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Reproductive longevity is essential for fertility and influences healthy ageing in women 1,2 , but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations 3 . The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: To evaluate the performance of the Mental Component of the Short-Form 12 Health Survey, Version 1(SF-12v1), as a screening measure of depressive disorders., Methods: Data come from the European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross-sectional survey carried out on representative samples of 21,425 individuals from the noninstitutionalized adult general population of six European countries (response rate = 61.2%). The SF-12 was administered and scored according to three algorithms: the "original" method (mental component summary of SF-12 [MCS-12]), the RAND-12 (RAND-12 Mental Health Composite [RAND-12 MHC]), and the Bidemensional Response Process Model 12 mental health score (BRP-12 MHS), based on a two-factor Item Response Theory graded response model. Thirty-day and 12-month depressive disorders (major depressive episode or dysthymia) were assessed with the Composite International Diagnostic Interview, Version 3.0, by using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Receiver operating characteristic curves analysis was carried out, and optimal cutoff points maximizing balance between sensitivity (SN) and specificity (SP) were chosen for the three methods., Results: Prevalence of 30-day and 12-month depressive disorders in the overall sample was 1.5% and 4.4%, respectively. The area under the curve for 30-day depressive disorders was 0.92, and it decreased to 0.85 for 12-month disorders, regardless of the scoring method. Optimal cutoff for 30-day depressive disorders was 45.6 (SN = 0.86; SP = 0.88) for the MCS-12, 44.5 for the RAND-12 MHC (SN = 0.87, SP = 0.86), and 40.2 for the BRP-12 MHS (SN = 0.87, SP = 0.87). The selected 12-month cutoffs for MCS-12 and RAND-12 MHC were between 4.2 and 5.8 points below the general population means of each country, with SN range 0.67 to 0.78 and SP range 0.77 to 0.87., Conclusions: The SF-12 yielded acceptable results for detecting both active and recent depressive disorders in general population samples, suggesting that the questionnaire could be used as a useful screening tool for monitoring the prevalence of affective disorders and for targeting treatment and prevention., (Copyright © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Most patients with chronic obstructive pulmonary disease (COPD) in Europe are treated in primary care, but perceptions on what guides primary care physicians (PCPs) in managing patients are lacking., Aims: To describe factors associated with the assessment by PCPs of COPD severity and those associated with impaired health status, as assessed by patient-reported outcomes., Methods: This cross-sectional study evaluated health-related quality of life (HRQL) in 2,294 COPD patients from five European countries. The severity of COPD was clinically judged by the PCPs and GOLD stage severity was calculated using spirometry data., Results: PCPs' categories of severity reflected a wider range of HRQL scores (St George's Respiratory Questionnaire (SGRQ) total score: mild 30.3; moderate 41.7; severe 55.0; very severe 66.1) than GOLD severity grading (Stage I 38.2; Stage II 41.1; Stage III 49.9; Stage IV 58.5). Multiple ordinal logistic regression models showed that factors most closely related to PCP-rated COPD severity were Medical Research Council (MRC) dyspnoea grade, forced expiratory volume in 1 second (FEV₁) percent predicted, HRQL score (either SGRQ or COPD Assessment Test (CAT)), and previous hospitalisations (model generalised R²=0.45 or 0.44 (SQRQ or CAT in model, respectively); all factors p<0.0001). Factors with the highest association with HRQL scores (SGRQ or CAT) were MRC dyspnoea grade, COPD severity (PCP-rated), sputum production, and number of co-morbidities (model R²=0.46 or 0.37 (SQRQ or CAT in multiple linear regression model, respectively); all factors p<0.0001)., Conclusions: PCPs successfully graded COPD severity clinically and appeared to have greater discriminative power for assessing severity in COPD than FEV₁-based staging. Their more holistic approach appeared to reflect the patients' HRQL rating and was consistent across five European countries.

A short, easy-to-use health status questionnaire is needed in the multidimensional assessment of chronic obstructive pulmonary disease (COPD) in routine practice. The performance of the eight-item COPD assessment test (CAT) was analysed in 1,817 patients from primary care in seven European countries. The CAT has a scoring range of 0-40 (high score representing poor health status). Mean CAT scores indicated significant health status impairment that was related to severity of airway obstruction, but within each Global Initiative for Obstructive Lung Disease stage (I to IV) there was a wide range of scores (I: 16.2 ± 8.8; II: 16.3 ± 7.9; III: 19.3 ± 8.2; and IV: 22.3 ± 8.7; I versus II, p = 0.88; II versus III, p<0.0001; III versus IV, p = 0.0001). CAT scores showed relatively little variability across countries (within ± 12% of the mean across all countries). Scores were significantly better in patients who were stable (17.2 ± 8.3) versus those suffering an exacerbation (21.3 ± 8.4) (p<0.0001); and in patients with no (17.3 ± 8.1) or one or two (16.6 ± 8.2) versus three or more (19.7 ± 8.5) comorbidities (p<0.0001 for both). The CAT distinguished between classes of other impairment measures and was strongly correlated with the St George's Respiratory Questionnaire (r = 0.8, p<0.0001). The CAT is a simple and easy-to-use questionnaire that distinguishes between patients of different degrees of COPD severity and appears to behave the same way across countries.

