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1.  Level of Satisfaction of Older Persons with Their General Practitioner and Practice: Role of Complexity of Health Problems 
PLoS ONE  2014;9(4):e94326.
Satisfaction is widely used to evaluate and direct delivery of medical care; a complicated relationship exists between patient satisfaction, morbidity and age. This study investigates the relationships between complexity of health problems and level of patient satisfaction of older persons with their general practitioner (GP) and practice.
Methods and Findings
This study is embedded in the ISCOPE (Integrated Systematic Care for Older Persons) study. Enlisted patients aged ≥75 years from 59 practices received a written questionnaire to screen for complex health problems (somatic, functional, psychological and social). For 2664 randomly chosen respondents (median age 82 years; 68% female) information was collected on level of satisfaction (satisfied, neutral, dissatisfied) with their GP and general practice, and demographic and clinical characteristics including complexity of health problems. Of all participants, 4% was dissatisfied with their GP care, 59% neutral and 37% satisfied. Between these three categories no differences were observed in age, gender, country of birth or education level. The percentage of participants dissatisfied with their GP care increased from 0.4% in those with 0 problem domains to 8% in those with 4 domains, i.e. having complex health problems (p<0.001). Per additional health domain with problems, the risk of being dissatisfied increased 1.7 times (95% CI 1.4–2.14; p<0.001). This was independent of age, gender, and demographic and clinical parameters (adjusted OR 1.4, 95% CI 1.1–1.8; p = 0.021).
In older persons, dissatisfaction with general practice is strongly correlated with rising complexity of health problems, independent of age, demographic and clinical parameters. It remains unclear whether complexity of health problems is a patient characteristic influencing the perception of care, or whether the care is unable to handle the demands of these patients. Prospective studies are needed to investigate the causal associations between care organization, patient characteristics, indicators of quality, and patient perceptions.
PMCID: PMC3978057  PMID: 24710557
2.  Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality 
Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants’ age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.
To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.
Data Sources and Study Selection
The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.
Data Extraction
Individual data on 55 287 participants with 542 494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25 977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.
Among 55 287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51 837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86–1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96–1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28–2.80) for a TSH level of 10 to 19.9 mIU/L (n=70 events/235; 38.4/1000 person-years; P<.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91–1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03–1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10–2.27, n=28 deaths/333; 7.7/1000 person-years; P=.005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.
Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.
PMCID: PMC3923470  PMID: 20858880
3.  Subclinical Thyroid Dysfunction and the Risk of Heart Failure Events: An Individual Participant Data Analysis from Six Prospective Cohorts 
Circulation  2012;126(9):10.1161/CIRCULATIONAHA.112.096024.
ACC/AHA Guidelines for the Diagnosis and Management of Heart Failure (HF) recommend investigating exacerbating conditions, such as thyroid dysfunction, but without specifying impact of different TSH levels. Limited prospective data exist regarding the association between subclinical thyroid dysfunction and HF events.
Methods and Results
We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of HF events. Individual data on 25,390 participants with 216,248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH 0.45–4.49 mIU/L, subclinical hypothyroidism as TSH 4.5–19.9 mIU/L and subclinical hyperthyroidism as TSH <0.45 mIU/L, both with normal free thyroxine levels. Among 25,390 participants, 2068 had subclinical hypothyroidism (8.1%) and 648 subclinical hyperthyroidism (2.6%). In age- and gender-adjusted analyses, risks of HF events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01): hazard ratio (HR) was 1.01 (95% confidence interval [CI] 0.81–1.26) for TSH 4.5–6.9 mIU/L, 1.65 (CI 0.84–3.23) for TSH 7.0–9.9 mIU/L, 1.86 (CI 1.27–2.72) for TSH 10.0–19.9 mIUL/L (P for trend <0.01), and was 1.31 (CI 0.88–1.95) for TSH 0.10–0.44 mIU/L and 1.94 (CI 1.01–3.72) for TSH <0.10 mIU/L (P for trend = 0.047). Risks remained similar after adjustment for cardiovascular risk factors.
