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Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p-value < 5x10-8), which validated 12 previously reported loci for proinsulin and 10 additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher vs. lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait loci (eQTL) data, suggesting candidate genes including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal, but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms predisposing to disease.

PURPOSE: Hip osteoarthritis (HOA) is known to have a multifactorial pathogenesis. Recent studies suggest that spinopelvic alignment may represent an important additional pathogenic abnormality resulting in HOA. This study aims to assess the correlation between spinopelvic parameters (pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS) and lumbar lordosis (LL)) obtained in the supine position on MRI and HOA, lateral center edge (LCE) angle, and patient reported back pain. METHODS: Asymptomatic participants from the whole-body MRI cohort (FF4) from the cross-sectional case-control "Cooperative Health Research in the Region of Augsburg" study (KORA) were included. Whole-body MRI was performed in a standardized fashion in each case, on which hip osteoarthritis (HOA), anatomical spinopelvic parameters and lateral center edge angle were measured. Presence of back pain was assessed using a standardized questionnaire. Correlations were estimated by logistic regression models providing odds ratio. RESULTS: Among 340 subjects (mean age 56.3±9.3 years; 56.5% male), HOA was present in 89.1% (male: 87.0%, female: 91.7%, p=0.17). The LCE angle was 30.0° ± 5.5 (men: 29.8° ± 5.9; women: 30.1° ± 5.1; p=0.696). Mean PI was 54.0° ± 11.3°, PT was 13.7° ± 5.9°, SS was 40.3° ± 8.8° (significantly smaller in women p

OBJECTIVE: This study aimed to assess the association of changes in sleep behaviors from adolescence to young adulthood with the risk of overweight/obesity, and the reverse relationship. METHODS: Data of 1978 participants was obtained from the 15- and 20-year follow-ups of the GINIplus and LISA birth cohorts. Insufficient sleep was defined as reported sleep duration

BACKGROUND: As the climate changes, it is crucial to focus not only on mitigation measures but also on building climate change resilience by developing efficient adaptation strategies. Although population adaptation is a major determinant of future climate-related health burden, it is not well accounted for in studies that project the health impact of climate change. We propose a methodological framework for temperature-related mortality that incorporates two simultaneous adaptation-sensitivity pathways: the physiological pathway, considering both heat adaptation and cold sensitivity, and the socioeconomic pathway, which is influenced by changes in future adaptive capacities. To demonstrate its utility we apply the framework to a case study mortality time-series dataset from Bavaria, Germany. METHODS: In this modelling framework, we used extrapolated location-specific and age-specific baseline exposure-response functions and propose different future scenarios of cold sensitivity and heat adaptation on the basis of varying slopes of these exposure-response functions. We also incorporated future socioeconomic adaptation in the exposure-response functions using projections of gross domestic product under the respective shared socioeconomic pathways. Future adaptable fractions, representing the deaths avoided under each of the future scenarios, are projected under combinations of two climate change scenarios (shared socioeconomic pathway [SSP]1-2.6 and SSP3-7.0) and the respective plausible population projection scenarios (SSP1 and SSP3), also incorporating the future changes in demographic age structure and mortality. The case study for this framework was done for five districts in Bavaria, for both total non-accidental mortality and cardiovascular disease mortality. The baseline data was obtained for the period 1990-2006, and the future period was defined as 2083-99. FINDINGS: In our Bavaria case study, average temperature was projected to increase by 2099 by an average of 1·1°C under SSP1-2.6 and by 4·1°C under SSP3-7.0. We observed the adaptable fraction to be largely influenced by socioeconomic adaptation for both total mortality and cardiovascular disease mortality, and for both climate change scenarios. For example, for total mortality, the highest adaptable fraction of 18·56% (95% empirical CI 10·77-23·67) was observed under the SSP1-2.6 future scenario, in the presence of socioeconomic adaptation and under the highest heat adaptation (10%) provided the cold sensitivity remains 0%. The cold adaptable fraction is lower than the heat adaptable fraction under all scenarios. In the absence of socioeconomic adaptation, population ageing will lead to higher temperature-related mortality. INTERPRETATION: Our developed framework helps to systematically understand the effectiveness of adaptation mechanisms. In the future, socioeconomic adaptation is estimated to play a major role in determining temperature-related excess mortality. Furthermore, cold sensitivity might outweigh heat adaptation in the majority of locations worldwide. Similarly, population ageing is projected to continue to determine future temperature-related mortality. FUNDING: EU Horizon 2020 (EXHAUSTION).

The phase angle (PhA) measured with bioelectrical impedance analysis is considered to reflect the interrelated components body cell mass and fluid distribution based on technical and physical aspects of the PhA measurement. However, the biomedical meaning of the PhA remains vague. Previous studies mainly assessed associations of the PhA with numerous diseases and health outcomes, but few connected protein markers to the PhA. To broaden our understanding of the biomedical background of the PhA, we aimed to explore a proteomics profile associated with the PhA and related biological factors.The study sample encompassed 1484 participants (725 women and 759 men) aged 55-74 years from the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4 study. Proteomics measurements were performed with a proximity extension assay. We employed boosting with stability selection to establish a set of markers that was strongly associated with the PhA from a group of 233 plasma protein markers. We integrated the selected protein markers into a network and enrichment analysis to identify gene ontology (GO) terms significantly overrepresented for the selected PhA protein markers.Boosting with stability selection identified seven protein markers that were strongly and independently associated with the PhA: N-terminal prohormone brain natriuretic peptide (NT-proBNP), insulin-like growth factor-binding protein 2 (IGFBP2), adrenomedullin (ADM), myoglobin (MB), matrix metalloproteinase-9 (MMP9), protein-glutamine gamma-glutamyltransferase 2 (TGM2), and fractalkine (CX3CL1) [beta coefficient per 1 standard deviation increase in normalized protein expression values on a log 2 scale (95% confidence interval): -0.12 (-0.15, -0.08), -0.13 (-0.17, -0.09), -0.14 (-0.18, -0.10), 0.10 (0.07, 0.14), 0.07 (0.04, 0.10), 0.08 (0.05, 0.11), -0.06 (-0.10, -0.03), respectively]. According to the enrichment analysis, this protein profile was significantly overrepresented in the following top five GO terms: positive regulation of cell population proliferation (p-value: 1.32E-04), extracellular space (p-value: 1.34E-04), anatomical structure formation involved in morphogenesis (p-value: 2.92E-04), regulation of multicellular organismal development (p-value: 5.72E-04), and metal ion homeostasis (p-value: 8.86E-04).Implementing a proteomics approach, we identified six new protein markers strongly associated with the PhA and confirmed that NT-proBNP is a key PhA marker. The main biological processes that were related to this PhA's protein profile are involved in regulating the amount and growth of cells, reinforcing, from a biomedical perspective, the current technical-based consensus of the PhA to reflect body cell mass.

