To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A ...(p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.
Aims/hypothesis
Cardiac autonomic nervous dysfunction (CAND) raises the risk of mortality, but the glycaemic threshold at which it develops is unclear. We aimed to determine the prevalence of, risk ...factors for and impact of CAND in glucose intolerance and diabetes.
Methods
Among 1,332 eligible participants aged 55–74 years in the population-based cross-sectional KORA S4 study, 130 had known diabetes mellitus (k-DM), and the remaining 1,202 underwent an OGTT. Heart rate variability (HRV) and QT variability were computed from supine 5 min ECGs.
Results
In all, 565 individuals had normal glucose tolerance (NGT), 336 had isolated impaired fasting glucose (i-IFG), 72 had isolated impaired glucose tolerance (i-IGT), 151 had combined IFG–IGT (IFG–IGT) and 78 had newly detected diabetes mellitus (n-DM). Adjusted normal HRV limits were defined in the NGT population (5th and 95th percentiles). Three HRV measures were more frequently abnormal in those with k-DM, n-DM, IFG–IGT and i-IFG than in those with NGT (
p <
0.05). The rates of CAND (≥2 of 4 HRV indices abnormal) were: NGT, 4.5%; i-IFG, 8.1%; i-IGT, 5.9%; IFG–IGT, 11.4%; n-DM, 11.7%; and k-DM, 17.5% (
p <
0.05 vs NGT, except for i-IGT). Reduced HRV was associated with cardiovascular risk factors used to construct a simple screening score for CAND. Mortality was higher in participants with reduced HRV (
p <
0.05 vs normal HRV).
Conclusions/interpretation
In the general population aged 55–74 years, the prevalence of CAND is increased not only in individuals with diabetes, but also in those with IFG–IGT and, to a lesser degree, in those with i-IFG. It is associated with mortality and modifiable cardiovascular risk factors which may be used to screen for diminished HRV in clinical practice.
Intensity and duration of physical activity are associated with the achievement of health benefits. Our aim was to characterize physical activity behavior in terms of intensity, duration pattern, and ...adherence to the WHO physical activity recommendations in a population-based sample of adults from southern Germany. Further, we investigated associations between physical activity and sex, age, and body mass index (BMI), considering also common chronic diseases.
We analyzed 475 subjects (47% males, mean age 58 years, range 48-68 years) who wore ActiGraph accelerometers for up to seven days. Measured accelerations per minute obtained from the vertical axis (uniaxial) and the vector magnitude of all three axes (triaxial) were classified as sedentary, light or moderate-to-vigorous physical activity (MVPA) according to predefined acceleration count cut-offs. The average minutes/day spent in each activity level per subject served as outcome. Associations of sex, age, BMI, and seven chronic diseases or health limitations, with the activity levels were analyzed by negative binomial regression.
Most of the wear time was spent in sedentarism (median 61%/day), whereas the median time spent in MVPA was only 3%, with men achieving more MVPA than women (35 vs. 28 minutes/day, p<0.05). Almost two thirds of MVPA was achieved in short bouts of less than 5 minutes, and 35% of the subjects did not achieve a single 10-minute bout. Hence, only 14% adhered to the WHO recommendation of 2.5 hours of MVPA/week in at least 10-minute bouts. Females, older subjects and obese subjects spent less time in MVPA (p<0.05), but no clear association with hypertension, asthma, diabetes, chronic obstructive pulmonary disease, anxiety/depression, pain or walking difficulties was observed in regression analyses with MVPA as outcome.
Activity behavior among middle-aged German adults was highly insufficient, indicating a further need for physical activity promotion in order to gain health benefits.
Sample collection, processing, storage and isolation methods constitute pre-analytic factors that can influence the quality of samples used in research and clinical practice. With regard to ...biobanking practices, a critical point in the sample's life chain is storage, particularly long-term storage. Since most studies examine the influence of different temperatures (4°C, room temperature) or delays in sample processing on sample quality, there is only little information on the effects of long-term storage at ultra-low (vapor phase of liquid nitrogen) temperatures on biomarker levels. Among these biomarkers, circulating miRNAs hold great potential for diagnosis or prognosis for a variety of diseases, like cancer, infections and chronic diseases, and are thus of high interest in several scientific questions. We therefore investigated the influence of long-term storage on levels of eight circulating miRNAs (miR-103a-3p, miR-191-5p, miR-124-3p, miR-30c-5p, miR-451a, miR-23a-3p, miR-93-5p, miR-24-3p, and miR-33b-5p) from 10 participants from the population-based cohort study KORA. Sample collection took place during the baseline survey S4 and the follow-up surveys F4 and FF4, over a time period spanning from 1999 to 2014. The influence of freeze-thaw (f/t) cycles on miRNA stability was also investigated using samples from volunteers (n = 6). Obtained plasma samples were profiled using Exiqon's miRCURYTM real-time PCR profiling system, and repeated measures ANOVA was used to check for storage or f/t effects. Our results show that detected levels of most of the studied miRNAs showed no statistically significant changes due to storage at ultra-low temperatures for up to 17 years; miR-451a levels were altered due to contamination during sampling. Freeze-thawing of one to four cycles showed an effect only on miR-30c-5p. Our results highlight the robustness of this set of circulating miRNAs for decades of storage at ultra-low temperatures and several freeze-thaw cycles, which makes our findings increasingly relevant for research conducted with biobanked samples.
