glioma who underwent surgical tumor removal between 2012 and 2018 were eligible for this study. All individuals and their closest relatives received thorough preoperative (

Epidemiology and Prognostic Implications of Coronary Artery Calcium in Asymptomatic Individuals With Prediabetes: A Multicohort Study.

OBJECTIVE: To describe the epidemiology and prognostic value of coronary artery calcium (CAC) in individuals with prediabetes. RESEARCH DESIGN AND METHODS: We pooled participants free of clinical atherosclerotic cardiovascular disease (ASCVD) from four prospective cohorts: the Multi-Ethnic Study of Atherosclerosis, Heinz Nixdorf Recall Study, Framingham Heart Study, and Jackson Heart Study. Two definitions were used for prediabetes: inclusive (fasting plasma glucose [FPG] ≥100 to <126 mg/dL and hemoglobin A1c [HbA1c] ≥5.7% to <6.5%, if available, and no glucose-lowering medications) and restrictive (FPG ≥110 to <126 mg/dL and HbA1c ≥5.7% to <6.5%, if available, among participants not taking glucose-lowering medications). RESULTS: The study included 13,376 participants (mean age 58 years; 54% women; 57% White; 27% Black). The proportions with CAC ≥100 were 17%, 22%, and 37% in those with euglycemia, prediabetes, and diabetes, respectively. Over a median (25th-75th percentile) follow-up time of 14.6 (interquartile range 7.8-16.4) years, individuals with prediabetes and CAC ≥100 had a higher unadjusted 10-year incidence of ASCVD (13.4%) than the overall group of those with diabetes (10.6%). In adjusted analyses, using the inclusive definition of prediabetes, compared with euglycemia, the hazard ratios (HRs) for ASCVD were 0.79 (95% CI 0.62, 1.01) for prediabetes and CAC 0, 0.70 (0.54, 0.89) for prediabetes and CAC 1-99, 1.54 (1.27, 1.88) for prediabetes and CAC ≥100, and 1.64 (1.39, 1.93) for diabetes. Using the restrictive definition, the HR for ASCVD was 1.63 (1.29, 2.06) for prediabetes and CAC ≥100. CONCLUSIONS: CAC ≥100 is frequent among individuals with prediabetes and identifies a high ASCVD risk subgroup in which the adjusted ASCVD risk is similar to that in individuals with diabetes.

Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Aggregation of type-2 diabetes, prediabetes, and metabolic syndrome in German couples.

We aimed to examine the concordance of type-2 diabetes, prediabetes and the metabolic syndrome in couples. In cross-sectional analyses, we used data from 1173 couples with index persons from the Heinz Nixdorf Recall Study (2011-2015), a population-based cohort study in Western Germany, and partners from the associated Heinz Nixdorf Multigeneration Study (2013-2016). Mean age (standard deviation) was 67.2 (6.6) years in index persons, and 67.8 (7.7) years in partners. The exposure was the presence of diabetes, prediabetes or metabolic syndrome in index persons, the outcome was the presence of the same health status in partners. Diabetes was defined by either self-reported diagnosis, intake of antidiabetic drugs or insulin, or HbA1c ≥ 6.5%. If the index person had prediabetes or diabetes, the partner was 1.46 (95% CI 1.07-2.00) times more likely to have diabetes than partners of index persons without the condition in the crude model (adjusted model: 1.33 (0.97-1.83)). For self-reported diabetes and for the metabolic syndrome, the corresponding prevalence ratios were 1.33 (0.90-1.97) and 1.17 (1.03-1.32), respectively (adjusted models: 1.23 (0.77-1.94), 1.04 (0.91-1.18)). In German couples, there was weak to moderate concordance of type-2 diabetes, prediabetes and the metabolic syndrome in crude, but poor concordance in adjusted models.

Differences in Anthropometric Measures Based on Sex, Age, and Health Status: Findings From the German National Cohort (NAKO).