Background and aims: High lipoprotein(a) [Lp(a)] concentrations are associated with increased coronary artery disease (CAD) risk. Lp(a) is regulated mainly genetically by the LPA gene but involved genetic variants have not been fully elucidated. Improved understanding of the entanglements of genetic Lp(a) regulation may enhance genetic prediction of Lp(a) and CAD risk. We investigated an interaction between the well-known LPA missense SNP rs41272110 (known as Thr3888Pro) and the frequent LPA splicing mutation KIV-2 4925G>A. Methods: Effects on Lp(a) concentrations were investigated by multiple quantile regression in the German Chronic Kidney Disease (GCKD) study, KORA-F3 and KORA-F4 (ntotal = 10,405) as well as in the UK Biobank (UKB) 200k exome dataset (n = 173,878). The impact of the interaction on CAD risk was assessed by survival analysis in UKB. Results: We observed a significant SNP-SNP interaction in all studies (p = 1.26e-05 to 3.03e-04). In quantile regression analysis, rs41272110 as a predictor shows no impact on Lp(a) (β = −0.06 [-0.79; 0.68], p = 0.879), but in a joint model including both SNPs as predictors, rs41272110 is associated with markedly higher Lp(a) (β = +9.40 mg/dL [6.45; 12.34], p = 4.07e-10). Similarly, rs41272110 shows no effect on CAD in UKB (HR = 1.01 [0.97; 1.04], p = 0.731), while rs41272110 carriers not carrying 4925G>A show an increased CAD risk (HR = 1.10 [1.04; 1.16], p = 6.9e-04). This group corresponds to 4% of the population. Adjustment for apolipoprotein(a) isoforms further modified the effect estimates markedly. Conclusions: This work emphasizes the complexity of the genetic regulation of Lp(a) and the importance to account for genetic subgroups in Lp(a) association studies and when interpreting genetic cardiovascular risk profiles.

The correlation between physical inactivity, thoracolumbar disc degeneration, and back pain remains unclear.This study investigated the relationship between short- and long-term physical inactivity and degenerative changes of the thoracic and lumbar spine in a southern German cohort from the general population over a time period of 14 years.This study was designed as a cross-sectional case-control study, nested in a prospective cohort from the "Cooperative Health Research in the Region of Augsburg/Kooperative Gesundheitsforschung in der Region Augsburg" (KORA) study.All participants in the population-based KORA study were assessed using a physical activity questionnaire to establish a baseline in 1999-2001 (exam 1), within an initial follow up questionnaire in 2006-2008 (exam 2), and a second follow-up questionnaire between 2013 and 2014 (exam 3). A subsample of this group (400 subjects) underwent full body MR scan performed on a 3T magnetic resonance imaging scanner current with exam 3.Data regarding physical inactivity over a time period of 14 years and back pain, and quantification of thoracic and lumbar disc degeneration on magnetic resonance imaging.Quantification of thoracic and lumbar disc degeneration was performed using the Pfirrmann score. Physical activity was grouped as no physical activity, irregularly for 1 hour, regularly for 1 hour, or regularly for ≥2 hours. This was used to calculate another variable "physical inactivity," with the options of irregular activity ≤1 hour per week or regularly ≥1 hour. Physical labor, walking, and cycling activity were additionally investigated. Correlations between physical inactivity measurements and thoracic and lumbar disc degeneration were analyzed via linear regression models adjusted for age, sex, BMI, hypertension, diabetes, and back pain.In total, 385 individuals (mean age: 56 years, SD ± 9.19; 58.2% male) were included in this study. Mean summed Pfirrmann score was 2.41 (SD ± 4.19) in the thoracic and 1.78 (SD ± 1.81) in the lumbar spine. The level of current exercise in our cohort varied with 113 (29.4%) subjects exercising regularly ≥2 hours per week, 118 (30.7%) regularly 1 hour per week, 57 (14%) irregularly for about 1 hour per week, and 97 (25.2%) stated not to exercise at exam 3. Disc degeneration was more apparent in those with irregular activity1 hour compared to those with regular activity of ≥1 hour and more per week (p.01) and in those with no activity compared to those with regular activity of ≥2 (p.001) measured using exam 3. Less physical activity over a time period of 14 years correlated with an increase of disc degeneration of the thoracic and lumbar spine after adjustment for age, sex, BMI, hypertension and diabetes mellitus (p.05). There was no statistically significant association between physical labor, walking activity, or cycling activity with disc degeneration. Additionally, no significant correlations between degree of disc degeneration (p=.990), degree of physical inactivity (p=.158), and back pain were observed.Degree of physical inactivity as measured over a time period of 14 years demonstrated a strong correlation with disc degeneration of the thoracic and lumbar spine.

Epidemiological studies investigating the association between daily particle exposure and health effects are frequently based on a single monitoring site located in an urban background. Using a central site in epidemiological time-series studies has been established based on the premises of low spatial variability of particles within the areas of interest and hence the adequacy of the central sites to monitor the exposure. This is true to a large extent in relation to larger particles (PM2.5, PM10) that are typically monitored and regulated. However, the distribution of ultrafine particles (UFP), which in cities predominantly originate from traffic, is heterogeneous. With increasing pressure to improve the epidemiology of UFP, an important question to ask is, whether central site monitoring is representative of community exposure to this size fraction of particulate matter; addressing this question is the aim of this paper. To achieve this aim, we measured personal exposure to UFP, expressed as particle number concentration (PNC), using Philips Aerasense Nanotracers (NT) carried by the participants of the study, and condensation particle counters (CPC) or scanning mobility particle sizers (SMPS) at central fixed-site monitoring stations. The measurements were conducted at three locations in Brisbane (Australia), Cassino (Italy) and Accra (Ghana). We then used paired t-tests to compare the average personal and average fixed-site PNC measured over the same 24-h, and hourly, periods. We found that, at all three locations, the 24-h average fixed-site PNC was no different to the personal PNC, when averaged over the study period and all the participants. However, the corresponding hourly averages were significantly different at certain times of the day. These were generally times spent commuting and during cooking and eating at home. Our analysis of the data obtained in Brisbane, showed that maximum personal exposure occurred in the home microenvironment during morning breakfast and evening dinner time. The main source of PNC for personal exposure was from the home-microenvironment. We conclude that the 24-h average PNC from the central-site can be used to estimate the 24-h average personal exposure for a community. However, the hourly average PNC from the central site cannot consistently be used to estimate hourly average personal exposure, mainly because they are affected by very different sources.

