Copenhagen Aging And Midlife Biobank Research Articles

Who continues to work after retirement age?

BackgroundDemographic changes in all industrialized countries have led to a keen interest in extending working lives for older workers. To achieve this goal, it is essential to understand the patterns of retirement and specifically what characterizes individuals who continue to work beyond retirement age. Thus, the aim of this paper was to contribute to the international body of empirical knowledge about individuals who continue in the workforce after retirement age. We present evidence from Denmark and examine what characterizes individuals who continue in the workforce after retirement age and investigate the likelihood of continued work after retirement age while controlling for a set of socio-economic and lifestyle factors.MethodsThe study population consisted of 5,474 respondents to the Copenhagen Aging and Midlife Biobank (CAMB) 2021 survey, divided into two groups. The first group included subjects (n = 1,293) who stayed longer in the workforce even though they had the possibility to retire. The second group consisted of subjects who had retired full-time at the time of the survey (n = 4,181). Survey data was linked to register data to provide a broader dataset. In order to investigate the heterogeneity between the two groups in terms of important socio-economic, work-related and health-related variables, t-test, Mann-Whitney U (Wilcoxon Rank) test, and chi-square tests were employed. Further, to examine the probability of an individual working after retirement age a logit model with step-wise inclusion was utilized.ResultsOverall, individuals who continue to work even though they could retire tend to be wealthier, healthier, and males compared to individuals who are retired full-time. Further, there are more older workers who have partners and are co-habitants than retirees. The likelihood of continuing in the workforce past retirement age is affected by several work-related factors as well as life-style factors. The likelihood of working past retirement age decreases by years spent in the workforce (marginal effect of -0.003), if you have a partner (-0.080) and if your partner is outside of the workforce (marginal effect of -0.106). The likelihood increases by health (marginal effect of -0.044 of moving from excellent/very good health to good health or to fair/poor health, physical working capability (marginal effect of -0.083 of moving from no/some problems to severe problems or cannot work at all) and income (marginal effect of 0.083 from moving from the lowest income-quantile to higher quantiles).ConclusionThese results are in line with the previous literature and suggest the importance of designing retirement policies that tailor the transition toward retirement according to specific characteristics of both the individual and the segment of occupation.

The relationship between self-perceived fatigue, muscle endurance, and circulating markers of inflammation in participants of the Copenhagen aging and Midlife Biobank (CAMB)

BackgroundFatigue, low muscle endurance, muscle weakness and low-grade inflammation are strongly related to frailty at higher age. When signs of self-perceived fatigue and low muscle endurance are interrelated with low-grade inflammation at midlife, they might be used as early markers for frailty. This study investigated whether the interrelationships among self-perceived fatigue, muscle endurance and inflammation can be observed at midlife.MethodsA total of 965 participants of the Copenhagen Aging and Midlife Biobank (aged 52 ± 4 years, 536 males, 426 females) were assessed for self-perceived fatigue (20-item multidimensional fatigue inventory), muscle endurance (grip work), circulating markers of inflammation (hsCRP, IL-6, IL-10, TNF-alpha and IFN-γ), daily physical activity (PAS-2), body composition (%body fat assessed by bio-impedance) and self-reported health status. Participants were categorised (correcting for age and gender) according to high fatigue and/or low muscle endurance, differences in inflammatory profile between fatigue categories were assessed by ANCOVA (corrected for PAS-2, %body fat and presence of inflammatory conditions).ResultsOverall, muscle endurance, fatigue and inflammatory markers were significantly interrelated. Higher levels of hsCRP (p < 0.001), IL-6 (p < 0.001), IL-10 (p = 0.035) and TNF-alpha (p = 0.028) were observed in participants presenting both low muscle endurance and high fatigue. IFN-γ was highest in those with high fatigue but normal muscle endurance (p = 0.015).ConclusionsMiddle-aged participants with higher fatigue in combination with low muscle endurance show higher levels of inflammation, independently from physical activity, body fat and inflammatory pathology. The underlying mechanisms should be identified and future studies should also investigate whether these individuals show early signs of reduced physiological reserve capacity, which in later life come to full expression by means of frailty.

