Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study.

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

Longitudinal association between panic disorder and health care costs in older adults.

BACKGROUND: To analyze whether probable panic disorder (PD) is associated with health care costs in older age over time. METHODS: Data regarding individuals aged 65 and over were derived from two waves of the ESTHER cohort study (nt1 = 2,348, nt2 = 2,090). Probable PD was assessed using the panic screening module from the Patient Health Questionnaire. Health care costs were obtained through monetary valuation of self-reported health care use data. Fixed effects regressions analyzed the association between transitions in probable PD status and change in health care costs, while adjusting for potential confounders. RESULTS: On a descriptive level, study participants with a positive PD screening displayed higher three-month health care costs compared to those without (incremental costs: € 259 for t1 , € 1,544 for t2 ). Transitions in probable PD were associated with an approximate increase of 65% in outpatient health care costs (ß = 0.50, p < .05). There was no significant association between probable PD transition and change in any other cost category. CONCLUSIONS: Using longitudinal data, our results highlight the economic consequences of probable PD in older adults. Future research should address whether reducing PD in older adults may reduce the associated economic burden and analyze underlying mechanisms.

Epidemiology and health care utilization of patients suffering from Huntington's disease in Germany: real world evidence based on German claims data.

BACKGROUND: Huntington's disease (HD) is a rare, genetic, neurodegenerative and ultimately fatal disease with no cure or progression-delaying treatment currently available. HD is characterized by a triad of cognitive, behavioural and motor symptoms. Evidence on epidemiology and management of HD is limited, especially for Germany. This study aims to estimate the incidence and prevalence of HD and analyze the current routine care based on German claims data. METHODS: The source of data was a sample of the Institute for Applied Health Research Berlin (InGef) Research Database, comprising data of approximately four million insured persons from approximately 70 German statutory health insurances. The study was conducted in a retrospective cross-sectional design using 2015 and 2016 as a two-year observation period. At least two outpatient or inpatient ICD-10 codes for HD (ICD-10: G10) during the study period were required for case identification. Patients were considered incident if no HD diagnoses in the 4 years prior to the year of case identification were documented. Information on outpatient drug dispensations, medical aids and remedies were considered to describe the current treatment situation of HD patients. RESULTS: A 2-year incidence of 1.8 per 100,000 persons (95%-Confidence interval (CI): 1.4-2.4) and a 2-year period prevalence of 9.3 per 100,000 persons (95%-CI: 8.3-10.4) was observed. The prevalence of HD increased with advancing age, peaking at 60-69 years (16.8 per 100,000 persons; 95%-CI: 13.4-21.0) and decreasing afterwards. The most frequently observed comorbidities and disease-associated symptoms in HD patients were depression (42.9%), dementia (37.7%), urinary incontinence (32.5%), extrapyramidal and movement disorders (30.5%), dysphagia (28.6%) and disorders of the lipoprotein metabolism (28.2%). The most common medications in HD patients were antipsychotics (66.9%), followed by antidepressants (45.1%). Anticonvulsants (16.6%), opioids (14.6%) and hypnotics (9.7%) were observed less frequently. Physical therapy was the most often used medical aid in HD patients (46.4%). Nursing services and speech therapy were used by 27.9 and 22.7% of HD patients, respectively, whereas use of psychotherapy was rare (3.2%). CONCLUSIONS: Based on a representative sample, this study provides new insights into the epidemiology and routine care of HD patients in Germany, and thus, may serve as a starting point for further research.

Association of serum markers of oxidative stress with myocardial infarction and stroke: pooled results from four large European cohort studies.

Oxidative stress contributes to endothelial dysfunction and is involved in the pathogenesis of myocardial infarction (MI) and stroke. However, associations of biomarkers of oxidative stress with MI and stroke have not yet been addressed in large cohort studies. A nested case-control design was applied in four population-based cohort studies from Germany, Czech Republic, Poland and Lithuania. Derivatives of reactive oxygen metabolites (d-ROMs) levels, as a proxy for the reactive oxygen species burden, and total thiol levels (TTL), as a proxy for the reductive capacity, were measured in baseline serum samples of 476 incident MI cases and 454 incident stroke cases as well as five controls per case individually matched by study center, age and sex. Statistical analyses were conducted with multi-variable adjusted conditional logistic regression models. d-ROMs levels were associated with both MI (odds ratio (OR), 1.21 [95% confidence interval (CI) 1.05-1.40] for 100 Carr units increase) and stroke (OR, 1.17 [95% CI 1.01-1.35] for 100 Carr units increase). TTL were only associated with stroke incidence (OR, 0.79 [95% CI 0.63-0.99] for quartiles 2-4 vs. quartile 1). The observed relationships were stronger with fatal than with non-fatal endpoints; association of TTL with fatal MI was statistically significant (OR, 0.69 [95% CI 0.51-0.93] for 100 µmol/L-increase). This pooled analysis of four large population-based cohorts suggests an important contribution of an imbalanced redox system to the etiology of mainly fatal MI and stroke events.