Background: Long-term exposure to air pollution has been associated with cardiopulmonary diseases, while the underlying mechanisms remain unclear. Objectives: To investigate changes in serum metabolites associated with long-term exposure to air pollution and explore the susceptibility characteristics. Methods: We used data from the German population-based Cooperative Health Research in the Region of Augsburg (KORA) S4 survey (1999–2001) and two follow-up examinations (F4: 2006–08 and FF4: 2013–14). Mass-spectrometry-based targeted metabolomics was used to quantify metabolites among serum samples. Only participants with repeated metabolites measurements were included in the current analysis. Land-use regression (LUR) models were used to estimate annual average concentrations of ultrafine particles, particulate matter (PM) with an aerodynamic diameter less than 10 μm (PM10), coarse particles (PMcoarse), fine particles, PM2.5 absorbance (a proxy of elemental carbon related to traffic exhaust, PM2.5abs), nitrogen oxides (NO2, NOx), and ozone at individuals’ residences. We applied confounder-adjusted mixed-effects regression models to examine the associations between long-term exposure to air pollution and metabolites. Results: Among 9,620 observations from 4,261 KORA participants, we included 5,772 (60.0%) observations from 2,583 (60.6%) participants in this analysis. Out of 108 metabolites that passed stringent quality control across three study points in time, we identified nine significant negative associations between phosphatidylcholines (PCs) and ambient pollutants at a Benjamini-Hochberg false discovery rate (FDR) corrected p-value < 0.05. The strongest association was seen for an increase of 0.27 μg/m3 (interquartile range) in PM2.5abs and decreased phosphatidylcholine acyl-alkyl C36:3 (PC ae C36:3) concentrations [percent change in the geometric mean: −2.5% (95% confidence interval: −3.6%, −1.5%)]. Conclusions: Our study suggested that long-term exposure to air pollution is associated with metabolic alterations, particularly in PCs with unsaturated long-chain fatty acids. These findings might provide new insights into potential mechanisms for air pollution-related adverse outcomes.

An increasing number of epidemiological studies have examined the association between ultrafine particles (UFP) and imbalanced autonomic control of the heart, a potential mechanism linking particulate matter air pollution to cardiovascular disease. This study systematically reviews and meta-analyzes studies on short-term effects of UFP on autonomic function, as assessed by heart rate variability (HRV). We searched PubMed and Web of Science for articles published until June 30, 2022. We extracted quantitative measures of UFP effects on HRV with a maximum lag of 15 days from single-pollutant models. We assessed the risk of bias in the included studies regarding confounding, selection bias, exposure assessment, outcome measurement, missing data, and selective reporting. Random-effects models were applied to synthesize effect estimates on HRV of various time courses. Twelve studies with altogether 1,337 subjects were included in the meta-analysis. For an increase of 10,000 particles/cm3 in UFP assessed by central outdoor measurements, our meta-analysis showed immediate decreases in the standard deviation of the normal-to-normal intervals (SDNN) by 4.0% [95% confidence interval (CI): 7.1%, −0.9%] and root mean square of successive R-R interval differences (RMSSD) by 4.7% (95% CI: 9.1%, 0.0%) within 6 h after exposure. The immediate decreases in SDNN and RMSSD associated with UFP assessed by personal measurements were smaller and borderline significant. Elevated UFP were also associated with decreases in SDNN, low-frequency power, and the ratio of low-frequency to high-frequency power when pooling estimates of lags across hours to days. We did not find associations between HRV and concurrent-day UFP exposure (daily average of at least 18 h) or exposure at lags ≥ one day. Our study indicates that short-term exposure to ambient UFP is associated with decreased HRV, predominantly as an immediate response within hours. This finding highlights that UFP may contribute to the onset of cardiovascular events through autonomic dysregulation.

Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2 concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.

Background: Associations between several persistent organic pollutants (POPs) and type 2 diabetes have been found in humans, but the relationship has rarely been investigated in the general population. The current nested case-control study examined internal exposure to polychlorinated biphenyls (PCB) and pesticides and the incidence of type 2 diabetes among participants of two population-based German cohort studies. Methods: We retrospectively selected 132 incident cases of type 2 diabetes and 264 age- and sex-matched controls from the CARdiovascular Living and Aging in Halle (CARLA) study (2002–2006, East Germany) and the Cooperative Health Research in the Region of Augsburg (KORA) study (1999–2001, South Germany) based on diabetes status at follow-up examinations in 2007–2010 and 2006–08, respectively (60% male, mean age 63 and 54 years). We assessed the association between baseline POP concentrations and incident diabetes by conditional logistic regression adjusted for cohort, BMI, cholesterol, alcohol, smoking, physical activity, and parental diabetes. Additionally, we examined effect modification by sex, obesity, parental diabetes and cohort. Results: In both cohorts, diabetes cases showed a higher BMI, a higher frequency of parental diabetes, and higher levels of POPs. We observed an increased chance for incident diabetes for PCB-138 and PCB-153 with an odds ratio (OR) of 1.50 (95%CI: 1.07–2.11) and 1.53 (1.15–2.04) per interquartile range increase in the respective POP. In addition, explorative results suggested higher OR for women and non-obese participants. Conclusions: Our results add to the evidence on diabetogenic effects of POPs in the general population, and warrant both policies to prevent human exposure to POPs and additional research on the adverse effects of more complex chemical mixtures. Keywords: Type 2 diabetes, Incidence, Environmental contaminates, Case-control study, Epidemiology

Low emission zones (LEZs) aiming at improving the air quality in urban areas have been implemented in many European cities. However, studies are limited in evaluating the effects of LEZ, and most of which used simple methods. In this study, a general additive mixed model was utilized to account for confounders in the atmosphere and validate the effects of LEZ on PM10 and NO2 concentrations in two German cities. In addition, the effects of LEZ on elemental carbon (EC) and total carbon (TC) in Berlin were also evaluated. The LEZ effects were estimated after taking into account air pollutant concentrations at a reference site located in the regional background, and adjusting for hour of the week, public holidays, season, and wind direction. The LEZ in Berlin, and the LEZ in combination with the heavy-duty vehicle (HDV) transit ban in Munich significantly reduced the PM10 concentrations, at both traffic sites (TS) and urban background sites (UB). The effects were greater in LEZ stage 3 than in LEZ stages 2 and 1. Moreover, compared with PM10, LEZ was more efficient in reducing EC, a component that is considered more toxic than PM10 mass. In contrast, the LEZ had no consistent effect on NO2 levels: no effects were observed in Berlin; in Munich, the combination of the LEZ and the HDV transit ban reduced NO2 at UB site in LEZ stage 1, but without further reductions in subsequent stages of the LEZ. Overall, our study indicated that LEZs, which target the major primary air pollution source in the highly populated city center could be an effective way to improve urban air quality such as PM mass concentration and EC level.

The Global Burden of Disease (GBD) is a comparative assessment of the health impact of the major and well-established risk factors, including ambient air pollution (AAP) assessed by concentrations of PM2.5 (particles less than 2.5 µm) and ozone. Over the last two decades, major improvements have emerged for two important inputs in the methodology for estimating the impacts of PM2.5: the assessment of global exposure to PM2.5 and the development of integrated exposure risk models (IERs) that relate the entire range of global exposures of PM2.5 to cause-specific mortality. As a result, the estimated annual mortality attributed to AAP increased from less than 1 million in 2000 to roughly 3 million for GBD in years 2010 and 2013, to 4.2 million for GBD 2015. However, the magnitude of the recent change and uncertainty regarding its rationale have resulted, in some cases, in skepticism and reduced confidence in the overall estimates. To understand the underlying reasons for the change in mortality, we examined the estimates for the years 2013 and 2015to determine the quantitative implications of alternative model input assumptions. We calculated that the year 2013 estimates increased by 8% after applying the updated exposure data used in GBD 2015, and increased by 23% with the application of the updated IERsfrom GBD 2015. The application of both upgraded methodologies together increased the GBD 2013 estimates by 35%, or about one million deaths. We also quantified the impact of the changes indemographics and the assumed threshold level. Since the global estimates of air pollution-related deaths will continue to change over time, a clear documentation of the modifications in the methodology and their impacts is necessary.In addition, there is need for additional monitoring and epidemiological studies to reduce uncertainties in the estimates for low- and medium-income countries, which contribute to about one-half of the mortality.

