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Background While loneliness has been regarded as a risk to mental and physical health, there is a lack of current community data covering a broad age range. This study used a large and representative German adult sample to investigate loneliness. Methods Baseline data of the Gutenberg Health Study (GHS) collected between April 2007 and April 2012 ( N  = 15,010; 35–74 years), were analyzed. Recruitment for the community-based, prospective, observational cohort study was performed in equal strata for gender, residence and age decades. Measures were provided by self-report and interview. Loneliness was used as a predictor for distress (depression, generalized anxiety, and suicidal ideation) in logistic regression analyses adjusting for sociodemographic variables and mental distress. Results A total of 10.5% of participants reported some degree of loneliness (4.9% slight, 3.9% moderate and 1.7% severely distressed by loneliness). Loneliness declined across age groups. Loneliness was stronger in women, in participants without a partner, and in those living alone and without children. Controlling for demographic variables and other sources of distress loneliness was associated with depression (OR = 1.91), generalized anxiety (OR = 1.21) and suicidal ideation (OR = 1.35). Lonely participants also smoked more and visited physicians more frequently. Conclusions The findings support the view that loneliness poses a significant health problem for a sizeable part of the population with increased risks in terms of distress (depression, anxiety), suicidal ideation, health behavior and health care utilization.

Technical variation plays an important role in microarray-based gene expression studies, and batch effects explain a large proportion of this noise. It is therefore mandatory to eliminate technical variation while maintaining biological variability. Several strategies have been proposed for the removal of batch effects, although they have not been evaluated in large-scale longitudinal gene expression data. In this study, we aimed at identifying a suitable method for batch effect removal in a large study of microarray-based longitudinal gene expression. Monocytic gene expression was measured in 1092 participants of the Gutenberg Health Study at baseline and 5-year follow up. Replicates of selected samples were measured at both time points to identify technical variability. Deming regression, Passing-Bablok regression, linear mixed models, non-linear models as well as ReplicateRUV and ComBat were applied to eliminate batch effects between replicates. In a second step, quantile normalization prior to batch effect correction was performed for each method. Technical variation between batches was evaluated by principal component analysis. Associations between body mass index and transcriptomes were calculated before and after batch removal. Results from association analyses were compared to evaluate maintenance of biological variability. Quantile normalization, separately performed in each batch, combined with ComBat successfully reduced batch effects and maintained biological variability. ReplicateRUV performed perfectly in the replicate data subset of the study, but failed when applied to all samples. All other methods did not substantially reduce batch effects in the replicate data subset. Quantile normalization plus ComBat appears to be a valuable approach for batch correction in longitudinal gene expression data.

This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS). The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling. Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively. The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties.

Glomerular filtration rate (GFR) declines with age by approx. 1 ml/min/m 2 per year beginning in the third decade of life. At 70 years of age > 40 ml/min/m 2 of GFR will be lost. Thus, factors affecting loss of GFR have significant public health implications. Furthermore, the definition of chronic kidney disease based on GFR may not be appropriate for the elderly. We analyzed factors affecting absolute and relative change of eGFR over a 5 year period in 12,381 participants of the Gutenberg Health Study. We estimated GFR at baseline and after 5 years of follow-up by two different equations. Association with the decline of estimated GFR (eGFR) was assessed by multivariable regression analysis. We confirmed a median loss of eGFR per year of approx. 1 ml/min/m 2 . Aside from albuminuria systolic blood pressure was most strongly associated with faster decline of eGFR followed by echocardiographic evidence of left ventricular diastolic dysfunction and reduced ejection fraction. White blood cell count showed a moderate association with eGFR loss. Diastolic blood pressure, serum uric acid and serum albumin were associated with slower GFR decline in multivariable analysis. Sensitivity analysis with exclusion of individuals taking diuretics, antihypertensive, antidiabetic, or lipid lowering drugs confirmed these associations.