BACKGROUND: Obesity is a worldwide health problem. We conducted detailed analyses of anthropometric measures in a comprehensive, population-based, current cohort in Germany. METHODS: In the German National Cohort (NAKO), we analyzed cross-sectional data on body-mass index (BMI), waist and hip circumference, subcutaneous (SAT) and visceral adipose tissue (VAT) as measured by ultrasound, and body fat percentage. The data were stratified by sex, age, and self-reported physicians' diagnoses of cardiovascular diseases (CVD), metabolic diseases (MetD), cardiometabolic diseases (CMD), and cancer. RESULTS: Data were available from 204 751 participants (age, 49.9 ± 12.8 years; 50.5% women). Body size measures generally increased with age. Men had a higher BMI, larger waist circumference, and more VAT than women, while women had a larger hip circumference, more SAT, and a higher body fat percentage than men. For example, the mean BMI of participants over age 60 was 28.3 kg/m2 in men and 27.6 kg/m2 in women. CVD, MetD, and CMD were associated with higher anthropometric values, while cancer was not. For example, the mean BMI was 25.3 kg/m2 in healthy women, 29.4 kg/m2 in women with CMD, and 25.4 kg/m2 in women with cancer. CONCLUSION: Obesity is widespread in Germany, with notable differences between the sexes in anthropometric values. Obesity was more common in older participants and those with chronic diseases other than cancer. Elevated values were especially common in multimorbid individuals.

Changes in physical activity and sedentary behavior during the first COVID-19 pandemic- restrictions in Germany: a nationwide survey : Running head: physical activity during the COVID-19 restrictions.

BACKGROUND: The COVID-19 pandemic restrictions posed challenges to maintaining healthy lifestyles and physical well-being. During the first mobility restrictions from March to mid-July 2020, the German population was advised to stay home, except for work, exercise, and essential shopping. Our objective was to comprehensively assess the impact of these restrictions on changes in physical activity and sedentary behavior to identify the most affected groups. METHODS: Between April 30, 2020, and May 12, 2020, we distributed a COVID-19-specific questionnaire to participants of the German National Cohort (NAKO). This questionnaire gathered information about participants' physical activity and sedentary behavior currently compared to the time before the restrictions. We integrated this new data with existing information on anxiety, depressive symptoms, and physical activity. The analyses focused on sociodemographic factors, social relationships, physical health, and working conditions. RESULTS: Out of 152,421 respondents, a significant proportion reported altered physical activity and sedentary behavioral patterns due to COVID-19 restrictions. Over a third of the participants initially meeting the WHO's physical activity recommendation could no longer meet the guidelines during the restrictions. Participants reported substantial declines in sports activities (mean change (M) = -0.38; 95% CI: -.390; -.378; range from -2 to + 2) and reduced active transportation (M = -0.12; 95% CI: -.126; -.117). However, they also increased recreational physical activities (M = 0.12; 95% CI: .117; .126) while engaging in more sedentary behavior (M = 0.24; 95% CI: .240; .247) compared to pre-restriction levels. Multivariable linear and log-binomial regression models indicated that younger adults were more affected by the restrictions than older adults. The shift to remote work, self-rated health, and depressive symptoms were the factors most strongly associated with changes in all physical activity domains, including sedentary behavior, and the likelihood to continue following the physical activity guidelines. CONCLUSIONS: Mobility patterns shifted towards inactivity or low-intensity activities during the nationwide restrictions in the spring of 2020, potentially leading to considerable and lasting health risks.

Synergism between coexisting eye diseases and sex in increasing the prevalence of the dry eye syndrome.

The aim was to investigate prevalence of dry eye syndrome (DES) in a population-based sample in Germany. The association between coexisting eye diseases and DES was also of interest. We recontacted participants of the Heinz Nixdorf Recall study between 2018 and 2021 by postal questionnaire that included the Women's Health Study questionnaire on DES. We estimated prevalence of DES and examined DES-associated factors among 2095 participants aged 62-91 years. We performed interaction analyses between sex and coexisting eye diseases in relation to the DES prevalence and performed bias analyses to examine the robustness of the results. The DES prevalence was 31.5% (34-36% after correction for potential non-response bias, 24.1% after correction for outcome misclassification) and it was almost 2.1-times higher in women than in men (women 42.3%, men 20.4%). Among DES subjects, 70.3% had received treatment in the previous 12 months. There was synergism between female sex and coexisting eye diseases (cataract, glaucoma, macular degeneration) in terms of DES prevalence. The extrapolated numbers of patients aged 62-91 years with DES in Germany are 1.1-1.3 million men and 6.1-6.8 million women. The observed synergism may be explained by differences in ocular physiology, subjective perception and response behavior. Women with eye diseases (cataract, glaucoma, macula degeneration) appear to have a markedly higher susceptibility to suffer from DES than men, so that a diagnostic workup of DES symptoms is particularly justified in women with these eye diseases.