We hypothesize that MRI-based renal compartment volumes, particularly renal sinus fat as locally and potentially independently acting perivascular fat tissue, increase with glucose intolerance. We ...therefore analyze the distribution of renal volumes in individuals with normal glucose levels and prediabetic and diabetic individuals and investigate potential associations with other typical cardiometabolic biomarkers.
The sample comprised N = 366 participants who were either normoglycemic (N = 230), had prediabetes (N = 87) or diabetes (N = 49), as determined by Oral Glucose Tolerance Test. Other covariates were obtained by standardized measurements and interviews. Whole-body MR measurements were performed on a 3 Tesla scanner. For assessment of the kidneys, a coronal T1w dual-echo Dixon and a coronal T2w single shot fast spin echo sequence were employed. Stepwise semi-automated segmentation of the kidneys on the Dixon-sequences was based on thresholding and geometric assumptions generating volumes for the kidneys and sinus fat. Inter- and intra-reader variability were determined on a subset of 40 subjects. Associations between glycemic status and renal volumes were evaluated by linear regression models, adjusted for other potential confounding variables. Furthermore, the association of renal volumes with visceral adipose tissue was assessed by linear regression models and Pearson's correlation coefficient.
Renal volume, renal sinus volume and renal sinus fat increased gradually from normoglycemic controls to individuals with prediabetes to individuals with diabetes (renal volume: 280.3±64.7 ml vs 303.7±67.4 ml vs 320.6±77.7ml, respectively, p < 0.001). After adjustment for age and sex, prediabetes and diabetes were significantly associated to increased renal volume, sinus volume (e.g. βPrediabetes = 10.1, 95% CI: 6.5, 13.7; p<0.01, βDiabetes = 11.86, 95% CI: 7.2, 16.5; p<0.01) and sinus fat (e.g. βPrediabetes = 7.13, 95% CI: 4.5, 9.8; p<0.001, βDiabetes = 7.34, 95% CI: 4.0, 10.7; p<0.001). Associations attenuated after adjustment for additional confounders were only significant for prediabetes and sinus volume (ß = 4.0 95% CI 0.4, 7.6; p<0.05). Hypertension was significantly associated with increased sinus volume (β = 3.7, 95% CI: 0.4, 7.0; p<0.05) and absolute sinus fat volume (β = 3.0, 95% CI: 0.7, 5.3; p<0.05). GFR and all renal volumes were significantly associated as well as urine creatinine levels and renal sinus volume (β = 1.6, 95% CI: 0.1, 2.9; p<0.05).
Renal volume and particularly renal sinus fat volume already increases significantly in prediabetic subjects and is significantly associated with VAT. This shows, that renal sinus fat is a perivascular adipose tissue, which early undergoes changes in the development of metabolic disease. Our findings underpin that renal sinus fat is a link between metabolic disease and associated chronic kidney disease, making it a potential imaging biomarker when assessing perivascular adipose tissue.
•We estimated air pollution changes due to COVID-19 lockdowns in early 2020.•Region-specific air pollution-mortality relationships were applied in four regions.•Mortality benefits were observed in ...Jiangsu; California; and Central-southern Italy.•Increased PM2.5-attributable mortality burden was observed in Germany.
COVID-19 lockdowns reduced nitrogen dioxide (NO2) and fine particulate matter (PM2.5) emissions in many countries. We aim to quantify the changes in these pollutants and to assess the attributable changes in mortality in Jiangsu, China; California, U.S.; Central-southern Italy; and Germany during COVID-19 lockdowns in early 2020. Accounting for meteorological impacts and air pollution time trends, we use a machine learning-based meteorological normalization technique and the difference-in-differences approach to quantify the changes in NO2 and PM2.5 concentrations due to lockdowns. Using region-specific estimates of the association between air pollution and mortality derived from a causal modeling approach using data from 2015 to 2019, we assess the changes in mortality attributable to the air pollution changes caused by the lockdowns in early 2020. During the lockdowns, NO2 reductions avoided 1.41 (95% empirical confidence interval eCI: 0.94, 1.88), 0.44 (95% eCI: 0.17, 0.71), and 4.66 (95% eCI: 2.03, 7.44) deaths per 100,000 people in Jiangsu, China; California, U.S.; and Central-southern Italy, respectively. Mortality benefits attributable to PM2.5 reductions were also significant, albeit of a smaller magnitude. For Germany, the mortality benefits attributable to NO2 changes were not significant (0.11; 95% eCI: −0.03, 0.25), and an increase in PM2.5 concentrations was associated with an increase in mortality of 0.35 (95% eCI: 0.22, 0.48) deaths per 100,000 people during the lockdown. COVID-19 lockdowns overall improved air quality and brought attributable health benefits, especially associated with NO2 improvements, with notable heterogeneity across regions. This study underscores the importance of accounting for local characteristics when policymakers adapt successful emission control strategies from other regions.