Circulating microRNAs (miRNAs) have been described as potential diagnostic biomarkers in cardiovascular disease and in particular, coronary artery disease (CAD). Few studies were undertaken to perform analyses with regard to risk stratification of future cardiovascular events. miR-126, miR-197 and miR-223 are involved in endovascular inflammation and platelet activation and have been described as biomarkers in the diagnosis of CAD. They were identified in a prospective study in relation to future myocardial infarction. The aim of our study was to further evaluate the prognostic value of these miRNAs in a large prospective cohort of patients with documented CAD. Levels of miR-126, miR-197 and miR-223 were evaluated in serum samples of 873 CAD patients with respect to the endpoint cardiovascular death. miRNA quantification was performed using real time polymerase chain reaction (RT-qPCR). The median follow-up period was 4 years (IQR 2.78-5.04). The median age of all patients was 64 years (IQR 57-69) with 80.2% males. 38.9% of the patients presented with acute coronary syndrome (ACS), 61.1% were diagnosed with stable angina pectoris (SAP). Elevated levels of miRNA-197 and miRNA-223 reliably predicted future cardiovascular death in the overall group (miRNA-197: hazard ratio (HR) 1.77 per one standard deviation (SD) increase (95% confidence interval (CI) 1.20; 2.60), p = 0.004, C-index 0.78; miRNA-223: HR 2.23 per one SD increase (1.20; 4.14), p = 0.011, C-index 0.80). In ACS patients the prognostic power of both miRNAs was even higher (miRNA-197: HR 2.24 per one SD increase (1.25; 4.01), p = 0.006, C-index 0.89); miRA-223: HR 4.94 per one SD increase (1.42; 17.20), p = 0.012, C-index 0.89). Serum-derived circulating miRNA-197 and miRNA-223 were identified as predictors for cardiovascular death in a large patient cohort with CAD. These results reinforce the assumption that circulating miRNAs are promising biomarkers with prognostic value with respect to future cardiovascular events.

Diversification at the transcriptome 3′end is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. Here, we identify extensive transcriptome 3′end-alterations in neuroblastoma, a tumour entity with a paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. Utilising extensive RNAi-screening we reveal the landscape and drivers of transcriptome 3′end-diversification, discovering PCF11 as critical regulator, directing alternative polyadenylation (APA) of hundreds of transcripts including a differentiation RNA-operon. PCF11 shapes inputs converging on WNT-signalling, and governs cell cycle, proliferation, apoptosis and neurodifferentiation. Postnatal PCF11 down-regulation induces a neurodifferentiation program, and low-level PCF11 in neuroblastoma associates with favourable outcome and spontaneous tumour regression. Our findings document a critical role for APA in tumorigenesis and describe a novel mechanism for cell fate reprogramming in neuroblastoma with potentially important clinical implications. We provide an interactive data repository of transcriptome-wide APA covering > 170 RNAis, and an APA-network map with regulatory hubs. In gene regulation, diversification at the transcriptome 3′end is linked to differentiation and dedifferentiation. Here, the authors discover extensive transcriptome 3′end-alterations in neuroblastoma, regulated by PCF11, and provide an interactive data repository of transcriptome-wide alternative polyadenylation.

Fabry disease (FD) is an X-linked hereditary defect of glycosphingolipid storage caused by mutations in the gene encoding the lysosomal hydrolase α-galactosidase A (GLA, α-gal A). To date, over 400 mutations causing amino acid substitutions have been described. Most of these mutations are related to the classical Fabry phenotype. Generally in lysosomal storage disorders a reliable genotype/phenotype correlation is difficult to achieve, especially in FD with its X-linked mode of inheritance. In order to predict the metabolic consequence of a given mutation, we combined in vitro enzyme activity with in vivo biomarker data. Furthermore, we used the pharmacological chaperone (PC) 1-deoxygalactonojirimycin (DGJ) as a tool to analyse the influence of individual mutations on subcellular organelle-trafficking and stability. We analysed a significant number of mutations and correlated the obtained properties to the clinical manifestation related to the mutation in order to improve our knowledge of the identity of functional relevant amino acids. Additionally, we illustrate the consequences of different mutations on plasma lyso-globotriaosylsphingosine (lyso-Gb3) accumulation in the patients' plasma, a biomarker proven to reflect the impaired substrate clearance caused by specific mutations. The established system enables us to provide information for the clinical relevance of PC therapy for a given mutant. Finally, in order to generate reliable predictions of mutant GLA defects we compared the different data sets to reveal the most coherent system to reflect the clinical situation.