The Association of HIV-Specific Risk Factors with Cardiovascular Events in Addition to Traditional Risk Factors in People Living with HIV.

Traditional cardiovascular risk scores underestimate the incidence of cardiovascular diseases (CVD) in people living with HIV (PLH). This study compared the effect of HIV-specific cardiovascular risk factors (CRF) with traditional CRF at baseline for their association with incident CVD in PLH. The ongoing, prospective HIV HEART Aging (HIVH) study assesses CVD in PLH in the German Ruhr Area since 2004. PLH from the HIVH study with at least 5 years of follow-up were examined with the help of Cox proportional hazards models using inverse probability-of-censoring weights. The models were adjusted for age and sex. The obtained hazard ratios (HR) and 95% confidence limits (CL) assessed the strength of the associations between CRF and CVD. One thousand two hundred forty-three individuals (male 1,040, female 203; mean age of 43 ± 10 years) with 116 incident CVD events were analyzed. After adjusting for the traditional CRF, the HIV-specific CRF "a history of AIDS" and "higher age at diagnosis of HIV infection" (per 10 years) were associated with an increased CVD risk (HR 1.55, 95% CL: 1.05-2.28 and HR 1.55, 95% CL: 1.09-1.22, respectively). Higher CD4/CD8 ratio (per standard deviation), longer cumulative duration of antiretroviral therapies, and longer duration of HIV infection (per 10 years) showed indications for a decreased CVD risk (HR 0.75, 95% CL: 0.58-0.97, HR 0.71, 95% CL: 0.41-1.23, and HR 0.63, 95% CL: 0.44-0.90, respectively). Out of the traditional CRF, current smoking showed the strongest impact on CVD risk (HR 3.12, 95% CL: 2.06-4.74). In conclusion, HIV-specific factors, such as history of AIDS and CD4/CD8 ratio, were independently associated with an increased cardiovascular risk. Traditional CRF maintained a major effect on CVD. Clinical Trials Number (NCT04330287).

Childhood Trauma and Somatic and Mental Illness in Adulthood.

BACKGROUND: Childhood trauma is associated with somatic and mental illness in adulthood. The strength of the association varies as a function of age, sex, and type of trauma. Pertinent studies to date have mainly focused on individual diseases. In this study, we investigate the association between childhood trauma and a multiplicity of somatic and mental illnesses in adulthood. METHODS: Data from 156 807 NAKO Health Study participants were analyzed by means of logistic regressions, with adjustment for age, sex, years of education, and study site. The Childhood Trauma Screener differentiated between no/minor (n = 115 891) and moderate/severe childhood trauma (n = 40 916). The outcome variables were medical diagnoses of five somatic and two mental health conditions as stated in the clinical history. RESULTS: Persons with childhood trauma were more likely to bear a diagnosis of all of the studied conditions: cancer (odds ratio [OR] = 1.10; 95% confidence interval: [1.05; 1.15]), myocardial infarction (OR = 1.13 [1.03; 1.24]), diabetes (OR = 1.16, [1.10; 1.23]), stroke (OR = 1.35 [1.23; 1.48]), chronic obstructive pulmonary disease (OR = 1.45 [1.38; 1.52]), depression (OR = 2.36 [2.29; 2.43]), and anxiety disorders (OR = 2.08 [2.00; 2.17]). All of these associations were stronger in younger persons, regardless of the nature of childhood trauma. Differences between the sexes were observed only for some of these associations. CONCLUSION: Childhood trauma was associated with a higher probability of developing mental as well as somatic illness in adulthood. As childhood trauma is an element of individual history that the victim has little to no control over, and because the illnesses that can arise in adulthood in association with it are a heavy burden on the affected persons and on society, there is a need for research on these associations and for the development of preventive measures.