A short intervention targeting psychosomatic care in older adults with complex health care needs-results of a randomized controlled trial.

OBJECTIVE: The aim of this randomized controlled trial (RCT) was to assess the efficacy of a short intervention targeting psychosomatic care in older adults with complex health care needs. METHODS: Participants were recruited in the frame of the 11-year follow-up of a large population-based study by means of the INTERMED interview. The INTERMED interview is an integrative assessment method to identify bio-psycho-social health care needs. Persons with high health care needs (interview score ≥ 17) were invited to take part. Participants were randomized with a 1:1 ratio to a control and an intervention group. The intervention group received a home visit conducted by a doctor trained in psychosomatic medicine. The primary hypothesis stated that the intervention group would have a better outcome with respect to health related quality of life (HRQOL) measured by the 12-item short-form health survey (mental component score, MCS) 6 months after randomization (T1). Secondary outcomes were physical HRQOL, health care needs, depression, anxiety, and somatic symptom severity. RESULTS: In total, 175 participants were included. At the three-year follow-up (T2), 97 participants (55.4%) were included. At T1, we did not find a difference regarding MCS between the intervention and control groups. At T2, the intervention group showed significantly lower health care needs compared with the control group. Regarding HRQOL, depression, and somatic symptom severity the two groups did not differ at T2. CONCLUSIONS: The primary hypothesis was not confirmed. However, results indicate that a short intervention with complex patients could lead to reduced bio-psycho-social health care needs.

Evidence for underuse and overuse of antidepressants in older adults: Results of a large population-based study.

OBJECTIVES: Depression is common among elderly people. However, diagnosis and adequate treatment is frequently difficult. Research on underuse and overuse of antidepressants in elderly persons is scarce. This study investigates the utilization and appropriateness of pharmacological and psychological depression treatment in a large cohort of community-dwelling adults. METHODS: A subsample of 3117 participants (aged 55-85 y) of the third follow-up (2008-2010) of the large population-based German ESTHER study was included. Depression was assessed using the eight-item Patient Health Questionnaire (PHQ-8). In the course of a home visit, study doctors collected complete information on medication. Logistic regression analyses were conducted to determine the relationship of depression with both underuse and overuse of antidepressants. The analyses were then adjusted for socioeconomic variables, psychosomatic comorbidities, and motivation to seek help. RESULTS: One hundred sixty-three participants (5.2%; 95% confidence interval [CI], 4.5-6.1) fulfilled the criteria for major depression. Underuse of antidepressants was present in 126 depressed participants (77.3%; 70.1-83.5). Persons who were motivated to seek help, who had an established depression diagnosis, or who were taking more than five different medications had lower odds of underuse. Anxiety was associated with higher odds for underuse. Overuse of antidepressants (prescription without clinical indication) was found in 96 cases (41.7%; 35.3-48.4) of all antidepressant prescriptions. CONCLUSIONS: Depression treatment in older adults is frequently insufficient; it appears to depend on diagnosis as well as the patients' motivation to seek help. Education regarding the diagnosis of depression in the elderly as well as guidelines for appropriate treatment is needed.

Investigation of a possible association of potentially inappropriate medication for older adults and frailty in a prospective cohort study from Germany.