To investigate the organic composition and their sources of very fine atmospheric particulate matter (PM), size-segregated PM was sampled using rotating drum impactor (RDI) in series with a sequential filter sampler in Augsburg, Germany, from April 2014 to February 2015. Organic speciation analysis and organic carbon/elemental carbon (OC/EC) analysis was performed for the smallest size fraction PM0.36 (PM

Air pollution, traffic noise and noise annoyance are suggested to be associated with hypertension and blood pressure (BP); however, the evidence remains inconsistent. Our study examined the long-term associations of modeled and self-reported measures of air pollution and traffic noise on prevalent hypertension and BP. We analyzed cross-sectional data from 2552 participants aged 31-72years from the KORA F4 (2006-2008) study conducted in the region of Augsburg, Germany. Land-use regression models were used to estimate residential long-term exposure to particulate matter

Important health relevance has been suggested for ultrafine particles (UFP) and ozone, but studies on long-term effects are scarce, mainly due to the lack of appropriate spatial exposure models. We designed a measurement campaign to develop land use regression (LUR) models to predict the spatial variability focusing on particle number concentration (PNC) as indicator for UFP, ozone and several other air pollutants in the Augsburg region, Southern Germany. Three bi-weekly measurements of PNC, ozone, particulate matter (PM10, PM2.5), soot (PM2.5abs) and nitrogen oxides (NOx, NO2) were performed at 20 sites in 2014/15. Annual average concentration were calculated and temporally adjusted by measurements from a continuous background station. As geographic predictors we offered several traffic and land use variables, altitude, population and building density. Models were validated using leave-one-out cross-validation. Adjusted model explained variance (R2) was high for PNC and ozone (0.89 and 0.88). Cross-validation adjusted R2 was slightly lower (0.82 and 0.81) but still indicated a very good fit. LUR models for other pollutants performed well with adjusted R2 between 0.68 (PMcoarse) and 0.94 (NO2). Contrary to previous studies, ozone showed a moderate correlation with NO2 (Pearson's r=-0.26). PNC was moderately correlated with ozone and PM2.5, but highly correlated with NOx (r=0.91). For PNC and NOx, LUR models comprised similar predictors and future epidemiological analyses evaluating health effects need to consider these similarities.

Objectives We explored the male-female health-survival paradox in the context of health expectancy (HE) at age 65 and thereafter, using three different morbidity measures and different severity cut-offs with and without adjustments for the share of nursing home residents. Methods HE at ages 65, 70, 75, 80, and 85 was estimated with the Sullivan method, linking morbidity prevalence from the KORA (Cooperative Health Research in the Region of Augsburg)-Age study to 2016 Bavarian mortality data. Morbidity measures comprised deficit accumulation (Frailty Index, FI, cut-offs 0.08 and 0.25), disability (Health Assessment Questionnaire-Disability Index, HAQ-DI, cut-off >0) and participation (Global Activity Limitation Indicator, GALI, “limited” vs “not limited”). Results Morbidity data were available for 4083 participants (52.7% female). HE was lower in women than in men at all ages. Differences in morbidity prevalence, absolute HE, and health proportions of life expectancy (relative HE) increased with age for FI ≥ 0.25 and GALI, but not for HAQ-DI > 0 and FI > 0.08. Accounting for the share of nursing home residents resulted in a slight reduction of HE estimates but had no impact on estimated sex differences. Conclusions In HE at age 65 and thereafter, women's health disadvantage was larger than their life expectancy advantage over men.

Background: An association between long-term exposure to fine particulate matter (PM2.5) and lung cancer has been established in previous studies. PM2.5 is a complex mixture of chemical components from various sources and little is known about whether certain components contribute specifically to the associated lung cancer risk. The present study builds on recent findings from the “Effects of Low-level Air Pollution: A Study in Europe” (ELAPSE) collaboration and addresses the potential association between specific elemental components of PM2.5 and lung cancer incidence. Methods: We pooled seven cohorts from across Europe and assigned exposure estimates for eight components of PM2.5 representing non-tail pipe emissions (copper (Cu), iron (Fe), and zinc (Zn)), long-range transport (sulfur (S)), oil burning/industry emissions (nickel (Ni), vanadium (V)), crustal material (silicon (Si)), and biomass burning (potassium (K)) to cohort participants’ baseline residential address based on 100 m by 100 m grids from newly developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status). Results: The pooled study population comprised 306,550 individuals with 3916 incident lung cancer events during 5,541,672 person-years of follow-up. We observed a positive association between exposure to all eight components and lung cancer incidence, with adjusted HRs of 1.10 (95% CI 1.05, 1.16) per 50 ng/m3 PM2.5 K, 1.09 (95% CI 1.02, 1.15) per 1 ng/m3 PM2.5 Ni, 1.22 (95% CI 1.11, 1.35) per 200 ng/m3 PM2.5 S, and 1.07 (95% CI 1.02, 1.12) per 200 ng/m3 PM2.5 V. Effect estimates were largely unaffected by adjustment for nitrogen dioxide (NO2). After adjustment for PM2.5 mass, effect estimates of K, Ni, S, and V were slightly attenuated, whereas effect estimates of Cu, Si, Fe, and Zn became null or negative. Conclusions: Our results point towards an increased risk of lung cancer in connection with sources of combustion particles from oil and biomass burning and secondary inorganic aerosols rather than non-exhaust traffic emissions. Specific limit values or guidelines targeting these specific PM2.5 components may prove helpful in future lung cancer prevention strategies.

Nanoparticle-based drug delivery to ease anticancer therapy relies primarily on the enhanced permeability and retention effect (EPR). The leaky vascular structure in tumors allows extravasation of nanoparticles, often termed passive targeting. Long term retention of nanoparticles is attributed to the lack of lymphatic drainage, and unidirectional extravasation has been implied.Fluorescent liposomes with a plasma half-life of 29h were injected into tumor-bearing rats, and biodistribution in tumor, skin, paws and ears was monitored via in vivo fluorescence measurements. To calculate tissue accumulation, an algorithm was developed to subtract the blood signal from the total fluorescence recorded. Accumulation in tumor tissue was much higher than that in other tissues monitored, initially exhibiting very rapid accumulation followed by a long plateau phase with little change. Discontinuous plasmapheresis was established that was as effective as highly sophisticated clinical plasmapheresis. We observed no difference in the tumor tissue's accumulation when plasmapheresis was performed 22h after liposome injection. In contrast, plasmapheresis led to a significant inhibition of further accumulation in other tissues. When the liposomes' blood concentration was rapidly lowered, we detected no drop in tumor fluorescence. Thus extravasation via EPR is most likely a route of no return. These data support the emerging view of a more dynamic model of EPR, where gaps or entire vessels may open and close over time, or accumulated liposomes become entangled within the pores, hampering further accumulation.

