High-risk subtypes of chronic lymphocytic leukemia are detectable as early as 16 years prior to diagnosis.

Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.

Potential determinants of antibody responses after vaccination against SARS-CoV-2 in older persons: the Doetinchem Cohort Study.

BACKGROUND: Immune responses to vaccination vary widely between individuals. The aim of this study was to identify health-related variables potentially underlying the antibody responses to SARS-CoV-2 vaccination in older persons. We recruited participants in the long-running Doetinchem Cohort Study (DCS) who underwent vaccination as part of the national COVID-19 program, and measured antibody concentrations to SARS-CoV-2 Spike protein (S1) and Nucleoprotein (N) at baseline (T0), and a month after both the first vaccination (T1), and the second vaccination (T2). Associations between the antibody concentrations and demographic variables, including age, sex, socio-economic status (SES), comorbidities (cardiovascular diseases and immune mediated diseases), various health parameters (cardiometabolic markers, inflammation markers, kidney- and lung function) and a composite measure of frailty ('frailty index', ranging from 0 to 1) were tested using multivariate models. RESULTS: We included 1457 persons aged 50 to 92 years old. Of these persons 1257 were infection naïve after their primary vaccination series. The majority (N = 954) of these individuals were vaccinated with two doses of BNT162b2 (Pfizer) and their data were used for further analysis. A higher frailty index was associated with lower anti-S1 antibody responses at T1 and T2 for both men (RT1 = -0.095, PT1 = 0.05; RT2 = -0.11, PT2 = 0.02) and women (RT1 = -0.24, PT1 < 0.01; RT2 = -0.15, PT2 < 0.01). After correcting for age and sex the frailty index was also associated with the relative increase in anti-S1 IgG concentrations between the two vaccinations (ß = 1.6, P < 0.01). Within the construct of frailty, history of a cardiac catheterization, diabetes, gastrointestinal disease, a cognitive speed in the lowest decile of the population distribution, and impaired lung function were associated with lower antibody responses after both vaccinations. CONCLUSIONS: Components of frailty play a key role in the primary vaccination response to the BNT162b2 vaccine within an ageing population. Older persons with various comorbidities have a lowered immune response after their first vaccination, and while frail and sick older persons see a stronger increase after their second vaccination compared to healthy people, they still have a lower antibody response after their second vaccination.

Impaired JAK-STAT pathway signaling in leukocytes of the frail elderly.

BACKGROUND: Elderly often show reduced immune functioning and can develop chronic low-grade inflammation. Why some elderly are more prone to become frail is unknown. We investigated whether frailty is associated with altered cytokine signaling through the JAK-STAT pathway in leukocytes of 34 individuals aged 65-74 years. In addition, we investigated how this relation is affected by chronic low-grade inflammation during the previous 20 years. Cytokine signaling was quantified by measuring intracellular STAT1, STAT3, and STAT5 phosphorylation in monocytes, B cells, CD4+ T cells and CD8+ T cells upon stimulation with IL-2, IL-6, IL-10, IFNα and IFNγ, using phospho-flow cytometry. Presence of chronic low-grade inflammation was investigated by evaluating 18 different plasma inflammatory markers that had been measured repeatedly in the same individuals over the previous 20 years. Frailty was assessed as a score on a frailty index. RESULTS: We found that lower cytokine-induced pSTAT responsiveness in the various cell subsets was seen with higher frailty scores in both men and women, indicative of dysfunctional pSTAT responses in frailer individuals. Associations differed between men and women, with frailer women showing lower pSTAT1 responses in monocytes and frailer men showing lower pSTAT5 responses in CD4+ and CD8+ T cells. Notably, lower IL-10-induced pSTAT3 responses in men were related to both higher frailty scores and higher CRP levels over the past 20 years. This might indicate poor resolution of low-grade inflammation due to defective regulatory pSTAT signaling in older men. CONCLUSIONS: Our results emphasize the importance of preserved JAK-STAT pathway signaling in healthy aging and reveal cellular pSTAT levels as a candidate biomarker of frailty.