OBJECTIVE: potentially inappropriate medications (PIMs) are commonly defined as drugs that should be avoided in older adults because they are considered to have a negative risk-benefit ratio. PIMs are suspected to increase the risk for frailty, but this has yet to be examined. DESIGN: prospective population-based cohort study. SETTING AND PARTICIPANTS: a German cohort of community-dwelling older adults (≥60 years) was followed from October 2008 to September 2016. METHODS: in propensity score-adjusted logistic and Cox regression models, associations between baseline PIM use and prevalent/incident frailty were investigated. Frailty was assessed using the definition by Fried and co-workers, PIM were defined with the 2015 BEERS criteria, the BEERS criteria to avoid in cognitively impaired patients (BEERS dementia PIM), the EU(7)-PIM and the PRISCUS list. RESULTS: of 2,865 participants, 261 were frail at baseline and 423 became frail during follow-up. Only BEERS dementia PIM use was statistically significantly associated with prevalent frailty (odds ratio (95% confidence interval), 1.51 (1.04-2.17)). The strength of the association was comparable for all frailty components. Similarly, in longitudinal analyses, only BEERS dementia PIM use was associated with incident frailty albeit not statistically significant (hazard ratio, 1.19 (0.84-1.68)). CONCLUSIONS: the association of PIM use and frailty seems to be restricted to drug classes, which can induce frailty symptoms (anticholinergics, benzodiazepines, z-substances and antipsychotics). Physicians are advised to perform frailty assessments before and after prescribing these drug classes to older patients and to reconsider treatment decisions in case of negative performance changes.

Frailty and healthcare costs-longitudinal results of a prospective cohort study.

Objective: to investigate how frailty and frailty symptoms affect healthcare costs in older age longitudinally. Methods: data were gathered from a prospective cohort study in Saarland, Germany (two waves with 3-year interval, n = 1,636 aged 57-84 years at baseline). Frailty was assessed by the five Fried frailty criteria. Frailty was defined as having at least three criteria, the presence of 1-2 criteria as 'pre-frail'. Healthcare costs were quantified based on self-reported healthcare use in the sectors of inpatient treatment, outpatient treatment, professional nursing care and informal care as well as the provision of pharmaceuticals, medical supplies and dental prostheses. Results: while the onset of pre-frailty did not increase (log) total healthcare costs after adjusting for potential confounders including comorbidity, progression from non-frailty to frailty was associated with an increase in total healthcare costs (for example, costs increased by ~54 and 101% if 3 and 4 or 5 symptoms were present, respectively). This association of frailty onset with increased healthcare costs was in particular observed in the inpatient sector and for informal nursing care. Among the frailty symptoms, the onset of exhaustion was associated with an increase in total healthcare costs, whereas changes in slowness, weakness, weight loss and low-physical activity were not significantly associated with an increase in total healthcare costs. Conclusions: our data stress the economic relevance of frailty in late life. Postponing or reducing frailty might be fruitful in order to reduce healthcare costs.

Menstrual and reproductive factors and lung cancer risk: A pooled analysis from the international lung cancer consortium.

Many clinical features of lung cancer are different in women and men. Sex steroid hormones exert effects in nonreproductive organs, such as the lungs. The association between menstrual and childbearing factors and the risk of lung cancer among women is still debated. We performed a pooled analysis of eight studies contributing to the International Lung Cancer Consortium (4,386 cases and 4,177 controls). Pooled associations between menstrual or reproductive factors and lung cancer were estimated using multivariable unconditional logistic regression. Subgroup analyses were done for menopause status, smoking habits and histology. We found no strong support for an association of age at menarche and at menopause with lung cancer, but peri/postmenopausal women were at higher risk compared to premenopausal (OR 1.47, 95% CI 1.11-1.93). Premenopausal women showed increased risks associated with parity (OR 1.74, 95% CI 1.03-2.93) and number of children (OR 2.88, 95% CI 1.21-6.93 for more than 3 children; p for trend 0.01) and decreased with breastfeeding (OR 0.54, 95% CI 0.30-0.98). In contrast, peri/postmenopausal subjects had ORs around unity for the same exposures. No major effect modification was exerted by smoking status or cancer histology. Menstrual and reproductive factors may play a role in the genesis of lung cancer, yet the mechanisms are unclear, and smoking remains the most important modifiable risk factor. More investigations in large well-designed studies are needed to confirm these findings and to clarify the underlying mechanisms of gender differences in lung cancer risk.

Alcohol and lung cancer risk among never smokers: A pooled analysis from the international lung cancer consortium and the SYNERGY study.