Background: Previous studies suggest that pathways reducing oxidative stress may have a protective effect against adverse cardiac responses associated with ambient PM. However, few studies have directly assessed total antioxidant capacity (TAC) as a potential effect modifier of cardiac responses to increased ambient PM. Objectives: We examined if TAC modifies the association between ambient PM and markers of heart rate variability (HRV), repolarization, systemic inflammation, and systolic blood pressure (SBP) in post-infarction patients. Methods: We recruited 76 patients with a recent coronary event (myocardial infarction or unstable angina) who participated in a cardiac rehabilitation program from June 2006 to November 2009 in Rochester, New York. Ambient fine particle (PM2.5,≤2.5 μm in aerodynamic diameter), accumulation mode particle (AMP, 100-500 nm) and ultrafine particle (UFP, 10-100 nm) concentrations were measured continuously by fixed-site monitors. Markers of HRV and repolarization were measured by continuous Holter electrocardiogram (ECG) recordings before and during exercise sessions of the rehabilitation program. Blood pressure was measured and venous blood samples were collected before exercise to measure TAC and inflammation markers. We applied linear mixed models to assess changes in markers of HRV, repolarization, systemic inflammation, and SBP associated with increased PM concentrations in the low, medium and high TAC tertile groups, after adjusting for covariates including temperature, calendar time since the beginning of the study, visit number, month of year, and hour of day. Results: Based on subject-visits with available TAC, we observed increases in SBP, C-reactive protein, and fibrinogen, and decreases in rMSSD (square root of the mean of the sum of the squared differences between adjacent normal to normal intervals) and SDNN (standard deviation of normal to normal beat intervals) associated with increased PM2.5, AMP and UFP in the previous 6-120 h (e.g. change in SBP associated with each interquartile range (IQR) increase in PM2.5 lagged 0-5 h was 1.27 mmHg [95%CI: 0.09, 2.46 mmHg]). However, we did not observe a consistent pattern of effect measure modification by TAC for any combination of pollutant and outcome (e.g. changes in SBP associated with each IQR increase in PM2.5 lagged 0-5 h for the low, medium and high TAC tertile groups were 1.93 mmHg [95%CI: 0.23, 3.63 mmHg], -0.31 mmHg [95%CI: -2.62, 2.01 mmHg], and 1.29 mmHg [95%CI: -0.64, 3.21 mmHg], respectively. P for interaction=0.28). Conclusions: In a post-infarction population, total antioxidant capacity does not appear to modify the association between biomarkers of heart rate variability, repolarization, systemic inflammation, and systolic blood pressure and ambient PM concentrations in the previous 6-120 h.

BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license.

Data on the association between handgrip strength and multimorbidity (MMB) are missing.The purpose of this study was to examine if handgrip strength is related to MMB in a large population-based sample of older persons.The cross-sectional analysis was based on 1079 older people (aged 65-94years), who participated in the KORA-Age study in the Augsburg region, southern Germany. Participants underwent an interview and extensive examinations, including anthropometric measurements, registration of chronic diseases, determination of health-related behaviors (smoking, alcohol intake and physical activity), collection of blood samples, and muscle strength measurement using hand-grip dynamometry.In men, handgrip strength correlated strongly with the number of co-existing diseases (r=-0.176, p0.001), and the same pattern was observed for women (r=-0.287, p0.001). Among women, handgrip strength in the lower tertile compared to the upper tertile was significantly associated with an increased odds of having MMB (OR: 2.57, 95% CI: 1.30-5.07, p=0.007) after controlling for age, BMI, education, alcohol intake, smoking habits, medications number, inflammatory markers, telomere length and levels of physical activity. Contrary, no significant association between handgrip strength and MMB was found among men (OR: 1.32, 95% CI: 0.73-2.40, p=0.362) after multivariable adjustment.Lower levels of handgrip strength are associated with a higher odd of MMB among older women even after adjusting for traditional and novel confounders. Increasing the levels of muscular strength in older women seems to be important in order to reduce the risk for the co-occurrence of multiple chronic diseases.

Introduction Aging is associated with increasing loss of physiological resilience and successive accumulation of physiological deficits. This can be measured through a frailty index which sums up symptoms, health conditions and impairments. One possible factor in preventing or delaying deficit accumulation is physical activity. The effect of leisure time physical activity on health is well investigated; however, the effect of household physical activity is less clear. The objective of this cross-sectional study was to examine the association of household physical activity with deficit accumulation while controlling for level of leisure time physical activity. Methods Data originates from the 2008 baseline assessment of the KORA (Cooperative Health Research in the Region of Augsburg)-Age study from Southern Germany. A frailty index of deficit accumulation (Deficit Accumulation Index, DAI) was constructed from 31 age-related health deficits. Physical activity was measured with the Physical Activity Scale for the Elderly (PASE). The association of deficit accumulation and physical activity was analyzed using negative binomial regression analysis. Results The participants' (n = 960, mean age 76 years, 49.0% female) DAI ranged from 0.00 to 0.68. Higher levels of both types of physical activity were statistically significantly associated with less deficit accumulation. Participants in the highest household (leisure time) physical activity quartile had 29% (30%) less deficits than participants in the respective lowest quartiles. Conclusion High levels of household physical activity might compensate for low levels of leisure time physical activity in the prevention of deficit accumulation. Further research efforts investigating the temporal sequence of this association are needed.

Background: Reliable up-to-date estimates regarding the economic impact of chronic obstructive pulmonary disease (COPD) are lacking. This study investigates COPD excess healthcare utilization, work absenteeism, and resulting costs within the German COPD cohort COSYCONET. Methods: Data from 2139 COPD patients in GOLD grade 1-4 from COSYCONET were compared with 1537 lung-healthy control subjects from the population-based KORA platform. Multiple generalized linear models analyzed the association of COPD grades with healthcare utilization, work absence, and costs from a societal perspective while adjusting for sex, age, education, smoking status, body mass index (BMI), and several comorbidities. Results: COPD was significantly associated with excess healthcare utilization, work absence, and premature retirement. Adjusted annual excess cost of COPD in 2012 for GOLD grade 1-4 amounted to €2595 [1770-3678], €3475 [2966-4102], €5955 [5191-6843], and €8924 [7190-10,853] for direct costs, and €8621 [4104-13,857], €9871 [7692-12,777], €16,550 [13,743-20,457], and €27,658 [22,275-35,777] for indirect costs respectively. Comorbidities contributed to the primary effect of COPD on direct costs only. An additional history of cancer or stroke had the largest effect on direct costs, but the effects were smaller than those of COPD grade 3/4. Conclusions: COPD is associated with substantially higher costs than previously reported.

Retirement is a major life event potentially associated with changes in relevant risk factors for cardiovascular and metabolic conditions. This study analyzes the effect of retirement on behavioral and biomedical risk factors for chronic disease, together with subjective health parameters using Southern German epidemiological data. We used panel data from the KORA cohort study, consisting of 11,168 observations for individuals 45–80 years old. Outcomes included health behavior (alcohol, smoking, physical activity), biomedical risk factors (BMI, waist-to-hip ratio (WHR), glycosylated hemoglobin (HbA1c), total cholesterol/HDL quotient, systolic/diastolic blood pressure), and subjective health (SF12 mental and physical, self-rated health). We applied a parametric regression discontinuity design based on age thresholds for pension eligibility. Robust results after p-value corrections for multiple testing showed an increase in BMI in early retirees (at the age of 60) [β = 1.11, corrected p-val.