In-depth immune cellular profiling reveals sex-specific associations with frailty.

BACKGROUND: With advancing age, the composition of leukocyte subpopulations in peripheral blood is known to change, but how this change differs between men and women and how it relates to frailty is poorly understood. Our aim in this exploratory study was to investigate whether frailty is associated with changes in immune cell subpopulations and whether this differs between men and women. Therefore, we performed in-depth immune cellular profiling by enumerating a total of 37 subpopulations of T cells, B cells, NK cells, monocytes, and neutrophils in peripheral blood of 289 elderly people between 60-87 years of age. Associations between frailty and each immune cell subpopulation were tested separately in men and women and were adjusted for age and CMV serostatus. In addition, a random forest algorithm was used to predict a participant's frailty score based on enumeration of immune cell subpopulations. RESULTS: In the association study, frailty was found to be associated with increased numbers of neutrophils in both men and in women. Frailer women, but not men, showed higher numbers of total and CD16- monocytes, and lower numbers of both CD56+ T cells and late differentiated CD4+ TemRA cells. The random forest algorithm confirmed all the findings of the association studies in men and women. In men, the predictive accuracy of the algorithm was too low (5.5%) to warrant additional conclusions on top of the ones derived from the association study. In women however, the predictive accuracy was higher (23.1%), additionally revealing that total T cell numbers and total lymphocyte numbers also contribute in predicting frailty. CONCLUSIONS: In-depth immune cellular profiling revealed consistent associations of frailty with elevated numbers of myeloid cell subpopulations in both men and women. Furthermore, additional associations were found between frailty and lower numbers of some T cell subpopulations, in women only. Thus, our study indicates sex-specific associations of immune subpopulations with frailty. We hope that our study will prompt further investigation into the sex-specific immune mechanisms associated with the development of frailty.

A Window on Geographic Variation in Health Care: Insights from EuroHOPE.

The aim of EuroHOPE was to provide new evidence on the performance of healthcare systems, using a disease-based approach, linkable patient-level data and internationally standardized methods. This paper summarizes its main results. In the seven EuroHOPE countries, the Acute Myocardial Infarction (AMI), stroke and hip fracture patient populations were similar with regard to age, sex and comorbidity. However, non-negligible geographic variation in mortality and resource use was found to exist. Survival rates varied to similar extents between countries and regions for AMI, stroke, hip fracture and very low birth weight. Geographic variation in length of stay differed according to type of disease. Regression analyses showed that only a small part of geographic variation could be explained by demand and supply side factors. Furthermore, the impact of these factors varied between countries. The findings show that there is room for improvement in performance at all levels of analysis and call for more in-depth disease-based research. In using international patient-level data and a standardized methodology, the EuroHOPE approach provides a promising stepping-stone for future investigations in this field. Still, more detailed patient and provider information, including outside of hospital care, and better data sharing arrangements are needed to reach a more comprehensive understanding of geographic variations in health care.

Biochemical markers of aging for longitudinal studies in humans.

Much progress has been made in the past decades in unraveling the mechanisms that are responsible for aging. The discovery that particular gene mutations in experimental species such as yeast, flies, and nematodes are associated with longevity has led to many important insights into pathways that regulate aging processes. However, extrapolating laboratory findings in experimental species to knowledge that is valid for the complexity of human physiology remains a major challenge. Apart from the restricted experimental possibilities, studying aging in humans is further complicated by the development of various age-related diseases. The availability of a set of biomarkers that really reflect underlying aging processes would be of much value in disentangling age-associated pathology from specific aging mechanisms. In this review, we survey the literature to identify promising biochemical markers of aging, with a particular focus on using them in longitudinal studies of aging in humans that entail repeated measurements on easily obtainable material, such as blood samples. Our search strategy was a 2-pronged approach, one focused on general mechanisms of aging and one including studies on clinical biomarkers of age-related diseases.