It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversely associated with lung cancer risk with evidence most strongly supporting lower risk for light and moderate drinkers relative to non-drinkers (>0-4.9 g per day: OR = 0.80, 95% CI = 0.70-0.90; 5-9.9 g per day: OR = 0.82, 95% CI = 0.69-0.99; 10-19.9 g per day: OR = 0.79, 95% CI = 0.65-0.96). Inverse associations were found for consumption of wine and liquor, but not beer. The results indicate that alcohol consumption is inversely associated with lung cancer risk, particularly among subjects with low to moderate consumption levels, and among wine and liquor drinkers, but not beer drinkers. Although our results should have no relevant bias from the confounding effect of smoking we cannot preclude that confounding by other factors contributed to the observed associations. Confounding in relation to the non-drinker reference category may be of particular importance.

Vitamin D Supplementation Trials Aimed at Reducing Mortality Have Much Higher Power When Focusing on People with Low Serum 25-Hydroxyvitamin D Concentrations.

Background: Evidence of an inverse association between serum vitamin D and mortality from epidemiological studies has prompted efforts to reduce mortality by vitamin D supplementation, either in targeted interventions for people with vitamin D insufficiency or deficiency, or in untargeted interventions regardless of baseline vitamin D status.Objective: We aimed to assess the expected impact of the 2 different approaches on effect sizes and power of intervention studies.Methods: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] were measured in 9579 participants aged 50-75 y in the German Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung (ESTHER) study who were followed for mortality for a median of 12.4 y. We estimated adjusted HRs of mortality from all causes, cardiovascular disease, and cancer for defined increases in serum 25(OH)D by Cox regression, both across the full range of 25(OH)D concentrations and for those with vitamin D insufficiency [30 nmol/L ≤ 25(OH)D < 50 nmol/L] or deficiency [25(OH)D <30 nmol/L] only, and we calculated the power of intervention studies achieving those effect sizes.Results: An inverse association between serum 25(OH)D and mortality was observed only for participants with vitamin D insufficiency or deficiency and was strongest for the latter. Accordingly, the expected effects were much stronger and the expected power was much higher for interventions that targeted these groups than for untargeted interventions. For example, a targeted intervention study with 10,000 older adults (age 50-75 y) with serum 25(OH)D <50 nmol/L that increases serum 25(OH)D concentrations by 20 nmol/L in the intervention group (n = 5000) would be expected to yield a 26% reduction of all-cause mortality that could be detected with 89% power within 5 y of follow-up compared with a 10% mortality reduction and 20% power in an untargeted intervention study of the same size.Conclusions: Vitamin D supplementation trials aimed at reducing mortality in older adults have much higher power when focused on those with low serum 25(OH)D concentrations.

Comparison of Nine Instruments to Calculate Anticholinergic Load in a Large Cohort of Older Outpatients: Association with Cognitive and Functional Decline, Falls, and Use of Laxatives.

OBJECTIVE: A patient's risk for anticholinergic adverse effects is frequently estimated by instruments evaluating the drugs included in his medication profile. It remains unknown, however, which characteristics should be included in such an assessment instrument aiming to reliably predict adverse anticholinergic outcomes. DESIGN: Cross-sectional study. SETTING: ESTHER cohort (Germany). PARTICIPANTS: Home-dwelling participants (N = 2,761) aged between 60 and 87 years. MEASUREMENTS: The association between anticholinergic load calculated with nine different instruments and four anticholinergic adverse outcomes was investigated in univariate and multivariate analyses. Therefore, linear models complemented with Kendall's tau rank correlation coefficients (ԏ) were applied for continuous outcomes and generalized linear models were used to derive odds ratios (ORs) with 95% confidence intervals (CIs) for binary endpoints. RESULTS: Based on the respective identification criteria for anticholinergic drugs, the nine instruments identified between 245 (9%) and 866 (31%) anticholinergic drug users (mean age ± SD: 73 ± 6 years; Mini-Mental State Examination [MMSE] score: 28.3 ± 2.07; Barthel Index: 97.1 ± 7.5; 291 reporting falls; 29 taking laxatives [surrogate for constipation]). In the multivariate analysis, only two instruments indicated a significant association between anticholinergic load and all four outcomes. The instrument considering the prescribed dose showed the strongest association with MMSE scores (ԏ = -0.10), falls (OR: 2.30; 95% CI: 1.50-3.52), and the use of laxatives (OR: 3.11; 95% CI: 1.04-9.36). CONCLUSIONS: Instruments most reliably predicted anticholinergicadverse events if they were either based on the drugs' serum anticholinergic activity and the suggestions of clinician experts or considered the actual prescribed dose.