Chronic disease outcome metadata from German observational studies - public availability and FAIR principles.

Metadata from epidemiological studies, including chronic disease outcome metadata (CDOM), are important to be findable to allow interpretability and reusability. We propose a comprehensive metadata schema and used it to assess public availability and findability of CDOM from German population-based observational studies participating in the consortium National Research Data Infrastructure for Personal Health Data (NFDI4Health). Additionally, principal investigators from the included studies completed a checklist evaluating consistency with FAIR principles (Findability, Accessibility, Interoperability, Reusability) within their studies. Overall, six of sixteen studies had complete publicly available CDOM. The most frequent CDOM source was scientific publications and the most frequently missing metadata were availability of codes of the International Classification of Diseases, Tenth Revision (ICD-10). Principal investigators' main perceived barriers for consistency with FAIR principles were limited human and financial resources. Our results reveal that CDOM from German population-based studies have incomplete availability and limited findability. There is a need to make CDOM publicly available in searchable platforms or metadata catalogues to improve their FAIRness, which requires human and financial resources.

Automated image quality assessment for selecting among multiple magnetic resonance image acquisitions in the German National Cohort study.

In magnetic resonance imaging (MRI), the perception of substandard image quality may prompt repetition of the respective image acquisition protocol. Subsequently selecting the preferred high-quality image data from a series of acquisitions can be challenging. An automated workflow may facilitate and improve this selection. We therefore aimed to investigate the applicability of an automated image quality assessment for the prediction of the subjectively preferred image acquisition. Our analysis included data from 11,347 participants with whole-body MRI examinations performed as part of the ongoing prospective multi-center German National Cohort (NAKO) study. Trained radiologic technologists repeated any of the twelve examination protocols due to induced setup errors and/or subjectively unsatisfactory image quality and chose a preferred acquisition from the resultant series. Up to 11 quantitative image quality parameters were automatically derived from all acquisitions. Regularized regression and standard estimates of diagnostic accuracy were calculated. Controlling for setup variations in 2342 series of two or more acquisitions, technologists preferred the repetition over the initial acquisition in 1116 of 1396 series in which the initial setup was retained (79.9%, range across protocols: 73-100%). Image quality parameters then commonly showed statistically significant differences between chosen and discarded acquisitions. In regularized regression across all protocols, 'structured noise maximum' was the strongest predictor for the technologists' choice, followed by 'N/2 ghosting average'. Combinations of the automatically derived parameters provided an area under the ROC curve between 0.51 and 0.74 for the prediction of the technologists' choice. It is concluded that automated image quality assessment can, despite considerable performance differences between protocols and anatomical regions, contribute substantially to identifying the subjective preference in a series of MRI acquisitions and thus provide effective decision support to readers.

Long-term exposure to air pollution and prevalent nonalcoholic fatty liver disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is a disease characterized by lipid accumulation within hepatocytes, ranging from simple steatosis to steatohepatitis, in the absence of secondary causes of hepatic fat accumulation. Although air pollution (AP) has been associated with several conditions related to NAFLD (e.g., metabolic syndrome, type 2 diabetes mellitus), few studies have explored an association between AP and NAFLD. The aim of the study was to investigate whether exposure to AP is associated with NAFLD prevalence. Methods: We used baseline cross-sectional data (2000-2003) of the Heinz-Nixdorf-Recall cohort study in Germany (baseline n = 4,814), a prospective population-based cohort study in the urbanized Ruhr Area. Mean annual exposure to size-fractioned particulate matter (PM10, PM2.5, PMcoarse, and PM2.5abs), nitrogen dioxide, and particle number was assessed using two different exposure models: a chemistry transport dispersion model, which captures urban background AP exposure on a 1 km2 grid at participant's residential addresses, and a land use regression model, which captures point-specific AP exposure at participant's residential addresses. NAFLD was assessed with the fatty liver index (n = 4,065), with NAFLD defined as fatty liver index ≥60. We estimated ORs of NAFLD per interquartile range of exposure using logistic regression, adjusted for socio-demographic and lifestyle variables. Results: We observed a NAFLD prevalence of 31.7% (n = 1,288). All air pollutants were positively associated with NAFLD prevalence, with an OR per interquartile range for PM2.5 of 1.11 (95% confidence interval [CI] = 1.00, 1.24) using chemistry transport model, and 1.06 (95% CI = 0.94, 1.19) using the land use regression model, respectively. Conclusion: There was a positive association between long-term AP exposure and NAFLD.