Background There is evidence for a seasonal pattern of suicides with peaks in spring and early summer; however, only a limited number of studies has investigated whether daily changes in meteorological variables may trigger suicides. Methods Daily fatal suicide (N = 10,595) and meteorological data were available for four Bavarian cities and ten counties (Germany) for 1990–2006. City/county-specific immediate, delayed and cumulative effects of air temperature, sunshine duration, and cloud cover on suicides were analyzed using a time-stratified case-crossover approach; city/county-specific effects were then combined using random effects meta-analysis. Potential effect modifiers were specific weather conditions, personal or regional characteristics, and season. Results A 5 °C increase in air temperature on the day before a suicide compared to the control days was associated with a 5.7% (95% confidence interval (CI): 0.6; 11.0) higher suicide risk. Further, the suicide risk was 6.5% (95% CI: 0.2; 13.3) higher on days with low/medium cloud cover (0–6 oktas) compared to days with high cloud cover (7–8 oktas). While daily changes in temperature were not associated with suicides in spring, we found a higher suicide risk in summer, autumn, and winter in association with temperature increases. The effects of cloud cover were strongest in summer and autumn and on days with temperature above the median (>8.8 °C). Sunshine duration was not associated with suicides. Conclusion We found a higher risk for suicides in association with short-term increases in air temperature on the day before the event compared to the control days and on days with low to medium cloud cover. This may highlight times when people are more likely to commit suicide.

Background: DNA methylation at GFI1-locus has been repeatedly associated with exposure to smoking from foetal period onwards. We explored whether DNA methylation maybe a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n=18212). DNA methylation at GFI1-locus was measured in whole-blood. Multivariable regression analyses were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Hypomethylation at four out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Cg14179389 hypomethylation, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, hypomethylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10 - 7 < P < 0·01). Similarly, hypo-methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10 - 8 < P < 0·001). Hypomethylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. This introduces a molecular mechanism and biomarker of smoking exposure. Funding: Not applicable Declaration of interests: The authors declare no competing interests. Ethical Approval Statement: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.

INTRODUCTION: Smoking is known to be a major cause of death among middle-aged adults, but evidence on its impact and the benefits of smoking cessation among older adults has remained limited. There ...

Introduction Mutations in TUBB4A have recently been implicated in two seemingly different disease entities, namely DYT4-isolated dystonia and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), a disorder characterized by considerable clinical variability. While several follow-up studies confirmed the importance of TUBB4A mutations in the development of H-ABC, their contribution to isolated dystonia remains uncertain. Methods We screened the TUBB4A coding regions in a large population of 709 isolated dystonia patients of German/Austrian ancestry as well as in 376 ancestry-matched control subjects by means of Sanger sequencing and high-resolution melting. In addition, we assessed the overall frequency of rare non-synonymous TUBB4A genetic variation in the huge exome dataset released by the Exome Aggregation Consortium (ExAC). Results We were unable to identify any possibly pathogenic sequence alteration in either patients or controls. According to ExAC, the overall prevalence of rare missense and loss-of-function alleles in the TUBB4A gene can be estimated at ∼1:706. Conclusions In accordance with previous work, our data indicate that TUBB4A coding mutations do not play a critical role in the broad population of isolated dystonia patients. Rather, isolated dystonia as seen in DYT4 might be an exceptional feature occurring in the heterogeneous phenotypic spectrum due to TUBB4A mutations.

Background Supplementation of calcium (Ca) and vitamin D for the prevention of osteoporosis is frequently found in Western countries. Recent re-analyses of clinical trials observed a higher risk of myocardial infarction and stroke in subjects taking Ca (+vitamin D) supplements, although the underlying mechanisms are not clear. Objective Thus, we analyzed the associations between Ca and vitamin D supplementation as well as serum concentrations of Ca and 25-hydroxyvitamin D (25(OH)D) and subclinical cardiovascular disease (CVD) phenotypes, namely intima-media thickness, ankle-brachial-index (ABI), intermittent claudication, and atrial fibrillation (AF). Design Data of 1601 participants aged 50–81 years of the population-based cross-sectional Cooperative Health Research in the Region of Augsburg (KORA) F4 study in Germany were analyzed. Logistic and linear regression models were used to estimate odds ratios (OR) (95% confidence intervals (CI)) and β-estimates (p-values), respectively. Results Regular Ca supplementation showed a significant positive association with the presence of AF after multivariable adjustment (OR = 3.89; 95% CI 1.28–11.81). Higher serum 25(OH)D concentrations were independently associated with a lower prevalence of asymptomatic peripheral arterial disease as assessed by ABI measurements (β = 0.007; p = 0.01). No other significant associations between supplementation or serum concentrations of Ca or vitamin D and CVD phenotypes were identified. Conclusions Although based on few cases the finding of a significant higher prevalence of AF in Ca supplement users hints at one possible mechanism that may contribute to an increased risk of myocardial infarction and stroke. The observed association between serum 25(OH)D and ABI supports results from other studies.

Short-term exposure to increased particulate matter (PM) concentration has been reported to trigger myocardial infarction (MI). However, the association with ultrafine particles remains unclear.We aimed to assess the effects of short-term air pollution and especially ultrafine particles on registry-based MI events and coronary deaths in the area of Augsburg, Germany.Between 1995 and 2009, the MONICA/KORA myocardial infarction registry recorded 15,417 cases of MI and coronary deaths. Concentrations of PM10μm (PM10), PM2.5μm (PM2.5), particle number concentration (PNC) as indicator for ultrafine particles, and meteorological parameters were measured in the study region. Quasi-Poisson regression adjusting for time trend, temperature, season, and weekday was used to estimate immediate, delayed and cumulative effects of air pollutants on the occurrence of MI. The daily numbers of total MI, nonfatal and fatal events as well as incident and recurrent events were analysed.We observed a 1.3% risk increase (95%-confidence interval: [-0.9%; 3.6%]) for all events and a 4.4% [-0.4%; 9.4%] risk increase for recurrent events per 24.3μg/m(3) increase in same day PM10 concentrations. Nonfatal events indicated a risk increase of 3.1% [-0.1%; 6.5%] with previous day PM10. No association was seen for PM2.5 which was only available from 1999 on. PNC showed a risk increase of 6.0% [0.6%; 11.7%] for recurrent events per 5529 particles/cm(3) increase in 5-day average PNC.Our results suggested an association between short-term PM10 concentration and numbers of MI, especially for nonfatal and recurrent events. For ultrafine particles, risk increases were notably high for recurrent events. Thus, persons who already suffered a MI seemed to be more susceptible to air pollution.