Polypharmacy and mortality: new insights from a large cohort of older adults by detection of effect modification by multi-morbidity and comprehensive correction of confounding by indication.

PURPOSE: The objective was to investigate whether the association of polypharmacy with non-cancer mortality is independent from comorbidity and is not a result of confounding by indication. METHODS: Analyses were conducted in 2687 participants of a German, population-based cohort of older adults with data collection 2008-2010. Polypharmacy was defined as ≥5 drugs and hyperpolypharmacy as ≥10 drugs. Drugs without relevant propensity of causing adverse drug reactions or drug-drug interactions were not counted. Confounding by indication was addressed by model adjustment for a propensity score for polypharmacy. RESULTS: The median age of study participants was 70 years, 10.7% had multi-morbidity, and 47.4% took five drugs or more (8.6% took ≥10 drugs). During 4.4 years of follow-up, 87 participants died of a cause other than cancer. Statistically significant, more than twofold increased non-cancer mortality was observed for subjects with polypharmacy or hyperpolypharmacy in a model adjusted for age, sex, education, lifestyle variables, and comorbidity, but associations lost statistical significance after additional adjustment for a propensity score for polypharmacy. However, a significant interaction of hyperpolypharmacy and multi-morbidity was detected (p = 0.019). The hazard ratio for the association of hyperpolypharmacy with non-cancer mortality was 1.42 (95%CI 0.57; 3.57) in subjects without multi-morbidity and 0.51 (95%CI 0.11; 2.27) in subjects with multi-morbidity. CONCLUSIONS: Polypharmacy was not independently associated with non-cancer mortality. This study highlights the importance to adjust for confounding by indication in studies on polypharmacy by a propensity score. The detected interaction suggests that hyperpolypharmacy can be indicated in subjects with multi-morbidity and may only be harmful in subjects without multi-morbidity.

Self-perceived coping resources of middle-aged and older adults - results of a large population-based study.

OBJECTIVES: Psychosocial resources (personal resources, social resources, and other) are important for coping with aging and impairment. The aim of this study was to describe the resources of older adults and to compare subgroups with frailty, complex health care needs, and/or mental disorders. METHOD: At the third follow-up of the large population-based German ESTHER study, 3124 elderly persons (aged 55-85) were included. Psychosocial resources were assessed during a home visit by trained study doctors by using a list of 26 different items. Resources were described for the total group, separated by sex, and for the three subgroups of persons with frailty, complex health care needs, and mental disorders. RESULTS: Family, self-efficacy, and financial security were the most frequently reported resources of older adults. Women and men showed significant differences in their self-perceived resources. Personal resources (self-efficacy, optimism, mastery), social resources, and financial security were reported significantly less frequently by frail persons, persons with complex health care needs, and mentally ill older adults compared to non-impaired participants. Apart from external support, patients who experienced complex health care needs reported resources less frequently compared to frail and mentally ill patients. CONCLUSION: Coping resources in older adults are associated with sex and impairment. Evaluation and support of personal resources of frail or mentally ill persons or individuals with complex health care needs should be integrated in the therapeutic process.

Longitudinal evaluation of medication underuse in older outpatients and its association with quality of life.

PURPOSE: We investigated the factors promoting prescribing omissions (medication underuse) in long-term medical care and the impact of withholding indicated medications on quality of life. METHODS: In a population-based cohort study of older ambulatory patients (ESTHER), we collected data with sequential questionnaires from participants and from their GPs. Concurrently, in two consecutive home visits, trained study physicians performed comprehensive geriatric assessments and recorded all medicines currently taken. Each patient's medication was screened for underuse using the START-2 criteria. RESULTS: Medication underuse (absence of ≥1 indicated medication) was present in 70.3 and 73.2 % of 989 participants at two consecutive home visit assessments, respectively. Following variable selection accounting for subject-specific heterogeneity over time, multivariate results revealed that more drugs (odds ratio with 95 % confidence intervals: 0.83 [0.78;0.87] per drug) and better cognitive status (0.93 [0.87;0.99] per point on the MMSE scale) were preventive factors, while worse self-reported health status (1.33 [1.05;1.67] per point on an 5-point scale) and increasing frequency of GP consultations (1.07 [1.00;1.15] per visit within the preceding 3 months) were positively associated with medication underuse. An increase in omitted medications over time was associated with worse quality of life as determined on the EuroQuol EQ-Vas and EQ-5D scales. CONCLUSION: In addition to general and physician-related factors, also patient-related aspects, such as individual health appraisal, were associated with medication underuse. Because withholding indicated drugs was associated with substantially reduced quality of life, controlled intervention studies are necessary to confirm the notion that pharmacological appropriateness improves personal wellbeing.