Social relations and contact with general practitioner in a middle-aged Danish population: a prospective register- and survey-based cohort study

BackgroundFindings about the relationship between individuals’ social relations and general practitioner (GP) contact are ambiguous as to whether weak social relations are associated with an increased or decreased consultation pattern. Furthermore, social relations may affect GP contact differently for men compared to women, between socioeconomic groups and according to perceived need. The overall aim of the study is to examine the association between functional aspects of social relations, perceived emotional and instrumental social support, the tendency to consult a GP and the frequency of GP contact.MethodsThe study comprised 6911 individuals aged 49–61 at baseline from the Copenhagen Aging and Midlife Biobank (CAMB). We conducted a two-part regression to explore the association between perceived emotional and instrumental social support and GP contact (tendency and frequency), controlling for age, sex, occupational social class, cohabitation status and number of morbidities.ResultsResults show no overall effect of the perceived social support aspects of social relations on GP contact independent of health-related needs.ConclusionsOur results do not support that perceived social support, reflecting functional aspects of social relations, are associated with general practitioner contact among middle-aged people.Trial registrationThe study has been registered and approved by the Danish Data Protection Agency and the local ethical committee (approval No.H-A-2008-126 and No. 2013-41-1814).Keywords: social relations, perceived social support, healthcare utilisation, general practitioner, middle-aged

Do partnership dissolutions and living alone affect systemic chronic inflammation? A cohort study of Danish adults

BackgroundPartnership breakups and living alone are associated with several adverse health outcomes. The aim of this study, carried out in Denmark, is to investigate whether accumulated numbers of divorces/partnership breakups...

Lifecourse partnership breakups or years lived alone and low grade inflammation in middle-aged adults

Abstract Background Divorce and living alone are associated with several adverse health outcomes. There is however very limited knowledge on the potential effects of exposure across the life course. The aim of this study is to investigate whether accumulated number of divorces/partnership breakups or years lived alone across 26 years of adult life, is associated with levels of low grade inflammation and if vulnerability with regards to gender or educational level can be identified. Methods 4,835 participants from Copenhagen Aging and Midlife Biobank (CAMB) aged 48-62 were included. Accumulated number of partnership breakups and years living alone, were retrieved from a national standardized annual register. Inflammatory markers, Interleukin-6 (IL-6) and high sensitivity C-Reactive Protein (hsCRP), were measured in plasma samples. Multivariate linear regression analyses were adjusted for age, educational level, early major life events, BMI, chronic diseases, medicinal intake that affects inflammation, acute inflammation, and personality scores (neuroticism, agreeableness, conscientiousness). Results For men, two or more partnership breakups as well as living alone for 7+ years was associated with significantly higher levels of and inflammatory markers, i.e. 12-17% higher level of hsCRP and IL6 compared to the reference groups (no break-ups/0-1 years living alone) p-values &amp;lt;0.0001-0.024. No associations were found for women, and no joint effect of partnership breakups and educational level was found for either gender. Conclusions The findings suggest a strong association between accumulated number of partnership breakups or years lived alone across 26 year of adult life and low grade inflammation for middle-aged men but not for women. No specific vulnerability among the lower was identified. The findings points towards the importance of developing tailored preventive initiatives to males experiencing several partner-break-ups or who lives alone for many years. Key messages Two or more partnership breakups or 7+ years lived alone across 26 year of adult life is associated with increased low grade inflammation for middle-aged men but not for women. No increased vulnerability among the low educated was identified.

Longitudinal associations of self-reported satisfaction with life and vitality with risk of mortality

ObjectiveThe aims of the current study were to investigate the associations between two aspects of well-being - satisfaction with life and vitality - and all-cause mortality, and examine the impact of potential confounding factors on the associations. MethodsBaseline satisfaction with life was assessed using the Satisfaction With Life Scale (n = 7058) and vitality was assessed using the Short-Form 36 vitality subscale (n = 6987). The study sample consisted of midlife participants from the Copenhagen Aging and Midlife Biobank (CAMB) study conducted from 2009 to 2011. Deaths (n = 312) in the study sample in the follow-up period (mean of 8.6 years) were assessed using Danish register data. The hazard ratios of all-cause mortality according to satisfaction with life and vitality scores adjusted for potential covariates were examined with proportional hazard regression. ResultsA one standard deviation increase on the SWLS and the SF-36 vitality scale was associated with a 39% (HR = 0.61, 95% CI = 0.55–0.67) and 40% (HR = 0.60, 95% CI = 0.54–0.66) decreased risk of mortality respectively, after adjustment for baseline sociodemographic factors. The associations remained significant after separate adjustment for lifestyle (SWLS: HR = 0.67, SF-36 vitality: HR = 0.67), health (SWLS: HR = 0.65, SF-36 vitality: HR = 0.64), depressive symptoms (SWLS: HR = 0.72, SF-36 vitality: HR = 0.71) and social factors (SWLS: HR = 0.76, SF-36 vitality: HR = 0.69). ConclusionsSatisfaction with life and vitality are of predictive value for mortality, independently of sociodemographics, lifestyle, health, depressive symptoms, and social factors.