Risks of HF events were increased with both higher and lower TSH levels, particularly for TSH ≥10 mIU/L and for TSH <0.10 mIU/L.
PMCID: PMC3884576  PMID: 22821943
cohort study; epidemiology; heart failure; meta-analysis; thyroid
4.  Subclinical Hyperthyroidism and the Risk of Coronary Heart Disease and Mortality 
Archives of internal medicine  2012;172(10):10.1001/archinternmed.2012.402.
Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting. We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.
Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.
Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age-and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio [HR], 1.24, 95% CI, 1.06–1.46), CHD mortality (HR, 1.29; 95% CI, 1.02–1.62), CHD events (HR, 1.21; 95% CI, 0.99–1.46), and AF (HR, 1.68; 95% CI, 1.16–2.43). Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% for AF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L (for both, P value for trend, ≤.03).
Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.
PMCID: PMC3872478  PMID: 22529182
5.  The Development of the Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS): A Large-Scale Data Sharing Initiative 
PLoS ONE  2013;8(12):e81673.
In 2008, the Ministry of Health, Welfare and Sport commissioned the National Care for the Elderly Programme. While numerous research projects in older persons’ health care were to be conducted under this national agenda, the Programme further advocated the development of The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS) which would be integrated into all funded research protocols. In this context, we describe TOPICS data sharing initiative (
Materials and Methods
A working group drafted TOPICS-MDS prototype, which was subsequently approved by a multidisciplinary panel. Using instruments validated for older populations, information was collected on demographics, morbidity, quality of life, functional limitations, mental health, social functioning and health service utilisation. For informal caregivers, information was collected on demographics, hours of informal care and quality of life (including subjective care-related burden).
Between 2010 and 2013, a total of 41 research projects contributed data to TOPICS-MDS, resulting in preliminary data available for 32,310 older persons and 3,940 informal caregivers. The majority of studies sampled were from primary care settings and inclusion criteria differed across studies.
TOPICS-MDS is a public data repository which contains essential data to better understand health challenges experienced by older persons and informal caregivers. Such findings are relevant for countries where increasing health-related expenditure has necessitated the evaluation of contemporary health care delivery. Although open sharing of data can be difficult to achieve in practice, proactively addressing issues of data protection, conflicting data analysis requests and funding limitations during TOPICS-MDS developmental phase has fostered a data sharing culture. To date, TOPICS-MDS has been successfully incorporated into 41 research projects, thus supporting the feasibility of constructing a large (>30,000 observations), standardised dataset pooled from various study protocols with different sampling frameworks. This unique implementation strategy improves efficiency and facilitates individual-level data meta-analysis.
PMCID: PMC3852259  PMID: 24324716
6.  Disability transitions in the oldest old in the general population. The Leiden 85-plus study 
Age  2013;36(1):483-493.
Transitions between disability states in older people occur frequently. This study investigated predictors of disability transitions in the oldest old and was performed in the Leiden 85-plus study, a population-based prospective cohort study among 597 participants aged 85 years. At baseline (age 85 years), data on sociodemographic characteristics and chronic diseases were obtained. Disabilities in basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were measured annually for 5 years with the Groningen Activities Restriction Scale (GARS). Mortality data were obtained. A statistical multi-state model was used to assess the risks of transitions between no disabilities, IADL disability, BADL disability, and death. At baseline, 299 participants (50.0 %) were disabled in IADL only, and 155 participants (26.0 %) were disabled in both BADL and IADL. During 5-year follow-up, 374 participants (62.6 %) made >1 transition between disability states, mostly deterioration in disability. Males had a lower risk of deterioration [hazard ratio (HR), 0.75 (95 % CI, 0.58–0.96)] compared to females. No gender differences were observed for improvement [HR, 0.64 (95 % CI, 0.37–1.11)]. Participants with depressive symptoms were less likely to improve [HR, 0.50 (95 % CI, 0.28–0.87)]. Participants with depressive symptoms [HR, 1.46 (95 % CI, 1.12–1.91)], >1 chronic disease [HR, 1.60 (95 % CI, 1.27–2.01)], and with cognitive impairment [HR, 1.60 (95 % CI, 1.20–2.13)] had the highest risk of deteriorating. Disability is a dynamic process in the oldest old. Deterioration is more common than improvement. Older men are less likely to deteriorate than women. The presence of depressive symptoms, chronic disease, and cognitive impairment predicts deterioration.