According to early experiments with natural extracts, phosphatidylcholines (PCs) are widely considered essentially non-toxic. In addition to these physiological mixed-chain PCs, many different synthetic diacyl-PCs are currently available, but they have never been systematically evaluated for any interference with cell proliferation. We thus investigated the cell proliferation of several cell lines in the presence of various liposomes consisting of a single PC component and cholesterol.Most of the PCs investigated did not interfere with cell proliferation, supporting the notion that most PCs are safe excipients. Significant IC50 values below 0.5mM were detected for PC(12:0/12:0), PC(14:1/14:1)trans and all diacyl-PCs containing two polyunsaturated fatty acids (PUFAs). The ω-3 PC(22:6/22:6) was the most toxic PC assessed, revealing IC50 values below 100μM, but no rule concerning ω-3/6 configuration or acyl chain length could be observed. Physiological mixed-chain PCs containing PUFAs were much less toxic than respective non-physiological diacyl-PCs. All trans fatty acids in diacyl-PCs interfered more with proliferation than their respective cis-configured counterparts. Depending on the concentration, those diacyl-PCs not only inhibited proliferation but also induced cell death.Unlike the non-toxic PCs usually used for liposomal drug delivery, the elucidated diacyl-PCs may be worthy of further examination to eventually construct a toxic shell for toxic drugs, thereby enhancing anticancer drug delivery via lipid particles.

Isolated dystonia is a disorder characterized by involuntary twisting postures arising from sustained muscle contractions. Although autosomal-dominant mutations in TOR1A, THAP1, and GNAL have been found in some cases, the molecular mechanisms underlying isolated dystonia are largely unknown. In addition, although emphasis has been placed on dominant isolated dystonia, the disorder is also transmitted as a recessive trait, for which no mutations have been defined. Using whole-exome sequencing in a recessive isolated dystonia-affected kindred, we identified disease-segregating compound heterozygous mutations in COL6A3, a collagen VI gene associated previously with muscular dystrophy. Genetic screening of a further 367 isolated dystonia subjects revealed two additional recessive pedigrees harboring compound heterozygous mutations in COL6A3. Strikingly, all affected individuals had at least one pathogenic allele in exon 41, including an exon-skipping mutation that induced an in-frame deletion. We tested the hypothesis that disruption of this exon is pathognomonic for isolated dystonia by inducing a series of in-frame deletions in zebrafish embryos. Consistent with our human genetics data, suppression of the exon 41 ortholog caused deficits in axonal outgrowth, whereas suppression of other exons phenocopied collagen deposition mutants. All recessive mutation carriers demonstrated early-onset segmental isolated dystonia without muscular disease. Finally, we show that Col6a3 is expressed in neurons, with relevant mRNA levels detectable throughout the adult mouse brain. Taken together, our data indicate that loss-of-function mutations affecting a specific region of COL6A3 cause recessive isolated dystonia with underlying neurodevelopmental deficits and highlight the brain extracellular matrix as a contributor to dystonia pathogenesis.

Psoriasis has been linked to cardiometabolic diseases, but epidemiological findings are inconsistent. We investigated the association between psoriasis and cardiometabolic outcomes in a German cross-sectional study ( n =4,185) and a prospective cohort of German Health Insurance beneficiaries ( n =1,811,098). A potential genetic overlap was explored using genome-wide data from >22,000 coronary artery disease and >4,000 psoriasis cases, and with a dense genotyping study of cardiometabolic risk loci on 927 psoriasis cases and 3,717 controls. After controlling for major confounders, in the cross-sectional analysis psoriasis was significantly associated with type 2 diabetes (T2D, adjusted odds ratio (OR)=2.36; 95% confidence interval CI=1.26–4.41) and myocardial infarction (MI, OR=2.26; 95% CI=1.03–4.96). In the longitudinal study, psoriasis slightly increased the risk for incident T2D (adjusted relative risk (RR)=1.11; 95% CI=1.08–1.14) and MI (RR=1.14; 95% CI=1.06–1.22), with highest risk increments in systemically treated psoriasis, which accounted for 11 and 17 excess cases of T2D and MI per 10,000 person-years. Except for weak signals from within the major histocompatibility complex, there was no evidence of genetic risk loci shared between psoriasis and cardiometabolic traits. Our findings suggest that psoriasis, in particular severe psoriasis, increases the risk for T2D and MI, and that the genetic architecture of psoriasis and cardiometabolic traits is largely distinct.

Summary Background A dysregulated hypothalamic–pituitary–adrenocortical axis (HPA) is thought to play a role in the pathophysiology of cognitive impairment. Surprisingly, little agreement exists on the association of cortisol and cognitive impairment. Thus, we sought to examine the association between cognitive function and salivary cortisol levels in a representative sample of older men and women. Methods A cross-sectional analysis was conducted among 733 study participants (65–90 years old, mean age = 74.9) of the population-based KORA (Cooperative Health Research in the Region of Augsburg)-Age study. Associations were examined between cognitive function (determined by telephone interview for cognitive status-modified, TICS-m) and salivary cortisol measured upon waking (M1), 30 min after awakening (M2), and in the late evening (E). Results In a dose response manner, lower morning (M1 and M2), and increased evening levels were observed in participants with probable dementia (4.5%, N = 33) and slightly increased in those with mild cognitive impairment (MCI) (13.8%, N = 101) compared to healthy individuals. Higher morning to evening ratios were associated with reduced odds of cognitive impairment, even after adjustments for important confounders (M1/E ratio: OR = 1.50, 95% CI = 1.08–2.07, M2/E ratio: 1.41, 1.01–1.95, per 1 standard deviation (SD) increase). However, the significant association of an increased risk for cognitive impairment was observed among men (M1/E: OR = 1.94, 95% CI = 1.24–3.02; M2/E = 1.74, 1.12–2.71) but not women (M1/E: OR = 1.11, 0.69–1.78; M2/E = 1.09, 0.67–1.77). Conclusion Our findings suggest that dysregulated HPA axis reactivity, evidenced by blunted diurnal cortisol responses, are associated with impaired cognitive function in an aged population.

Aims Since screening for distal sensorimotor polyneuropathy (DSPN) in individuals with diabetes is being underused, our aim was to develop a clinical screening score for identifying individuals with DSPN. Methods All participants with type 2 diabetes and aged 61–82 years from the German population-based KORA F4 Study (n=177) and the Australian population-based AusDiab Study (n=244) were combined into one study sample. Risk indicators of DSPN were identified and entered into a stepwise model-selection procedure, constructing two consecutive scores with increasing complexity (a base and clinical model). Results The prevalence of DSPN was 18.2% (95% confidence interval (CI): 14.7–22.3). The base model comprised age (years), height (cm), weight (kg), pain or discomfort in the feet and/or legs (yes/no), and duration of diabetes (years), yielding an area under the receiver operating characteristics curve (AUC) of 0.80 (95% CI: 0.76–0.85). The clinical model additionally included diastolic blood pressure (mmHg) and serum creatinine levels (mmol/l). The AUC increased only marginally to 0.82 (0.77–0.87) (p for AUC comparison=0.188). The internal validation of the scores produced similar AUCs. Conclusions The screening scores developed in this study are a simple tool to differentiate between a high and low likelihood of having DSPN among individuals with type 2 diabetes.