Satisfaction with life and SF-36 vitality predict risk of ischemic heart disease: a prospective cohort study

Objectives The main objective of the current study was to investigate associations between two aspects of well-being – satisfaction with life and vitality – and incidence of and mortality from ischemic heart disease. Study design. The Copenhagen Aging and Midlife Biobank (CAMB) was conducted from 2009 to 2011 and was used as baseline data with 6750 individuals having complete information on The Satisfaction with Life Scale (SWLS) and 6652 individuals with complete information on the Short Form Health Survey (SF-36) vitality scale. Incidence of and mortality from ischemic heart disease were assessed using Danish register data and a total of 349 CAMB individuals were registered with either a diagnosis (n = 337) or had died (n = 12) from ischemic heart disease before the end of follow-up (31 December 2017). The hazard ratios of ischemic heart disease according to satisfaction with life and vitality scores were investigated using Cox proportional hazard regression adjusted for potential covariates. Results. A one standard deviation increase on the SWLS was associated with an 18% reduced risk of ischemic heart disease while a one standard deviation increase on the SF-36 vitality scale was associated with a 24% reduced risk of ischemic heart disease after adjustment for baseline socio-demographic factors. These associations remained when separately adjusting for lifestyle, objective health, and social factors, but became non-significant when adjusting for self-reported health. Conclusion. Our study indicates that both psychological and health-related components of wellbeing are important in relation to ischemic heart disease.

Risk of dementia and cognitive dysfunction in individuals with diabetes or elevated blood glucose.

To determine the risk of dementia in patients with type 1 or type 2 diabetes and in individuals with glycosylated haemoglobin, type A1C (HbA1c) of ⩾48 mmol/mol, which is the diagnostic limit for diabetes. We included the following cohorts: all incident diabetes cases aged 15 or above registered in the National Diabetes Registry (NDR) from January 2000 through December 2012 (n = 148 036) and a reference population, adult participants from the Glostrup cohort (n = 16 801), the ADDITION Study (n = 26 586) and Copenhagen Aging and Midlife Biobank (CAMB) (n = 5408). Using these cohorts, we analysed if a diagnosis of type 1 or type 2 diabetes in the NDR or HbA1c level of ⩾ 6.5% (48 mmol/mol) in the cohorts increased risk of dementia in the Danish National Patient Registry or cognitive performance assessed by the Intelligenz-Struktur-Test 2000R (IST2000R). A diagnosis of type 1 or type 2 diabetes in the NDR was associated with increased risk of dementia diagnosed both before or after age 65 as well as across different subtypes of dementia. Self-reported diabetes or high HbA1c levels were associated with lower cognitive performance (p = 0.004), while high HbA1c was associated with increased risk of dementia (HR 1.94 (1.10-3.44) in the Glostrup cohort but not in the ADDITION Study (HR 0.96 (0.57-1.61)). Both type 1 and type 2 diabetes are associated with an increased risk of dementia, while the importance of screening-detected elevated HbA1c remains less clear.

Physical capability in midlife and risk of disability pension and long-term sickness absence: prospective cohort study with register follow-up