PMCID: PMC3889888  PMID: 23990275
Elderly/aged; Disability in activities of daily living; Recovery of function; Transitions between disability states
7.  Clinically diagnosed infections predict disability in activities of daily living among the oldest-old in the general population: the Leiden 85-plus Study 
Age and Ageing  2013;42(4):482-488.
Background: ageing is frequently accompanied by a higher incidence of infections and an increase in disability in activities of daily living (ADL).
Objective: this study examines whether clinical infections [urinary tract infections (UTI) and lower respiratory tract infections (LRTI)] predict an increase in ADL disability, stratified for the presence of ADL disability at baseline (age 86 years).
Design: the Leiden 85-plus Study. A population-based prospective follow-up study.
Setting: general population.
Participants: a total of 154 men and 319 women aged 86 years.
Methods: information on clinical infections was obtained from the medical records. ADL disability was determined at baseline and annually thereafter during 4 years of follow-up, using the 9 ADL items of the Groningen Activity Restriction Scale.
Results: in 86-year-old participants with ADL disability, there were no differences in ADL increase between participants with and without an infection (−0.32 points extra per year; P = 0.230). However, participants without ADL disability at age 86 years (n = 194; 41%) had an accelerated increase in ADL disability of 1.07 point extra per year (P < 0.001). For UTIs, this was 1.25 points per year (P < 0.001) and for LRTIs 0.70 points per year (P = 0.041). In this group, an infection between age 85 and 86 years was associated with a higher risk to develop ADL disability from age 86 onwards [HR: 1.63 (95% CI: 1.04–2.55)].
Conclusions: among the oldest-old in the general population, clinically diagnosed infections are predictive for the development of ADL disability in persons without ADL disability. No such association was found for persons with ADL disability.
PMCID: PMC3684111  PMID: 23482352
ADL disability; infections; oldest-old; general population; older people
8.  Predictive Value of a Profile of Routine Blood Measurements on Mortality in Older Persons in the General Population: The Leiden 85-Plus Study 
PLoS ONE  2013;8(3):e58050.
Various questionnaires and performance tests predict mortality in older people. However, most are heterogeneous, laborious and a validated consensus index is not available yet. Since most older people are regularly monitored by laboratory tests, we compared the predictive value of a profile of seven routine laboratory measurements on mortality in older persons in the general population with other predictors of mortality; gait speed and disability in instrumental activities of daily living (IADL).
Methodology/Principal Findings
Within the Leiden 85-plus Study, a prospective population-based study, we followed 562 participants aged 85 years for mortality over five years. At baseline (age 85 years) high-density lipoprotein cholesterol, albumin, alanine transaminase, hemoglobin, creatinin clearance, C-reactive protein and homocysteine were measured. Participants were stratified based on their number of laboratory abnormalities (0, 1, 2–4 and 5–7). The predictive capacity was compared with gait speed (6-meter walking test) and disability in IADL (Groningen Activity Restriction Scale) by C-statistics. At baseline, 418 (74%) 85-year old participants had at least one laboratory abnormality. All cause mortality risk increased with increasing number of laboratory abnormalities to a hazard ratio of 5.64 [95% CI 3.49–9.12] for those with 5–7 laboratory abnormalities (p<0.001) compared to those without abnormalities. The c-statistic was 0.66 [95% CI 0.59–0.69], similar to that of gait speed and disability in IADL.
In the general population of oldest old, the number of abnormalities in seven routine laboratory measurements predicts five-year mortality as accurately as gait speed and IADL disability.
PMCID: PMC3587570  PMID: 23483967
9.  Telomere length and anaemia in old age: results from the Newcastle 85-plus Study* and the Leiden 85-plus Study 
Age and Ageing  2011;40(4):494-500.