Neighbourhood socioeconomic inequalities in incidence of acute myocardial infarction: a cohort study quantifying age- and gender-specific differences in relative and absolute terms.

BACKGROUND: Socioeconomic status has a profound effect on the risk of having a first acute myocardial infarction (AMI). Information on socioeconomic inequalities in AMI incidence across age-gender-groups is lacking. Our objective was to examine socioeconomic inequalities in the incidence of AMI considering both relative and absolute measures of risk differences, with a particular focus on age and gender. METHODS: We identified all patients with a first AMI from 1997 to 2007 through linked hospital discharge and death records covering the Dutch population. Relative risks (RR) of AMI incidence were estimated by mean equivalent household income at neighbourhood-level for strata of age and gender using Poisson regression models. Socioeconomic inequalities were also shown within the stratified age-gender groups by calculating the total number of events attributable to socioeconomic disadvantage. RESULTS: Between 1997 and 2007, 317,564 people had a first AMI. When comparing the most deprived socioeconomic quintile with the most affluent quintile, the overall RR for AMI was 1.34 (95 % confidence interval (CI): 1.32-1.36) in men and 1.44 (95 % CI: 1.42-1.47) in women. The socioeconomic gradient decreased with age. Relative socioeconomic inequalities were most apparent in men under 35 years and in women under 65 years. The largest number of events attributable to socioeconomic inequalities was found in men aged 45-74 years and in women aged 65-84 years. The total proportion of AMIs that was attributable to socioeconomic inequalities in the Dutch population of 1997 to 2007 was 14 % in men and 18 % in women. CONCLUSIONS: Neighbourhood socioeconomic inequalities were observed in AMI incidence in the Netherlands, but the magnitude across age-gender groups depended on whether inequality was expressed in relative or absolute terms. Relative socioeconomic inequalities were high in young persons and women, where the absolute burden of AMI was low. Absolute socioeconomic inequalities in AMI were highest in the age-gender groups of middle-aged men and elderly women, where the number of cases was largest.

Healthy lifestyle over the life course: Population trends and individual changes over 30 years of the Doetinchem Cohort Study.

For five health-related lifestyle factors (physical activity, weight, smoking, sleep, and alcohol consumption) we describe both population trends and individual changes over a period of 30 years in the same adult population. Dichotomous indicators (healthy/unhealthy) of lifestyle were analyzed for 3,139 participants measured every 5 years in the Doetinchem Cohort Study (1987-2017). Population trends over 30 years in physical inactivity and "unhealthy" alcohol consumption were flat (i.e., stable); overweight and unhealthy sleep prevalence increased; smoking prevalence decreased. The proportion of the population being healthy on all five lifestyle factors declined from 17% in the round 1 to 10.8% in round 6. Underlying these trends a dynamic pattern of changes at the individual level was seen: sleep duration and physical activity level changed in almost half of the individuals; Body Mass Index (BMI) and alcohol consumption in one-third; smoking in one-fourth. Population trends don't give insight into change at the individual level. In order to be able to gauge the potential for change of health-related lifestyle, it is important to take changes at the individual level into account.

Inflammatory marker trajectories associated with frailty and ageing in a 20-year longitudinal study.

OBJECTIVE: The aim of this exploratory study was to investigate the development of low-grade inflammation during ageing and its relationship with frailty. METHODS: The trajectories of 18 inflammatory markers measured in blood samples, collected at 5-year intervals over a period of 20 years from 144 individuals aged 65-75 years at the study endpoint, were related to the degree of frailty later in life. RESULTS: IFN-γ-related markers and platelet activation markers were found to change in synchrony. Chronically elevated levels of IL-6 pathway markers, such as CRP and sIL-6R, were associated with more frailty, poorer lung function and reduced physical strength. Being overweight was a possible driver of these associations. More and stronger associations were detected in women, such as a relation between increasing sCD14 levels and frailty, indicating a possible role for monocyte overactivation. Multivariate prediction of frailty confirmed the main results, but predictive accuracy was low. CONCLUSION: In summary, we documented temporal changes in and between inflammatory markers in an ageing population over a period of 20 years, and related these to clinically relevant health outcomes.