Objective The aim of this study was to determine the association of physical capability with health-related labor market outcomes among older workers. Methods The prospective risk of disability pension and long-term sickness absence (LTSA) of ≥6 weeks was estimated from physical capability on 5076 older workers (age 49-63 years) from the Copenhagen Aging and Midlife Biobank (CAMB). Physical capability was objectively measured through nine different tests (jump performance, postural balance, chair-rise, explosive muscle strength, maximal strength of the hand, back and abdominal muscles, lung capacity, and aerobic fitness) and linked to a high-quality register on social transfer payments among all Danish residents. Cox-regression analyses estimated the association of physical capability with risk of disability pension and LTSA. Results For all measures, low physical capability [≥1 standard deviation (SD) below the mean for each gender] was associated with increased risk of disability pension and/or LTSA, whereas high physical capability (≥1 SD above the mean for each gender) was not. A capability-response association was observed between the number of tests with low capability and disability pension and LTSA (P<0.0001) - with the risk-estimate for disability pension being 8.52 (95% confidence interval 3.98-18.25) when low capability was present in ≥5 physical tests. Population attributable risks analyses indicate that 42% of the disability pension cases were attributable to low physical capability whereas this was the case for 12% of the LTSA cases. Conclusions Using objective measures of predictors and outcomes, our study shows that low physical capability in midlife was associated with increased risk of disability pension and LTSA. The results indicate that increasing physical capability to an average level among older workers with low capability could potentially contribute to preventing >40% of premature exits from the labor market.

Associations between tooth loss, prostheses and self-reported oral health, general health, socioeconomic position and satisfaction with life.

To investigate whether the location of tooth loss and prosthesis are associated with self-reported oral health, general health, socioeconomic position and satisfaction with life. From the Copenhagen Aging and Midlife Biobank (CAMB) investigation, 1517 persons had their oral status ranked (full dentition, fixed prosthesis in the masticatory zone, tooth loss in the masticatory zone, fixed prosthesis in the aesthetic zone, removable prosthesis, tooth loss in the aesthetic zone). Self-reported oral health, general health, socioeconomic position and satisfaction with life were obtained. Information on gender, normative socioeconomic position, frequency of seeing a dentist, acute dental treatment within the last 5years and general diseases was also recorded. Patients with tooth loss in the aesthetic zone and removable prosthesis showed high odds ratios for reporting poor rather than good oral health compared to patients having a full dentition. Having a removable prosthesis was further associated with rating socioeconomic position as low rather than high (odds ratio=27.7 [95% CI: 5.07; 151.6]) compared to a full dentition after controlling for normative socioeconomic position and gender. In the bivariate analyses, a tendency towards poorer general health and poorer satisfaction with life was found with worse oral status, meanwhile the multiple regression analyses did not show significant associations between oral status and general health and satisfaction with life. Missing teeth and having prostheses are associated with worse self-reported oral health compared to having a full dentition. Removable dental prosthesis may be associated with a worse self-perception of socioeconomic status.

Maternal infections during pregnancy and offspring midlife inflammation

BackgroundMicrobial exposures early in life have been found to be associated with lower levels of inflammation in adulthood; however, the role of prenatal exposure to infection on offspring inflammatory profiles is unexplored. The aim was to study if maternal infections during pregnancy are associated with inflammation among offspring in later life and to determine if there are sensitive periods of exposure.MethodsThe study was comprised of 1719 participants in the Copenhagen Aging and Midlife Biobank (CAMB) who were also members of the Copenhagen Perinatal Cohort (CPC). When the CPC was established, information on maternal infections during pregnancy was prospectively collected by a trained medical doctor. The inflammatory measures collected in late midlife included, C-reactive protein (CRP), Interleukin-6 (IL-6), TNF-alpha (TNF-α) and Interleukin-10 (IL-10). Multivariable ordinary least squared regression models were implemented to explore associations between maternal infection and inflammatory measures in offspring, controlling for maternal smoking, pre-pregnancy body mass index, age, marital status and parity.ResultsMaternal infection was associated with a 7% lower CRP level (95% CI, − 17,5%) among offspring compared with offspring born to women without an infection and similarly an 8% lower level of IL-6 (95% CI -15,1%), and a 9% lower level of IL-10 (95% CI, − 23,20%). However, differences did not reach significance. The effects of infection during the first trimester did not differ from infections later in the pregnancy.ConclusionsOur results suggested that prenatal exposure to infection may be associated with lower levels of inflammatory markers among adult offspring. Additional prospective studies are needed to further explore this finding.