Background: reduced telomere length in blood cells has been associated with increased risk of multiple age-related diseases and is widely regarded as a general biomarker of ageing. Therefore, it is important to know both the extent and limitations of this association. We investigated the relation between telomere length and anaemia in two independent cohorts, with the prior expectation of adding anaemia to the list of conditions for which telomere reduction is a risk factor.
Participants and methods: the present study is embedded in the Newcastle 85-plus Study and Leiden 85-plus Study, two population-based studies of inhabitants of Newcastle and North Tyneside, UK (n = 749) and Leiden, the Netherlands (n = 658) aged 85 and over. High-molecular-weight DNA was isolated from full fresh blood (Newcastle) and peripheral blood mononuclear cells samples (Leiden). Telomere length was measured as abundance of telomeric template versus a single gene by quantitative real-time polymerase chain reaction. Anaemia was defined according to World Health Organization criteria.
Results: in both studies, no differences in median telomere length were observed between participants with anaemia and participants without anaemia (Newcastle: 2,846 bp (interquartile range (IQR) 2,433–3,630) versus 2,920 bp (IQR 2,425–3,570), P = 0.63; Leiden: 4,136 bp (IQR 3,879–4,428) versus 4,167 bp (IQR 3,893–4,501), P = 0.41). Telomere length also did not correlate with any other haematological parameter in both men and women.
Conclusions: in contrast to other age-related diseases, telomere length is not associated with anaemia or any other haematological parameter in older individuals in the general population.
PMCID: PMC3114621  PMID: 21622673
aging; anaemia; telomeres; elderly
10.  The effect of cognitive impairment on the predictive value of multimorbidity for the increase in disability in the oldest old: the Leiden 85-plus Study 
Age and Ageing  2011;40(3):352-357.
Background: prevention of disability is an important aim of healthcare for older persons. Selection of persons at risk is a first crucial step in this process.
Objectives: this study investigates the predictive value of multimorbidity for the development of disability in the general population of very old people and the role of cognitive impairment in this association.
Design: the Leiden 85-plus Study (1997–2004) is an observational prospective cohort study with 5 years of follow-up.
Setting: general population of the city of Leiden, the Netherlands.
Subjects: population based sample of 594 participants aged 85 years.
Methods: disability in activities of daily living (ADL) was measured annually for 5 years with the Groningen Activity Restriction Scale (range 9–36, 9 = optimal). Multimorbidity is defined as the presence of two or more chronic diseases at age 85 years. Cognitive function was measured at baseline with the mini-mental state examination (MMSE).
Results: at baseline participants with multimorbidity had higher ADL disability scores compared with those without [median 11 inter-quartile range (IQR 9–16) versus 9 (IQR 9–13) ADL points, Mann–Whitney U test P < 0.001]. Stratified into four MMSE groups, ADL disability increased over time in all groups, even in participants without multimorbidity (P trend <0.001). Multimorbidity predicted accelerated increase in ADL disability in participants with MMSE of 28–30 points (n = 205, 0.67 points/year, P < 0.001), but not in participants with lower MMSE scores (all P > 0.100).
Conclusion: the predictive value of multimorbidity for the increase in ADL disability varies with cognitive function in very old people. In very old people with good cognitive function, multimorbidity predicts accelerated increase in ADL disability. This relation is absent in very old people with cognitive impairment.
PMCID: PMC3080242  PMID: 21414945
disability; multimorbidity; cognitive impairment; prediction; elderly
11.  Effect of erythropoietin levels on mortality in old age: the Leiden 85-plus Study 
The production of erythropoietin is triggered by impaired oxygen delivery to the kidney, either because of anemia or hypoxemia. High erythropoietin levels have been shown to predict the risk of death among patients with chronic heart failure. We investigated the prognostic value of elevated erythropoietin levels on mortality among very elderly people in the general population.
The Leiden 85-plus Study is a population-based prospective follow-up study involving 599 people aged 85 years in Leiden, the Netherlands, enrolled between September 1997 and September 1999. Erythropoietin levels were determined at age 86. For this analysis, we included 428 participants with a creatinine clearance of at least 30 mL/min. Mortality data, recorded until Feb. 1, 2008, were obtained from the municipal registry.