Self-reported smoking, serum cotinine, and blood DNA methylation.

BACKGROUND: Epigenome-wide profiling of DNA methylation pattern with respect to tobacco smoking has given rise to a new measure of smoking exposure. We investigated the relationships of methylation markers with both cotinine, an established marker of internal smoking exposure, and self-reported smoking. METHODS: Blood DNA methylation levels across the genome and serum cotinine were measured in 1000 older adults aged 50-75 years. Epigenome-wide scans were performed to identify methylation markers associated with cotinine. The inter-dose-response relationships between the number of cigarettes smoked per day, cotinine concentration, and DNA methylation were modeled by restricted cubic spline regression. RESULTS: Of 61 CpGs that passed the genome-wide significance threshold (p<1.13×10(-7)), 40 CpGs in 25 chromosomal regions were successfully replicated, showing 0.2-3% demethylation per 10ng/ml increases in cotinine. The strongest associations were observed for several loci at AHRR, F2RL3, 2q37.1, 6p21.33, and GFI1 that were previously identified to be related to self-reported smoking. One locus at RAB34 was newly discovered. Both cotinine and methylation markers exhibited non-linear relationships with the number of cigarettes smoked per day, where the highest rates of increase in cotinine and decreases in methylation were observed at low smoking intensity (1-15 cigarettes/day) and plateaued at high smoking intensity (>15-20 cigarettes/day). A clear linear relationship was observed between cotinine concentration and methylation level. Both cotinine and methylation markers showed similar accuracy in distinguishing current from never smoker, but only methylation markers distinguished former from never smoker with high accuracy. CONCLUSIONS: Our study corroborates and expands the list of smoking-associated DNA methylation markers. Methylation levels were linearly related to cotinine concentration and provided accurate measures for both current and past smoking exposure.

Associations of metabolic, inflammatory and oxidative stress markers with total morbidity and multi-morbidity in a large cohort of older German adults.

BACKGROUND: imbalances in metabolic, inflammatory and redox homeostasis play an important role in the leading theories of age-related morbidity, but no large-scale epidemiological study has been conducted so far assessing their associations with total morbidity and multi-morbidity in the same model. METHODS: analyses were conducted in 2,547 participants of an established population-based cohort study from Germany. The participants' median age was 70 years (range: 57-84) and 51.9% were women. End points were total somatic morbidity and multi-morbidity, assessed by the Cumulative Illness Rating Scale-Geriatric version. RESULTS: overall, 251 study participants had multi-morbidity (9.9%). Except for the redox marker 'total thiol levels of proteins', all other assessed metabolic (obesity, diabetes, dyslipidaemia and hypertension), inflammatory (C-reactive protein) and oxidative stress markers (derivatives of reactive oxygen metabolites) were significantly associated with total somatic morbidity and multi-morbidity if assessed individually. If modelled jointly, effect estimates were attenuated but remained statistically significant for the outcome 'total morbidity' and for low weight, obesity, insufficiently controlled diabetes and derivatives of reactive oxygen metabolites with respect to the outcome 'multi-morbidity'. CONCLUSIONS: results from this large sample of older adults support hypotheses that relate imbalances in metabolic, inflammatory and redox homeostasis to age-related morbidity. Despite over adjustment for closely related metabolic, inflammatory and oxidative stress conditions in the full model, independent associations of the markers with total morbidity and/or multi-morbidity were observed. Therefore, adverse metabolic, inflammatory and oxidative stress conditions may all play important roles in the pathogenesis of age-related morbidity, which should be investigated further in future longitudinal studies.

Associations of frailty with health care costs--results of the ESTHER cohort study.