Abstract Background Cross-sectional studies have shown that noise annoyance is strongly associated with mental distress, however, its long-term effects on mental health is unknown. We therefore investigated whether noise annoyance predicts depression, anxiety and sleep disturbance in a large, representative sample 5 years later. Methods We investigated longitudinal data of N = 11 905 participants of the Gutenberg Health Study, a population-based, prospective, single-centre cohort study in mid-Germany (age at baseline 35–74 years). Noise annoyance was assessed at baseline and 5-year follow-up (sources: road traffic, aircraft, railways, industrial, neighbourhood indoor and outdoor noise; and day vs. nighttime). Depression, anxiety and sleep disturbance were assessed using the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-2. Participants suffering from depression, anxiety or sleep disturbance at baseline were excluded from the respective multivariate analyses of new onset at follow-up. Results General noise annoyance remained stable. Daytime noise annoyance predicted new onset of depressive, anxiety symptoms (also nighttime annoyance) and sleep disturbance (beyond respective baseline scores). Additional predictors were female sex, lower age and low socioeconomic status (SES). Regarding specific sources, daytime baseline aircraft annoyance predicted depression and anxiety. Sleep disturbance was most consistently predicted by neighbourhood annoyance (baseline and follow-up) and follow-up annoyance by aircraft (night) and road traffic (day and night). Conclusions We identified current and past noise annoyances as risk factors for mental distress and sleep disturbance. Furthermore, women, younger adults and those with lower SES are particularly susceptible to noise annoyance. Our results indicate the need to provide regulatory measures in affected areas to prevent mental health problems.

Antiphospholipid antibodies (aPL), assumed to cause antiphospholipid syndrome (APS), are notorious for their heterogeneity in targeting phospholipids and phospholipid-binding proteins. The persistent presence of Lupus anticoagulant and/or aPL against cardiolipin and/or β2-glycoprotein I have been shown to be independent risk factors for vascular thrombosis and pregnancy morbidity in APS. aPL production is thought to be triggered by–among other factors–viral infections, though infection-associated aPL have mostly been considered non-pathogenic. Recently, the potential pathogenicity of infection-associated aPL has gained momentum since an increasing number of patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been described with coagulation abnormalities and hyperinflammation, together with the presence of aPL. Here, we present data from a multicentric, mixed-severity study including three cohorts of individuals who contracted SARS-CoV-2 as well as non-infected blood donors. We simultaneously measured 10 different criteria and non-criteria aPL (IgM and IgG) by using a line immunoassay. Further, IgG antibody response against three SARS-CoV-2 proteins was investigated using tripartite automated blood immunoassay technology. Our analyses revealed that selected non-criteria aPL were enriched concomitant to or after an infection with SARS-CoV-2. Linear mixed-effects models suggest an association of aPL with prothrombin (PT). The strength of the antibody response against SARS-CoV-2 was further influenced by SARS-CoV-2 disease severity and sex of the individuals. In conclusion, our study is the first to report an association between disease severity, anti-SARS-CoV-2 immunoreactivity, and aPL against PT in patients with SARS-CoV-2.

Previous studies on self-rated health and mortality have usually not differentiated between physical and mental health, respectively have not considered physical diseases. This study aims to determine self-rated physical and mental health from middle to old age, examine associations with mortality adjusted for objective risk factors and assess effect modification by gender. In a large population-based sample ( N  = 14,993 at baseline), self-rated physical and mental health were rated separately by a single-item. Associations to mortality were modelled by Cox regressions, adjusting for potential confounding variables. Most participants rated their physical (79.4%), resp. mental health (82.3%) as good. Poor self-rated physical health was lowest in the youngest group (19.6%, age 35–44), and highest in midlife (29.1%, age 55–64). Poor self-rated mental health was lowest among the oldest (18.5%), and highest from 45 to 54 years (29.3%). Poor self-rated physical, but not mental health was predictive of mortality when adjusting for objective risk factors. Male gender and poor self-rated physical health interacted (RERI 0.43 95%-CI 0.02–0.85). Self-rated physical health was best in the youngest and worst in the midlife group, this pattern was reversed regarding self-rated mental health. Poor self-rated physical, but not mental health was predictive of mortality, adjusting for objective risk factors. It was more strongly predictive of mortality in men than in women. Poor subjective physical health ratings, should be taken seriously as an unfavorable prognostic sign, particularly in men.