Co-occurrence of diabetes, myocardial infarction, stroke, and cancer: quantifying age patterns in the Dutch population using health survey data.

BACKGROUND: The high prevalence of chronic diseases in Western countries implies that the presence of multiple chronic diseases within one person is common. Especially at older ages, when the likelihood of having a chronic disease increases, the co-occurrence of distinct diseases will be encountered more frequently. The aim of this study was to estimate the age-specific prevalence of multimorbidity in the general population. In particular, we investigate to what extent specific pairs of diseases cluster within people and how this deviates from what is to be expected under the assumption of the independent occurrence of diseases (i.e., sheer coincidence). METHODS: We used data from a Dutch health survey to estimate the prevalence of pairs of chronic diseases specified by age. Diseases we focused on were diabetes, myocardial infarction, stroke, and cancer. Multinomial P-splines were fitted to the data to model the relation between age and disease status (single versus two diseases). To assess to what extent co-occurrence cannot be explained by independent occurrence, we estimated observed/expected co-occurrence ratios using predictions of the fitted regression models. RESULTS: Prevalence increased with age for all disease pairs. For all disease pairs, prevalence at most ages was much higher than is to be expected on the basis of coincidence. Observed/expected ratios of disease combinations decreased with age. CONCLUSION: Common chronic diseases co-occur in one individual more frequently than is due to chance. In monitoring the occurrence of diseases among the population at large, such multimorbidity is insufficiently taken into account.

Estimating and comparing incidence and prevalence of chronic diseases by combining GP registry data: the role of uncertainty.

BACKGROUND: Estimates of disease incidence and prevalence are core indicators of public health. The manner in which these indicators stand out against each other provide guidance as to which diseases are most common and what health problems deserve priority. Our aim was to investigate how routinely collected data from different general practitioner registration networks (GPRNs) can be combined to estimate incidence and prevalence of chronic diseases and to explore the role of uncertainty when comparing diseases. METHODS: Incidence and prevalence counts, specified by gender and age, of 18 chronic diseases from 5 GPRNs in the Netherlands from the year 2007 were used as input. Generalized linear mixed models were fitted with the GPRN identifier acting as random intercept, and age and gender as explanatory variables. Using predictions of the regression models we estimated the incidence and prevalence for 18 chronic diseases and calculated a stochastic ranking of diseases in terms of incidence and prevalence per 1,000. RESULTS: Incidence was highest for coronary heart disease and prevalence was highest for diabetes if we looked at the point estimates. The between GPRN variance in general was higher for incidence than for prevalence. Since uncertainty intervals were wide for some diseases and overlapped, the ranking of diseases was subject to uncertainty. For incidence shifts in rank of up to twelve positions were observed. For prevalence, most diseases shifted maximally three or four places in rank. CONCLUSION: Estimates of incidence and prevalence can be obtained by combining data from GPRNs. Uncertainty in the estimates of absolute figures may lead to different rankings of diseases and, hence, should be taken into consideration when comparing disease incidences and prevalences.

A New Pipeline for the Normalization and Pooling of Metabolomics Data.

Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use variable sample types (e.g., serum versus plasma) collected, treated, and stored according to different protocols, and assayed in different laboratories using different instruments. To address these issues, a new pipeline was developed to normalize and pool metabolomics data through a set of sequential steps: (i) exclusions of the least informative observations and metabolites and removal of outliers; imputation of missing data; (ii) identification of the main sources of variability through principal component partial R-square (PC-PR2) analysis; (iii) application of linear mixed models to remove unwanted variability, including samples' originating study and batch, and preserve biological variations while accounting for potential differences in the residual variances across studies. This pipeline was applied to targeted metabolomics data acquired using Biocrates AbsoluteIDQ kits in eight case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Comprehensive examination of metabolomics measurements indicated that the pipeline improved the comparability of data across the studies. Our pipeline can be adapted to normalize other molecular data, including biomarkers as well as proteomics data, and could be used for pooling molecular datasets, for example in international consortia, to limit biases introduced by inter-study variability. This versatility of the pipeline makes our work of potential interest to molecular epidemiologists.