BACKGROUND: The concept of frailty is rapidly gaining attention as an independent syndrome with high prevalence in older adults. Thereby, frailty is often related to certain adverse outcomes like mortality or disability. Another adverse outcome discussed is increased health care utilization. However, only few studies examined the impact of frailty on health care utilization and corresponding costs. The aim of this study was therefore to investigate comprehensively the relationship between frailty, health care utilization and costs. METHODS: Cross sectional data from 2598 older participants (57-84 years) recruited in the Saarland, Germany, between 2008 and 2010 was used. Participants passed geriatric assessments that included Fried's five frailty criteria: weakness, slowness, exhaustion, unintentional weight loss, and physical inactivity. Health care utilization was recorded in the sectors of inpatient treatment, outpatient treatment, pharmaceuticals, and nursing care. RESULTS: Prevalence of frailty (≥3 symptoms) was 8.0%. Mean total 3-month costs of frail participants were €3659 (4 or 5 symptoms) and €1616 (3 symptoms) as compared to €642 of nonfrail participants (no symptom). Controlling for comorbidity and general socio-demographic characteristics in multiple regression models, the difference in total costs between frail and non-frail participants still amounted to €1917; p < .05 (4 or 5 symptoms) and €680; p < .05 (3 symptoms). Among the 5 symptoms of frailty, weight loss and exhaustion were significantly associated with total costs after controlling for comorbidity. CONCLUSIONS: The study provides evidence that frailty is associated with increased health care costs. The analyses furthermore indicate that frailty is an important factor for health care costs independent from pure age and comorbidity. Costs were rather attributable to frailty (and comorbidity) than to age. This stresses that the overlapping concepts of multimorbidity and frailty are both necessary to explain health care use and corresponding costs among older adults.

Discovery of a novel epigenetic cancer marker related to the oxidative status of human blood.

Long-lasting oxidative stress exposure may lead to relatively stable epigenetic modifications of the DNA in order to activate anti-oxidative defence mechanisms. Oxidative stress related DNA methylation may therefore be associated (causally or as a by-product) with cancer. We measured derivatives of reactive oxygen metabolites (D-ROM), total thiol levels (TTL) and DNA methylation with the Illumina Infinium 450K BeadChip in three samples of German individuals aged ≥50 years: n = 1,000 ESTHER study baseline participants (DNA methylation only), n = 99 ESTHER eight-year follow-up participants and n = 142 participants of the BLITZ study. The correlation coefficient of methylation at cg10342304 and D-ROM in the ESTHER 8-year follow-up sample (r = -0.427; P = 1 × 10(-5)) was replicated with a P-value indicating statistical significance after correction for multiple testing in the BLITZ sample (r = -0.192; P = 0.022). The association was robust to adjusting for potential confounders. In the ESTHER baseline sample, the hazard ratio for cancer development in 11 years of follow-up comparing bottom and top quartile of DNA methylation at cg10342304 was 1.86 (95%-confidence-interval 1.01-3.43). In summary, this first epigenome-wide screening and replication study with oxidative status markers observed a negative correlation of D-ROM levels and DNA methylation at cg10342304 in two independent cohorts. This CpG site is located in the body region of the nucleoredoxin gene. The nucleoredoxin protein is a redox-dependent inhibitor of the Wnt/ß-catenin signaling pathway, a well-characterized cancer pathway. If the observed CpG-cancer association can be successfully replicated by other studies, this epigenetic marker could be an interesting biomarker of cancer risk.

[Frailty in Germany: status and perspectives : Results from a workshop of the German Society for Epidemiology]. / Frailty in Deutschland: Stand und Perspektiven : Ergebnisse eines Workshops der Deutschen Gesellschaft für Epidemiologie.

BACKGROUND: A standardized, valid and comparable operationalization and assessment of frailty in population-based studies is essential in order to describe the prevalence and determinants of frailty in the population. AIM: After an introduction to the subject the main goal of a workshop at the 9th annual meeting of the German Society for Epidemiology (DGEpi) was to present approaches and results from four different studies in Germany. MATERIAL AND METHODS: The following four population-based studies were used to describe frailty in Germany: the German health interview and examination survey for adults (DEGS1), the epidemiological study on the chances of prevention, early recognition and optimized treatment of chronic diseases in the older population (ESTHER), the cooperative health research in the region Augsburg (KORA Age) study and the longitudinal urban cohort ageing study (LUCAS) in Hamburg. RESULTS: The four studies consistently showed that frailty is widespread in older and oldest-old persons in Germany. It is obvious that frailty represents a relevant concept in Germany even if there is currently no uniform basis for operationalization. CONCLUSION: Concepts and instruments for the collation of frailty should be included in future population-based studies in order to make a better assessment of older people's health situation and to describe the unused potential for prevention in an aging society.