Bedside Hyperspectral Imaging and Organ Dysfunction Severity in Critically Ill COVID-19 Patients-A Prospective, Monocentric Observational Study.

Hyperspectral imaging (HSI) is a non-invasive technology that provides information on biochemical tissue properties, including skin oxygenation and perfusion quality. Microcirculatory alterations are associated with organ dysfunction in septic COVID-19 patients. This prospective observational study investigated associations between skin HSI and organ dysfunction severity in critically ill COVID-19 patients. During the first seven days in the ICU, palmar HSI measurements were carried out with the TIVITA® tissue system. We report data from 52 critically ill COVID-19 patients, of whom 40 required extracorporeal membrane oxygenation (ECMO). HSI parameters for superficial tissue oxygenation (StO2) and oxygenation and perfusion quality (NPI) were persistently decreased. Hemoglobin tissue content (THI) increased, and tissue water content (TWI) was persistently elevated. Regression analysis showed strong indications for an association of NPI and weaker indications for associations of StO2, THI, and TWI with sequential organ failure assessment (SOFA) scoring. StO2 and NPI demonstrated negative associations with vasopressor support and lactate levels as well as positive associations with arterial oxygen saturation. These results suggest that skin HSI provides clinically relevant information, opening new perspectives for microcirculatory monitoring in critical care.

Prevalence of genital Mycoplasma in pregnancies with shortened cervix.

OBJECTIVE: To determine whether colonisation with genital Mycoplasma species (spp.) in patients presenting with a shortened cervix before 34th week of pregnancy is associated with preterm birth. METHODS: The collection of this retrospective study consisted of 100 pregnant women who presented to a German Tertiary Perinatal Center between 2017 and 2020 due to a shortened cervix defined as a cervical length of 25 mm or shorter measured by transvaginal ultrasound before 34 weeks of gestation. At the time of admission, gestational age ranged from 18 + 4 to 33 + 3 weeks (+ days) of pregnancy. All patients underwent urine polymerase chain reaction (PCR) for genital Mycoplasma [Ureaplasma (U.) urealyticum, U. parvum, M. hominis or M. genitalium]. Patients who were tested positive underwent a therapy with macrolides (azithromycin or clarithromycin). RESULTS: 37% of the patients were positive for Ureaplasma spp., whereas 5% (5 patients) were Mycoplasma spp.-positive. All the latter were simultaneously colonised with Ureaplasma spp. Ureaplasma-positive patients were significantly younger than those who were tested negative. Median maternal age at examination was 30 years (a) versus 31a (p = 0.04). There was no difference between Ureaplasma-positive and -negative patients regarding median maternal body mass index (BMI) (kg/m2) (23.4 versus 22.3, p = 0.41), cervical length at admission (mm) (15 versus 17, p = 0.17), gestational age at examination (days, d) (198 versus 197, p = 0.97) or gestational age at birth (d) (250 versus 257, p = 0.33), respectively. Comparing U. parvum-positive and U. urealyticum-positive patients, there was some weak indication that U. parvum-positive patients may get a shortening of the cervix earlier in pregnancy, as the median gestational age at examination was 196d versus 215d (p = 0.06). Regarding Mycoplasma-positive and -negative patients, there was no difference in all examined parameters. CONCLUSIONS: Overall, one-third of all women in our study with a shortened cervix before 34th week of pregnancy were colonised with genital Mycoplasma spp. We were able to show that pregnant women, who were treated with antibiotics when tested positive for genital Mycoplasma, gave birth at the same gestational age as patients with a shortened cervix without detected Mycoplasma. This raises the question of whether routine testing and early antibiotic treatment should be established in prenatal care.

Natural course of cerebral and spinal cavernous malformations: a complete ten-year follow-up study.