Pan-European data on health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) are lacking. This cross-sectional epidemiological study evaluated health status in 1817 COPD patients from an 'all-comers' primary care population in seven European countries (87% stable disease; 13% with current exacerbation) using: St George's Respiratory Questionnaire-COPD specific (SGRQ-C), the short form health survey (SF-12) and the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale. Mean total score for SGRQ was 44.7 ± 19.4 showing marked impairment of HRQL. Scores differed little between countries (range 39.2-50.1). Impairment was associated with the severity of airway obstruction, but within each GOLD stage the variation (SD) was wide [Stage I: 38.5 ± 19.3 (n = 223); Stage II: 40.4 ± 18.1 (n = 868); Stage III: 50.2 ± 18.6 (n = 551); Stage IV: 58.6 ± 17.7 (n = 144)]. Patients suffering an exacerbation had a worse SGRQ score (54.9 ± 19.3) than those with stable disease (43.3 ± 19.0). The presence of ≥3 co-morbidities (CM) was also associated with a significantly worse score (49.9 ± 19.1) vs. 1-2 CM (42.1 ± 19.1) or no CM (42.3 ± 18.6). Findings with the SF-12 and FACIT-F results were consistent with those from the SGRQ-C. This large observational primary care study shows that health status is significantly impaired in COPD patients of all severities, even in those with mild airway obstruction. Within each GOLD stage of severity there is considerable heterogeneity in HRQL impairment among patients. (Study number: 111749)., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The European project European and Latin American Systems of Ethics Regulation of Biomedical Research Project (EULABOR) has carried out the first comparative analysis of ethics regulation systems for biomedical research in seven countries in Europe and Latin America, evaluating their roles in the protection of human subjects. We developed a conceptual and methodological framework defining 'ethics regulation system for biomedical research' as a set of actors, institutions, codes and laws involved in overseeing the ethics of biomedical research on humans. This framework allowed us to develop comprehensive national reports by conducting semi-structured interviews to key informants. These reports were summarised and analysed in a comparative analysis. The study showed that the regulatory framework for clinical research in these countries differ in scope. It showed that despite the different political contexts, actors involved and motivations for creating the regulation, in most of the studied countries it was the government who took the lead in setting up the system. The study also showed that Europe and Latin America are similar regarding national bodies and research ethics committees, but the Brazilian system has strong and noteworthy specificities.

Background: The WHODAS-2 is a disability assessment instrument based on the conceptual framework of the International Classification of Functioning, Disability, and Health (ICF). It provides a global measure of disability and 7 domain-specific scores. The aim of this study was to assess WHODAS-2 conceptual model and metric properties in a set of chronic and prevalent clinical conditions accounting for a wide scope of disability in Europe., Methods: 1,119 patients with one of 13 chronic conditions were recruited in 7 European centres. Participants were clinically evaluated and administered the WHODAS-2 and the SF-36 at baseline, 6 weeks and 3 months of follow-up. The latent structure was explored and confirmed by factor analysis (FA). Reliability was assessed in terms of internal consistency (Cronbach's alpha) and reproducibility (intra-class correlation coefficients, ICC). Construct validity was evaluated by correlating the WHODAS-2 and SF-36 domains, and comparing known groups based on the clinical-severity and work status. Effect size (ES) coefficient was used to assess responsiveness. To assess reproducibility and responsiveness, subsamples of stable (at 6 weeks) and improved (after 3 moths) patients were defined, respectively, according to changes in their clinical-severity., Results: The satisfactory FA goodness of fit indexes confirmed a second order factor structure with 7 dimensions, and a global score for the WHODAS-2. Cronbach's alpha ranged from 0.77 (self care) to 0.98 (life activities: work or school), and the ICC was lower, but achieved the recommended standard of 0.7 for four domains. Correlations between global WHODAS-2 score and the different domains of the SF-36 ranged from -0.29 to -0.65. Most of the WHODAS-2 scores showed statistically significant differences among clinical-severity groups for all pathologies, and between working patients and those not working due to ill health (p < 0.001). Among the subsample of patients who had improved, responsiveness coefficients were small to moderate (ES = 0.3-0.7), but higher than those of the SF-36., Conclusions: The latent structure originally designed by WHODAS-2 developers has been confirmed for the first time, and it has shown good metric properties in clinic and rehabilitation samples. Therefore, considerable support is provided to the WHODAS-2 utilization as an international instrument to measure disability based on the ICF model.