Climate change is likely to further worsen ozone pollution in already heavily polluted areas, leading to increased ozone-related health burdens. However, little evidence exists in China, the world's ...largest greenhouse gas emitter and most populated country. As China is embracing an aging population with changing population size and falling age-standardized mortality rates, the potential impact of population change on ozone-related health burdens is unclear. Moreover, little is known about the seasonal variation of ozone-related health burdens under climate change. We aimed to assess near-term (mid-21st century) future annual and seasonal excess mortality from short-term exposure to ambient ozone in 104 Chinese cities under 2 climate and emission change scenarios and 6 population change scenarios.
We collected historical ambient ozone observations, population change projections, and baseline mortality rates in 104 cities across China during April 27, 2013, to October 31, 2015 (2013-2015), which included approximately 13% of the total population of mainland China. Using historical ozone monitoring data, we performed bias correction and spatially downscaled future ozone projections at a coarse spatial resolution (2.0° × 2.5°) for the period April 27, 2053, to October 31, 2055 (2053-2055), from a global chemistry-climate model to a fine spatial resolution (0.25° × 0.25°) under 2 Intergovernmental Panel on Climate Change Representative Concentration Pathways (RCPs): RCP4.5, a moderate global warming and emission scenario where global warming is between 1.5°C and 2.0°C, and RCP8.5, a high global warming and emission scenario where global warming exceeds 2.0°C. We then estimated the future annual and seasonal ozone-related acute excess mortality attributable to both climate and population changes using cause-specific, age-group-specific, and season-specific concentration-response functions (CRFs). We used Monte Carlo simulations to obtain empirical confidence intervals (eCIs), quantifying the uncertainty in CRFs and the variability across ensemble members (i.e., 3 predictions of future climate and air quality from slightly different starting conditions) of the global model. Estimates of future changes in annual ozone-related mortality are sensitive to the choice of global warming and emission scenario, decreasing under RCP4.5 (-24.0%) due to declining ozone precursor emissions but increasing under RCP8.5 (10.7%) due to warming climate in 2053-2055 relative to 2013-2015. Higher ambient ozone occurs under the high global warming and emission scenario (RCP8.5), leading to an excess 1,476 (95% eCI: 898 to 2,977) non-accidental deaths per year in 2053-2055 relative to 2013-2015. Future ozone-related acute excess mortality from cardiovascular diseases was 5-8 times greater than that from respiratory diseases. Ozone concentrations increase by 15.1 parts per billion (10-9) in colder months (November to April), contributing to a net yearly increase of 22.3% (95% eCI: 7.7% to 35.4%) in ozone-related mortality under RCP8.5. An aging population, with the proportion of the population aged 65 years and above increased from 8% in 2010 to 24%-33% in 2050, will substantially amplify future ozone-related mortality, leading to a net increase of 23,838 to 78,560 deaths (110% to 363%). Our analysis was mainly limited by using a single global chemistry-climate model and the statistical downscaling approach to project ozone changes under climate change.
Our analysis shows increased future ozone-related acute excess mortality under the high global warming and emission scenario RCP8.5 for an aging population in China. Comparison with the lower global warming and emission scenario RCP4.5 suggests that climate change mitigation measures are needed to prevent a rising health burden from exposure to ambient ozone pollution in China.
Inconsistent associations between long-term exposure to particles with an aerodynamic diameter
fine particulate matter (
) components and mortality have been reported, partly related to challenges in ...exposure assessment.
We investigated the associations between long-term exposure to
elemental components and mortality in a large pooled European cohort; to compare health effects of
components estimated with two exposure modeling approaches, namely, supervised linear regression (SLR) and random forest (RF) algorithms.
We pooled data from eight European cohorts with 323,782 participants, average age 49 y at baseline (1985-2005). Residential exposure to 2010 annual average concentration of eight
components copper (Cu), iron (Fe), potassium (K), nickel (Ni), sulfur (S), silicon (Si), vanadium (V), and zinc (Zn) was estimated with Europe-wide SLR and RF models at a
scale. We applied Cox proportional hazards models to investigate the associations between components and natural and cause-specific mortality. In addition, two-pollutant analyses were conducted by adjusting each component for
mass and nitrogen dioxide (
) separately.