Social relations and healthcare utilisation among middle-aged and older people: study protocol for an implementation and register-based study in Denmark

BackgroundWhile previous research establishes an association between social relations, health and use of healthcare services among older people, how to implement this knowledge in real-life settings has received much less attention. This study will explore the relationship between social relations, health and use of healthcare services in a Danish mid-life population sample. In addition, the study will explore individual and contextual factors affecting the implementation of a group-based life story intervention aimed at establishing and strengthening social relations among older people at nursing homes in Denmark.Methods/designA combined quantitative register-based approach and a qualitative implementation approach will be applied in this study. First, we will quantitatively analyse the relationship between social relations, health status and use of healthcare services among middle-aged people in Denmark by linking survey data on social relations, loneliness, self-perceived health and disease status from the Copenhagen Aging and Midlife Biobank (CAMB) (n = 7191) with national registries through the Public Health Database on use of healthcare services and demographic and socioeconomic factors. Second, we will qualitatively analyse individual and contextual factors affecting the implementation process of the group-based life story intervention based on semi-structured interviews (n = 16), observations and field notes with and among intervention stakeholders, i.e., participants and group leaders facilitating the intervention.DiscussionThe results of this study are expected to improve knowledge about mechanisms through which social relations are associated with health status and use of healthcare services and to inform the implementation of future interventions targeting social relations among older people at nursing homes.Trial registrationThe study has been registered and approved by the Danish Data Protection Agency. Seperate approvals have been attained for the qualitative data (Approval No. SUND-2016-08), and for the quantitative data in the CAMB database which has also received approval from the local ethical committee (approval No.H-A-2008-126 and No. 2013–41-1814, respectively).

Loneliness and objectively measured physical capability in middle-aged adults.

Loneliness is associated with poor functional ability in older people. Little is known about this association in the middle-aged. The aim is to investigate if perceived loneliness is associated with lower physical capability among middle-aged men and women and if the associations of loneliness with physical capability interact with socioeconomic position and cohabitation status. 5224 participants from Copenhagen Aging and Midlife Biobank (CAMB) aged 49-62 years (mean age 54) were included. Handgrip strength (measured by a dynamometer) and maximal number of chair rises in 30 s was recorded. Multivariate linear regression analyses were adjusted for age, occupational social class, cohabitation status, morbidity and personality traits. No association was found between loneliness and physical capability. For example estimates for handgrip strength in 'often' lonely men and women compared with the 'not lonely' were 1.2 kg (95% CI - 0.5;2.9)/1.0 kg (-0.7;2.6). Low occupational social class was associated with poorer physical capability, and living alone was associated with poorer handgrip strength in men [-2.4 kg (95% CI - 3.2;-1.5)] and poorer chair rise test in women [-0.8 rises (95% CI - 1.6;-0.1)]. There was no support for interactions. In contrast to earlier studies among older people, no association between loneliness and physical capability was found in this cohort of middle-aged men and women. Loneliness may not yet have resulted in detectable differences in physical capability in this age group. Further research is needed to clarify if, and at what point in the life course loneliness begins to affect physical capability.

Influence of physical and psychosocial work environment throughout life and physical and cognitive capacity in midlife on labor market attachment among older workers: study protocol for a prospective cohort study.

BackgroundAs average life span increases, elderly will account for an increasing proportion of the total population in most parts of the world. Thus, initiatives to retain older workers at the labor market are becoming increasingly important. This study will investigate the influence of physical and psychosocial work environment throughout working life and physical and cognitive capacity in midlife on labor market attachment among older workers.Methods/DesignApproximately 5000 participants (aged 50–60 years) from the Copenhagen Aging and Midlife Biobank (CAMB) will be followed prospectively in a national register (DREAM), containing information on a week-to-week basis about social transfer payments for about 5 million Danish residents. Using Cox regression, we will model the risk of long-term sickness absence, disability pension, early retirement and unemployment within a 4 to 6 year period from the baseline measurement as a function of the following predictors: 1) physical work demands throughout working life, 2) psychosocial working conditions throughout working life, 3) physical capacity in midlife, 4) cognitive capacity in midlife. Estimates will be adjusted for age, sex, lifestyle, socioeconomic position, chronic disease and long-term sickness absence prior to baseline.DiscussionThe project will generate new knowledge on risk factors for loss of labor market attachment. The results will potentially contribute in identifying factors that could be targeted in future interventions for maintaining a longer and healthier working life among older workers.

Does physical exposure throughout working life influence chair-rise performance in midlife? A retrospective cohort study of associations between work and physical function in Denmark

ObjectivesOur aim was to study associations between physical exposures throughout working life and physical function measured as chair-rise performance in midlife.MethodsThe Copenhagen Aging and Midlife Biobank (CAMB) provided data about...