Context: Few studies and no international comparisons have examined the impact of multiple chronic conditions on populations using a comprehensive health-related quality of life (HRQL) questionnaire., Objective: The impact of common chronic conditions on HRQL among the general populations of eight countries was assessed., Design: Cross-sectional mail and interview surveys were conducted., Participants and Setting: Sample representatives of the adult general population of eight countries (Denmark, France, Germany, Italy, Japan, The Netherlands, Norway and the United States) were evaluated. Sample sizes ranged from 2031 to 4084., Main Outcome Measures: Self-reported prevalence of chronic conditions (including allergies, arthritis, congestive heart failure, chronic lung disease, hypertension, diabetes, and ischemic heart disease), sociodemographic data and the SF-36 Health Survey were obtained. The SF-36 scale and summary scores were estimated for individuals with and without selected chronic conditions and compared across countries using multivariate linear regression analyses. Adjustments were made for age, gender, marital status, education and the mode of SF-36 administration., Results: More than half (55.1%) of the pooled sample reported at least one chronic condition, and 30.2% had more than one. Hypertension, allergies and arthritis were the most frequently reported conditions. The effect of ischemic heart disease on many of the physical health scales was noteworthy, as was the impact of diabetes on general health, or arthritis on bodily pain scale scores. Arthritis, chronic lung disease and congestive heart failure were the conditions with a higher impact on SF-36 physical summary score, whereas for hypertension and allergies, HRQL impact was low (comparing with a typical person without chronic conditions, deviation scores were around -4 points for the first group and -1 for the second). Differences between chronic conditions in terms of their impact on SF-36 mental summary score were low (deviation scores ranged between -1 and -2)., Conclusions: Arthritis has the highest HRQL impact in the general population of the countries studied due to the combination of a high deviation score on physical scales and a high frequency. Impact of chronic conditions on HRQL was similar roughly across countries, despite important variation in prevalence. The use of HRQL measures such as the SF-36 should be useful to better characterize the global burden of disease.

Objective: To describe the 12-month and lifetime prevalence rates of mood, anxiety and alcohol disorders in six European countries., Method: A representative random sample of non-institutionalized inhabitants from Belgium, France, Germany, Italy, the Netherlands and Spain aged 18 or older (n = 21425) were interviewed between January 2001 and August 2003. DSM-IV disorders were assessed by lay interviewers using a revised version of the Composite International Diagnostic Interview (WMH-CIDI)., Results: Fourteen per cent reported a lifetime history of any mood disorder, 13.6% any anxiety disorder and 5.2% a lifetime history of any alcohol disorder. More than 6% reported any anxiety disorder, 4.2% any mood disorder, and 1.0% any alcohol disorder in the last year. Major depression and specific phobia were the most common single mental disorders. Women were twice as likely to suffer 12-month mood and anxiety disorders as men, while men were more likely to suffer alcohol abuse disorders., Conclusion: ESEMeD is the first study to highlight the magnitude of mental disorders in the six European countries studied. Mental disorders were frequent, more common in female, unemployed, disabled persons, or persons who were never married or previously married. Younger persons were also more likely to have mental disorders, indicating an early age of onset for mood, anxiety and alcohol disorders.

Objective: The European Study of Epidemiology of Mental Disorders (ESEMeD) project was designed to evaluate the prevalence, the impact and the treatment patterns in Europe. This paper presents an overview of the methods implemented in the project., Method: ESEMeD is a cross-sectional study in a representative sample of 21 425 adults, 18 or older, from the general population of Belgium, France, Germany, Italy, the Netherlands and Spain. The Composite International Diagnostic Interview (WMH-CIDI) was administered by home interviews from January 2001 to August 2003 using Computer Assisted Personal Interview (CAPI) technology. Data quality was controlled to ensure reliability and validity of the information obtained., Results: Response rate varied from 78.6% in Spain to 45.9% in France. Less than 4% of the individuals had errors in the checking procedures performed., Conclusion: The sampling methodologies, comprehensive psychiatric instruments and quality control procedures used have rendered the ESEMeD database a unique and important source of information about the prevalence, the disability burden and unmet medical needs of mental disorders within Europe.