To evaluate the association between a family history of cardiovascular and metabolic diseases or risk factors and the presence of peripheral artery disease (PAD).Participants were recruited within one PAD case-control study (CAVASIC, n = 481) and two population-based studies (KORA-F3, n = 3118; KORA-F4, n = 1325). In the KORA studies, an ankle-brachial-index0.9 and/or symptomatic claudication was defined as PAD. For myocardial infarction, stroke, diabetes mellitus, hypertension, PAD, and obesity, family risk scores (FamRS) were calculated taking into account the number and age of diseased parents and siblings and regressed on prevalent PAD or ankle-brachial-index.A significant association with PAD was found for family history of myocardial infarction and hypertension in a combined analysis of all studies and for family history of PAD in the case-control study. A combined family history score was derived from FamRS myocardial infarction, stroke, diabetes mellitus, hypertension and PAD. A positive family history of at least two and/or a strong positive family history of at least one of these diseases was found to be associated with increased risk of prevalent PAD in all three studies, even after adjustment for classical risk factors (OR = 1.93, 95%CI = [1.53-2.44], p = 2.6 × 10(-8)).The presence of a positive family history for cardiovascular and metabolic diseases or risk factors was shown to be associated with the presence of PAD. A FamRS calculation tool that considers age and family size can guide a physician to perform extended examinations to prevent complications and progression of PAD.

Several studies have reported an association between air pollution and endothelial dysfunction, especially in individuals having diabetes. However, very few studies have examined the impact of air temperature on endothelial function. The objective of this analysis was to investigate short-term effects of temperature and ozone on endothelial function in individuals having diabetes. Moreover, we investigated interactive effects between air temperature and air pollution on markers of endothelial function. Between November 2004 and December 2005 flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NTGMD) and several blood markers representing endothelial function were measured using brachial artery ultrasound on four consecutive days in 22 individuals with type-2 diabetes mellitus in Chapel Hill, North Carolina (USA). Daily measurements of meteorological parameters, ozone and particulate matter with an aerodynamic diameter ≤2.5 µm (PM2.5) were obtained from fixed monitoring sites. We used additive mixed-models adjusting for time trend, day of the week, relative humidity and barometric pressure to assess temperature and ozone associations with endothelial function. A 1 °C decrease in the 24-h temperature average was associated with a decrease in mean FMD on the same day (-2.2% (95%-confidence interval:[-4.7;0.3%])) and with a delay of one and four days. A temperature decrement also led to an immediate (-1.7%[-3.3;-0.04]) decrease in NTGMD. Moreover, we observed an immediate (-14.6%[-26.3;-2.9%]) and a one day delayed (-13.5%[-27.0; 0.04%]) decrease in FMD in association with a 0.01 ppm increase in the maximum 8-h moving average of ozone. Temperature effects on FMD strengthened when PM2.5 and ozone concentrations were high. The associations were similar during winter and summer. We detected an association between temperature decreases and ozone increases on endothelial dysfunction in individuals having diabetes. We conclude that endothelial dysfunction might be a possible mechanism explaining cardiovascular events in association with environmental stimuli.

Objective Encouraging physical activity is an important public health measure to reduce disability prevalence in the aged. The aims of this study were to determine the association between midlife physical activity and late-life disability and to investigate gender-specific differences. Method This data originates from the KORA-Age cohort, a follow-up in 2008 of the MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases)/KORA (Cooperative Health Research in the Region of Augsburg) S1–S4 surveys (1984–2001) situated in Augsburg, a city in Southern Germany. We applied a multivariable hurdle model to investigate the association of physical activity and disability. Results We analysed 3333 persons with a mean follow-up of 18 ± 5.5 years. Using hurdle models, moderate activity and high activity had a protective effect on the occurrence of disability (OR (odds ratio) = 0.80 and 0.73), but not on severity (i.e. number of limitations). We observed a strong gender-specific difference in this association, with men benefitting more from exercise. Conclusion Elevated physical activity reduces the risk of becoming disabled and postpones the onset of disability by several years, but we could not show an effect on the severity of disability. In addition, men seem to benefit more from leisure-time physical activity than women.

BACKGROUND: Few studies on long-term exposure to air pollution and mortality have been reported from Europe. Within the multicentre European Study of Cohorts for Air Pollution Effects (ESCAPE), we aimed to investigate the association between natural-cause mortality and long-term exposure to several air pollutants. METHODS: We used data from 22 European cohort studies, which created a total study population of 367,251 participants. All cohorts were general population samples, although some were restricted to one sex only. With a strictly standardised protocol, we assessed residential exposure to air pollutants as annual average concentrations of particulate matter (PM) with diameters of less than 2.5 μm (PM2.5), less than 10 μm (PM10), and between 10 μm and 2.5 μm (PMcoarse), PM2.5 absorbance, and annual average concentrations of nitrogen oxides (NO2 and NOx), with land use regression models. We also investigated two traffic intensity variables-traffic intensity on the nearest road (vehicles per day) and total traffic load on all major roads within a 100 m buffer. We did cohort-specific statistical analyses using confounder models with increasing adjustment for confounder variables, and Cox proportional hazards models with a common protocol. We obtained pooled effect estimates through a random-effects meta-analysis. FINDINGS: The total study population consisted of 367,251 participants who contributed 5,118,039 person-years at risk (average follow-up 13.9 years), of whom 29,076 died from a natural cause during follow-up. A significantly increased hazard ratio (HR) for PM2.5 of 1.07 (95% CI 1.02-1.13) per 5 μg/m(3) was recorded. No heterogeneity was noted between individual cohort effect estimates (I(2) p value=0.95). HRs for PM2.5 remained significantly raised even when we included only participants exposed to pollutant concentrations lower than the European annual mean limit value of 25 μg/m(3) (HR 1.06, 95% CI 1.00-1.12) or below 20 μg/m(3) (1.07, 1.01-1.13). INTERPRETATION: Long-term exposure to fine particulate air pollution was associated with natural-cause mortality, even within concentration ranges well below the present European annual mean limit value. FUNDING: European Community's Seventh Framework Program (FP7/2007-2011).

To examine the association between electrocardiographic (ECG) findings and disability status in older adults.KORA-Age, a population-based cross-sectional study of the MONICA/KORA project, a randomized sample from Southern Germany of people aged 65 years or older.A total of 534 (51.5%) of 1,037 participants were characterized as disabled. Disabled participants were on average 4.5 years older than those who were not disabled. Crude associations of left-axis deviation, ventricular conduction defects, atrial fibrillation, and QT prolongation with disability status were significant (P0.05). In models controlled for age and sex, these effects remained constant except for QT prolongation. In the models adjusted for the minimal sufficient adjustment set (consisting of the variables sex, physical activity, age, obesity, diabetes, education, heart diseases, income, lung diseases, and stroke) identified by a directed acyclic graph (DAG), no significant association could be shown.Associations between specific ECG findings and disability were found in unadjusted analysis and logistic models adjusted for age and sex. However, when adjusting for other possible confounders identified by the DAG, all these associations were no longer significant. It is important to adequately identify confounding in such settings.