We observed 46,640 natural-cause deaths with 6,317,235 person-years and an average follow-up of 19.5 y. All SLR-modeled components were statistically significantly associated with natural-cause mortality in single-pollutant models with hazard ratios (HRs) from 1.05 to 1.27. Similar HRs were observed for RF-modeled Cu, Fe, K, S, V, and Zn with wider confidence intervals (CIs). HRs for SLR-modeled Ni, S, Si, V, and Zn remained above unity and (almost) significant after adjustment for both
and
. HRs only remained (almost) significant for RF-modeled K and V in two-pollutant models. The HRs for V were 1.03 (95% CI: 1.02, 1.05) and 1.06 (95% CI: 1.02, 1.10) for SLR- and RF-modeled exposures, respectively, per
, adjusting for
mass. Associations with cause-specific mortality were less consistent in two-pollutant models.
Long-term exposure to V in
was most consistently associated with increased mortality. Associations for the other components were weaker for exposure modeled with RF than SLR in two-pollutant models. https://doi.org/10.1289/EHP8368.
Multimorbidity is a common problem in aged populations with a wide range of individual and societal consequences. The objective of the study was to explore patterns of comorbidity and multimorbidity ...in an elderly population using different analytical approaches. Data were gathered from the population-based KORA-Age project, which included 4,127 persons aged 65-94 years living in the city of Augsburg and its two surrounding counties in Southern Germany. Information on the presence of 13 chronic conditions was collected in a standardized telephone interview and a self-administered questionnaire. Patterns of comorbidity and multimorbidity were analyzed using prevalence figures, logistic regression models and exploratory tetrachoric factor analysis. The prevalence of multimorbidity (≥2 diseases) was 58.6% in the total sample. Hypertension and diabetes (Odds Ratio OR 2.95, 99.58% confidence interval CI 2.19-3.96), as well as hypertension and stroke (OR 2.00, 99.58% CI 1.26-3.16) most often occurred in combination. This association was independent of age, sex and the presence of other conditions. Using factor analysis, we identified four patterns of multimorbidity: the first pattern includes cardiovascular and metabolic diseases, the second includes joint, liver, lung and eye diseases, the third covers mental and neurologic diseases and the fourth pattern includes gastrointestinal diseases and cancer. 44% of the persons were assigned to at least one of the four multimorbidity patterns; 14% could be assigned to both the cardiovascular/metabolic and the joint/liver/lung/eye pattern. Further common pairs were the mental/neurologic pattern combined with the cardiovascular/metabolic pattern (7.2%) or the joint/liver/lung/eye pattern (5.3%), respectively. Our results confirmed the existence of co-occurrence of certain diseases in elderly persons, which is not caused by chance. Some of the identified patterns of multimorbidity and their overlap may indicate common underlying pathological mechanisms.
It remains controversial whether measures of general or abdominal adiposity are better risk predictors for ischemic stroke. Furthermore, so far it is unclear whether body fat mass index (BFMI) and ...fat free mass index (FFMI) are risk predictors for ischemic stroke. This study examined the sex-specific relevance of body mass index (BMI), BROCA Index, waist circumference (WC), waist-height ratio (WHtR), BFMI and FFMI for the development of ischemic stroke in a Caucasian population.
The prospective population-based cohort study was based on 1917 men and 1832 women (aged 50 to 74 years) who participated in the third (1994/95) or fourth (1999/2001) MONICA/KORA Augsburg survey. Subjects were free of stroke at baseline. Standardized anthropometric and bioelectric impedance measurements were obtained at baseline. Hazard ratios (HR) were estimated from Cox proportional hazard models.
During a median follow-up of 9.3 years 128 ischemic strokes occurred in men and 81 in women, respectively. Coded as quartiles WC and WHtR were significantly associated with incident stroke in multivariable analyses in women (comparing the 4th vs. the bottom quartile), but none of the adiposity measures was significantly associated with incident stroke in multivariable adjusted analyses in men. When anthropometric measures were used as continuous variables, these findings were confirmed. After multivariable adjustment the associations between obesity measures and incident ischemic stroke were statistically significant only for WC (HR 1.39, 95%CI 1.12-1.72) and WHtR in women (HR 1.39, 95%CI 1.12-1.73) per increase of 1 standard deviation. In both sexes the measures BFMI and FFMI were no independent predictors for incident ischemic stroke.
Abdominal obesity measures are independent predictors of incident ischemic stroke in women but not in men from the general adult population. Thus, it may be of particular importance for women to prevent central obesity in order to reduce their risk of ischemic stroke.
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