Food and vessels: the importance of a healthy diet to prevent cardiovascular disease.

AIM: We attempted to quantify the burden of cardiovascular disease that can be prevented by broader adherence to recommendations on dietary intake of key nutrients. METHODS: A computer model capturing the epidemiology of chronic disease and risk factors in the Dutch population was used to simulate differences in the occurrence of cardiovascular disease under various scenarios defined by levels of intake of saturated and trans fatty acids, fruit, vegetables and fish. The following scenarios were compared with the current situation: (i) the whole population adhering to recommendations (optimum scenario); (ii) a moderate improvement and (iii) increased intake of fruit as has been achieved in an actual intervention ('fruit at work'). Other outcome measures assessed were (differences in) life expectancy and healthy life expectancy for a 40-year-old individual. RESULTS: In the optimum scenario, cumulative incidence prevented over a period of 20 years was 240,000 cases for acute myocardial infarction, or 30% of the expected number of cases, 328,000 (16%) for other coronary heart disease and 215,000 (21%) for stroke. For the moderate improvement scenario, the corresponding figures were 119,000 (14%), 163 000 (8%) and 105,000 (10%), respectively. The individual contributions of each of the separate dietary factors were greatest for fish, followed in decreasing order by fruit, vegetables, saturated and trans fatty acids. Only fish and fruit contributed to a decrease in strokes. In the optimum scenario, 1 year was added to the life expectancy of a 40-year-old individual and half a year in the moderate improvement scenario. CONCLUSION: Broader adherence to recommendations for daily intake of fruit, vegetables, fish and fatty acid composition may take away as much as 20-30% of the burden of cardiovascular disease and result in approximately 1 extra life year for a 40-year-old individual. Promotion of a healthy diet should be given more emphasis in the prevention of cardiovascular disease.

Diffusion of innovations in health care: does the structural context determine its direction?

OBJECTIVES: The aim of this study was to present and illustrate an instrument to measure the level of innovation at country level. METHODS: The data used are the Organisation for Economic Co-operation and Development (OECD) health data 2009, in particular the information on use of medical technology. Two composite scales expressing a relative level of adoption of innovations in health care are regressed, using multilevel regression analysis, on country characteristics. The country characteristics are selected as proxies on availability or scarcity of resources in a country. We expect that scarcity will promote adoption of innovations that enhance efficiency, and that availability of resources will promote advanced, expensive innovations. RESULTS: Two scales were constructed. One scale indicates the use of efficiency-enhancing innovations (day case treatment), and the other scale indicates availability of advanced technical innovations. The application of day case treatment is significantly associated with education level (+), the ratio of people aged 15-64 versus younger and older people (+) and the number of hospital beds (-). Availability of advanced medical devices are associated with the expenditure on health (+), demographic dependency (-), number of hospital beds (+), and the annual reduction of hospital beds (-). CONCLUSIONS: Diffusion of innovations is influenced by characteristics of the country and of the healthcare system; fewer resources encourage diffusion of innovations that enhance efficiency and more resources encourage diffusion of complex, expensive devices. This indicates that decisions by healthcare professionals on which innovation to adopt is embedded in a context that is influenced and shaped by the availability of resources on macro level.

Limited effect of duration of CMV infection on adaptive immunity and frailty: insights from a 27-year-long longitudinal study.