Knowledge of the bleeding risk and the long-term outcome of conservatively treated patients with cavernous malformations (CM) is poor. In this work, we studied the occurrence of CM-associated hemorrhage over a 10-year period and investigated risk factors for bleeding. Our institutional database was screened for patients with cerebral (CCM) or intramedullary spinal cord (ISCM) CM admitted between 2003 and 2021. Patients who underwent surgery and patients without completed follow-up were excluded. Analyses were performed to identify risk factors and to determine the cumulative risk for hemorrhage. A total of 91 CM patients were included. Adjusted multivariate logistic regression analysis identified bleeding at diagnosis (p = 0.039) and CM localization to the spine (p = 0.010) as predictors for (re)hemorrhage. Both risk factors remained independent predictors through Cox regression analysis (p = 0.049; p = 0.016). The cumulative 10-year risk of bleeding was 30% for the whole cohort, 39% for patients with bleeding at diagnosis and 67% for ISCM. During an untreated 10-year follow-up, the probability of hemorrhage increased over time, especially in cases with bleeding at presentation and spinal cord localization. The intensity of such increase may decline throughout time but remains considerably high. These findings may indicate a rather aggressive course in patients with ISCM and may endorse early surgical treatment.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.

BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.

Associations of Migration, Socioeconomic Position and Social Relations With Depressive Symptoms - Analyses of the German National Cohort Baseline Data.

Objectives: We analyze whether the prevalence of depressive symptoms differs among various migrant and non-migrant populations in Germany and to what extent these differences can be attributed to socioeconomic position (SEP) and social relations. Methods: The German National Cohort health study (NAKO) is a prospective multicenter cohort study (N = 204,878). Migration background (assessed based on citizenship and country of birth of both participant and parents) was used as independent variable, age, sex, Social Network Index, the availability of emotional support, SEP (relative income position and educational status) and employment status were introduced as covariates and depressive symptoms (PHQ-9) as dependent variable in logistic regression models. Results: Increased odds ratios of depressive symptoms were found in all migrant subgroups compared to non-migrants and varied regarding regions of origins. Elevated odds ratios decreased when SEP and social relations were included. Attenuations varied across migrant subgroups. Conclusion: The gap in depressive symptoms can partly be attributed to SEP and social relations, with variations between migrant subgroups. The integration paradox is likely to contribute to the explanation of the results. Future studies need to consider heterogeneity among migrant subgroups whenever possible.

Identification of radiomic biomarkers in a set of four skeletal muscle groups on Dixon MRI of the NAKO MR study.

In this work, we propose a processing pipeline for the extraction and identification of meaningful radiomics biomarkers in skeletal muscle tissue as displayed using Dixon-weighted MRI. Diverse and robust radiomics features can be identified that may be of aid in the accurate quantification e.g. varying degrees of sarcopenia in respective muscles of large cohorts. As such, the approach comprises the texture feature extraction from raw data based on well established approaches, such as a nnU-Net neural network and the Pyradiomics toolbox, a subsequent selection according to adequate conditions for the muscle tissue of the general population, and an importance-based ranking to further narrow the amount of meaningful features with respect to auxiliary targets. The performance was investigated with respect to the included auxiliary targets, namely age, body mass index (BMI), and fat fraction (FF). Four skeletal muscles with different fiber architecture were included: the mm. glutaei, m. psoas, as well as the extensors and adductors of the thigh. The selection allowed for a reduction from 1015 available texture features to 65 for age, 53 for BMI, and 36 for FF from the available fat/water contrast images considering all muscles jointly. Further, the dependence of the importance rankings calculated for the auxiliary targets on validation sets (in a cross-validation scheme) was investigated by boxplots. In addition, significant differences between subgroups of respective auxiliary targets as well as between both sexes were shown to be present within the ten lowest ranked features by means of Kruskal-Wallis H-tests and Mann-Whitney U-tests. The prediction performance for the selected features and the ranking scheme were verified on validation sets by a random forest based multi-class classification, with strong area under the curve (AUC) values of the receiver operator characteristic (ROC) of 73.03 ± 0.70 % and 73.63 ± 0.70 % for the water and fat images in age, 80.68 ± 0.30 % and 88.03 ± 0.89 % in BMI, as well as 98.36 ± 0.03 % and 98.52 ± 0.09 % in FF.