Cohort Profile: The Copenhagen Aging and Midlife Biobank (CAMB).

Cohort Profile: The Copenhagen Aging and Midlife Biobank (CAMB).

Early life adversity potentiates the effects of later life stress on cumulative physiological dysregulation

Background and Objectives: Previous research indicates that early life adversity may heighten stress reactivity and impair mechanisms for adaptive coping, suggesting that experience of stress in early life may also potentiate adults' physiological vulnerability to stress in later life. The study tested this hypothesis by investigating whether the experience of stressful events and circumstances (SEC) in childhood or adolescence amplified the effect of adulthood SEC on physiological dysregulation (allostatic load, AL) in later midlife. Design: Observational data were used in the present study. Physiological functioning was measured in later midlife (participants' age ranged from 49 to 63 years). Both childhood/adolescence and adulthood SEC were reported retrospectively on the same occasion. Methods: Participants were 5309 Danish men and women from Copenhagen Aging and Midlife Biobank (CAMB). SEC included socioeconomic and family factors. The AL index was based on nine cardiovascular, metabolic, and immune biomarkers. Results: Experience of SEC in both early life and adulthood independently predicted higher AL. In men, experience of SEC in early life also potentiated the effect of SEC in adulthood on AL. Conclusions: The results provide further insight into the mechanisms behind the “biological embedding” of childhood stress.

The Relationship Between Cognitive Ability and Demographic Factors in Late Midlife

The aim of the article is to analyze associations between sex, age, education, and social class and cognitive ability in late midlife and to evaluate differences in cognitive ability among the three Copenhagen Aging and Midlife Biobank (CAMB) cohorts. The sample comprised 5,417 CAMB participants from three cohorts with scores on the Intelligenz-Struktur-Test 2000 R (I-S-T 2000 R). Independent associations of cognitive ability with age, sex, education, and occupational social class were observed. Particularly, strong associations with cognitive ability were obtained for school education, and consistent sex differences were observed with higher cognitive ability in men. Differences in cognitive ability among the three cohorts were small and primarily reflected demographic differences. Late-midlife cognitive ability is associated with a number of demographic factors, and demographic differences may contribute to individual differences in health and early aging. In analyses of cognitive ability, the three CAMB cohorts can be combined provided the relevant demographic variables are included as covariates.

Addressing Social Inequality in Aging by the Danish Occupational Social Class Measurement

To present the Danish Occupational Social Class (DOSC) measurement as a measure of socioeconomic position (SEP) applicable in a late midlife population, and to analyze associations of this measure with three aging-related outcomes in midlife, adjusting for education. Systematic coding procedures of the DOSC measurement were applied to 7,084 participants from the Copenhagen Aging and Midlife Biobank (CAMB) survey. We examined the association of this measure of SEP with chronic conditions, self-rated health, and mobility in logistic regression analyses, adjusting for school education in the final analysis. The measure of SEP showed a strong social gradient along the social classes in terms of prevalence of chronic conditions, poor self-rated health, and mobility limitations. Adjusting for school education attenuated the association only to a minor degree. The DOSC measure was associated with aging-related outcomes in a midlife Danish population, and is, thus, well suited for future epidemiological research on social inequalities in health and aging.

Smoking and Drinking as Risk Indicators for Tooth Loss in Middle-Aged Danes

To investigate tobacco and alcohol consumption as risk indicators for missing teeth in late middle-aged Danes. In all, 1,517 Copenhagen Aging and Midlife Biobank (CAMB) participants received a clinical oral examination that included number of teeth. Information on smoking, drinking, and various covariates was obtained using self-administered, structured questionnaires. Descriptive statistics and logistic regression (dependent variable: 6+ vs. <6 missing teeth) were used to investigate smoking and drinking in relation to missing teeth. Current smokers, persons who currently or previously smoked >15 tobacco units/day, and persons who had smoked for 27+ years had elevated mean scores of missing teeth and associated odds ratios (OR) compared with never smokers. Relative to nondrinkers, alcohol consumption was associated with reduced odds of missing 6+ teeth. Our findings suggest that smoking is positively associated, while alcoholic beverage consumption is inversely related to tooth loss in middle-aged Danes.