During follow-up, 324 (75.7%) participants died. Compared with participants whose erythropoietin levels were in the lowest tertile (reference group), those whose levels were in the middle tertile had a 25% increased risk of death (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.95–1.64), and those whose levels were in the highest tertile had a 73% increased risk (HR 1.73, 95% CI 1.32–2.26) (p value for trend < 0.01). The association between erythropoietin levels and mortality remained largely unchanged after we adjusted for sex, creatinine clearance, hemoglobin level, comorbidity, smoking status and C-reactive protein level, and was similar for deaths from cardiovascular and noncardiovascular causes.
Among people aged 85 years and older, elevated erythropoietin levels were associated with an increased risk of death, independent of hemoglobin levels.
PMCID: PMC3001501  PMID: 21149533
12.  Effect of anemia and comorbidity on functional status and mortality in old age: results from the Leiden 85-plus Study 
There is limited insight into the attributable effect of anemia and comorbidity on functional status and mortality in old age.
The Leiden 85-plus Study is a population-based prospective follow-up study of 562 people aged 85 years. Anemia was defined according to World Health Organization criteria. We measured 3 parameters of functional status at baseline and annually thereafter for 5 years: disability in basic and instrumental activities of daily living, cognitive function and the presence of depressive symptoms. We obtained mortality data from the municipal registry.
The prevalence of anemia at baseline was 26.7% (150/562). Participants who had anemia at baseline had more disability in activities of daily living, worse cognitive function and more depressive symptoms than participants without anemia at baseline (p ≤ 0.01). These differences disappeared after adjustment for comorbidity. After adjustment for comorbidity in the prospective analyses, anemia at baseline was associated with an additional increase in disability in instrumental activities of daily living during follow-up; incident anemia during follow-up (n = 99) was associated with an additional increase in disability in basic activities of daily living. Prevalent and incident anemia were both associated with an increased risk of death, even after we adjusted for sex, education level, income, residence in a long-term care facility, C-reactive protein level, creatinine clearance and the presence of disease (hazard ratio for prevalent anemia 1.41, 95% confidence interval [CI] 1.13 to 1.76; hazard ratio for incident anemia 2.08, 95% CI 1.60 to 2.70).
Anemia in very elderly people appears to be associated with an increased risk of death, independent of comorbidity. However, the associated functional decline appears to be attributed mainly to comorbidity.
PMCID: PMC2717683  PMID: 19635749
13.  Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study 
Objectives To investigate the performance of classic risk factors, and of some new biomarkers, in predicting cardiovascular mortality in very old people from the general population with no history of cardiovascular disease.
Design The Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up.
Setting General population of the city of Leiden, the Netherlands.
Participants Population based sample of participants aged 85 years (215 women and 87 men) with no history of cardiovascular disease; no other exclusion criteria.
Main measurements Cause specific mortality was registered during follow-up. All classic risk factors included in the Framingham risk score (sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, smoking and electrocardiogram based left ventricular hypertrophy), as well as plasma concentrations of the new biomarkers homocysteine, folic acid, C reactive protein, and interleukin 6, were assessed at baseline.
Results During follow-up, 108 of the 302 participants died; 32% (35/108) of deaths were from cardiovascular causes. Classic risk factors did not predict cardiovascular mortality when used in the Framingham risk score (area under receiver operating characteristic curve 0.53, 95% confidence interval 0.42 to 0.63) or in a newly calibrated model (0.53, 0.43 to 0.64). Of the new biomarkers studied, homocysteine had most predictive power (0.65, 0.55 to 0.75). Entering any additional risk factor or combination of factors into the homocysteine prediction model did not increase its discriminative power.
Conclusions In very old people from the general population with no history of cardiovascular disease, concentrations of homocysteine alone can accurately identify those at high risk of cardiovascular mortality, whereas classic risk factors included in the Framingham risk score do not. These preliminary findings warrant validation in a separate cohort.
PMCID: PMC2615548  PMID: 19131384

Results 1-13 (13)