Objective: To assess psychotropic drug utilization in the general population of six European countries, and the pattern of use in individuals with different DSM-IV diagnoses of 12-month mental disorders., Method: Data were derived from the European Study of the Epidemiology of Mental Disorders (ESEMeD/MHEDEA 2000), a cross-sectional psychiatric epidemiological study in a representative sample of 21 425 adults aged 18 or older from six European countries (e.g. Belgium, France, Germany, Italy, the Netherlands and Spain). Individuals were asked about any psychotropic drug use in the past 12 months, even if they used the drug(s) just once. A colour booklet containing high-quality pictures of psychotropic drugs commonly used to treat mental disorders was provided to help respondents recall drug use., Results: Psychotropic drug utilization is generally low in individuals with any 12-month mental disorder (32.6%). The extent of psychotropic drug utilization varied according to the specific DSM-IV diagnosis. Among individuals with a 12-month diagnosis of pure major depression, only 21.2% had received any antidepressants within the same period; the exclusive use of antidepressants was even lower (4.6%), while more individuals took only anxiolytics (18.4%)., Conclusion: These data question the appropriateness of current pharmacological treatments, particularly for major depression, in which under-treatment is coupled with the high use of non-specific medications, such as anxiolytics.

Objective: This manuscript examines the impact of mental health state and specific mental and physical disorders on work role disability and quality of life in six European countries., Method: The ESEMeD study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. Individuals aged 18 years and over who were not institutionalized were eligible for an in-home computer-assisted interview. Common mental disorders, work loss days (WLD) in the past month and quality of life (QoL) were assessed, using the WMH-2000 version of the CIDI, the WHODAS-II, and the mental and physical component scores (MCS, PCS) of the 12-item short form, respectively. The presence of five chronic physical disorders: arthritis, heart disease, lung disease, diabetes and neurological disease was also assessed. Multivariate regression techniques were used to identify the independent association of mental and physical disorders while controlling for gender, age and country., Results: In each country, WLD and loss of QoL increased with the number of disorders. Most mental disorders had approximately 1.0 SD-unit lower mean MCS and lost three to four times more work days, compared with people without any 12-month mental disorder. The 10 disorders with the highest independent impact on WLD were: neurological disease, panic disorder, PTSD, major depressive episode, dysthymia, specific phobia, social phobia, arthritis, agoraphobia and heart disease. The impact of mental vs. physical disorders on QoL was specific, with mental disorders impacting more on MCS and physical disorders more on PCS. Compared to physical disorders, mental disorders had generally stronger 'cross-domain' effects., Conclusion: The results suggest that mental disorders are important determinants of work role disability and quality of life, often outnumbering the impact of common chronic physical disorders.

Objective: Comorbidity patterns of 12-month mood, anxiety and alcohol disorders and socio-demographic factors associated with comorbidity were studied among the general population of six European countries., Method: Data were derived from the European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross-sectional psychiatric epidemiological study in a representative sample of adults aged 18 years or older in Belgium, France, Germany, Italy, the Netherlands and Spain. The diagnostic instrument used was the Composite International Diagnostic Interview (WMH-CIDI). Data are based on 21 425 completed interviews., Results: In general, high associations were found within the separate anxiety disorders and between mood and anxiety disorders. Lowest comorbidity associations were found for specific phobia and alcohol abuse-the disorders with the least functional disabilities. Comorbidity patterns were consistent cross-nationally. Associated factors for comorbidity of mood and anxiety disorders were female gender, younger age, lower educational level, higher degree of urbanicity, not living with a partner and unemployment. Only younger people were at greater risk for comorbidity of alcohol disorder with mood, anxiety disorders or both., Conclusion: High levels of comorbidity are found in the general population. Comorbidity is more common in specific groups. To reduce psychiatric burden, early intervention in populations with a primary disorder is important to prevent comorbidity.

The European Study of the Epidemiology of Mental Disorders (ESEMeD/MHEDEA 2000) is a new cross-sectional study investigating the prevalence and the associated factors of mental disorders, as well as their effect on health-related quality of life and the use of services in six European countries. This paper describes the rationale, methods and the plan for the analysis of the project. A total of 22,000 individuals representative of the non-institutionalized population aged 18 and over from Belgium, France, Germany, Italy, the Netherlands and Spain are being interviewed in their homes. Trained interviewers use a computer-assisted personal interview (CAPI) including the most recent version of the Composite International Diagnostic Interview (CIDI, 2000), a well-established epidemiological survey for assessing mental disorders. This is the first international study using the standardized up-to-date methodology for epidemiological assessment. Sizeable differences in prevalence, impact and level of need that is met by the health services are expected. The analysis of these differences should facilitate the monitoring of ongoing mental health reform initiatives in Europe and provide new research hypotheses.

Massive amounts of acidic waters and mud (pH approximately 3) containing toxic metals such as zinc, lead, arsenic, copper, antimony, cobalt, thallium, bismuth, cadmium, silver, mercury and selenium were released in the surroundings of Doñana Park as a consequence of the mine tailings spill accident in Aznalcollar (SW Spain). This introductory paper describes the main characteristics of Doñana Park, the mine activities developed in Aznalcollar and their related environmental risks. The tailing spill accident and the first package of urgent actions undertaken for preventive and mitigation purposes are also summarized.