OBJECTIVES: Cytomegalovirus infection is thought to affect the immune system and to impact general health during ageing. Higher CMV-specific antibody levels in the elderly are generally assumed to reflect experienced viral reactivation during life. Furthermore, high levels of terminally differentiated and CMV-specific T cells are hallmarks of CMV infection, which are thought to expand over time, a process also referred to as memory inflation. METHODS: We studied CMV-specific antibody levels over ~ 27 years in 268 individuals (aged 60-89 years at study endpoint), and to link duration of CMV infection to T-cell numbers, CMV-specific T-cell functions, frailty and cardiovascular disease at study endpoint. RESULTS: In our study, 136/268 individuals were long-term CMV seropositive and 19 seroconverted during follow-up (seroconversion rate: 0.56%/year). CMV-specific antibody levels increased slightly over time. However, we did not find an association between duration of CMV infection and CMV-specific antibody levels at study endpoint. No clear association between duration of CMV infection and the size and function of the memory T-cell pool was observed. Elevated CMV-specific antibody levels were associated with the prevalence of cardiovascular disease but not with frailty. Age at CMV seroconversion was positively associated with CMV-specific antibody levels, memory CD4+ T-cell numbers and frailty. CONCLUSION: Cytomegalovirus-specific memory T cells develop shortly after CMV seroconversion but do not seem to further increase over time. Age-related effects other than duration of CMV infection seem to contribute to CMV-induced changes in the immune system. Although CMV-specific immunity is not evidently linked to frailty, it tends to associate with higher prevalence of cardiovascular disease.

The cost-effectiveness of implementing a new guideline for cardiovascular risk management in primary care in the Netherlands.

BACKGROUND: A new Dutch guideline for cardiovascular disease management substantially extends the number of individuals for whom treatment with statins and/or antihypertensive agents is recommended. We estimated the cost-effectiveness of implementing the new guideline at the national level. METHODS: First, the number of currently untreated individuals who would become eligible for cholesterol-lowering or antihypertensive treatment under the new guideline was estimated using data from a recent population study. Cost-effectiveness of treating this group of patients was then assessed using a mathematical model. RESULTS: Implementing the guideline in the age category 30-69 years would lead to an additional 465,000 individuals requiring treatment. Over a period of 20 years, the cumulative incidence of acute myocardial infarction in the whole population would drop by 3.0%, that of stroke by 3.9%, and all-cause mortality would drop by 0.9%. The lifetime cost-effectiveness ratio was calculated to be 15,000 Euro per quality-adjusted life year gained. In the age categories 70-79 years and 80 years or above, an additional 600,000 and 450,000 persons, respectively, would need to be treated, resulting in corresponding reductions in cumulative incidences of 14 and 18% (acute myocardial infarction), 17 and 22% (stroke), and 1.2 and 0.6% (all-cause mortality) with cost-effectiveness ratios of 20,800 and 32,300 Euro, respectively, per quality-adjusted life year. CONCLUSION: Complete implementation of the new guideline would lead to a considerable increase in the number of individuals requiring treatment. This would be cost-effective up to the age of 70 years.

Frailty is associated with elevated CRP trajectories and higher numbers of neutrophils and monocytes.

BACKGROUND: With aging, the human immune system undergoes several changes. The clinical relevance of these changes, however, is relatively unknown. We investigated immunological aspects of human aging in relation to frailty in the Doetinchem Cohort Study (DCS). METHODS: We calculated a frailty index score based on 36 health parameters for each individual in the DCS with data obtained in the period 2008-2016. The frailty index was used to define three health groups ('healthy', 'intermediate', and 'frail'), stratified by age and sex. In a subcohort (n = 289, 60-85 years, selected by balanced random sampling per frailty group), we collected blood samples between October 2016 and March 2017 to determine absolute numbers of leukocyte subsets. In addition, cytomegalovirus serostatus was assessed. C-reactive protein (CRP) levels were longitudinally assessed in four consecutive plasma samples per individual. These samples had been previously collected (1993-2013) as part of the DCS at regular time intervals and spanning a period of >15 years. RESULTS: We observed higher numbers of myeloid derived neutrophils and monocytes in the frail group compared to the healthy group in both men and women, and, retrospectively, consistently higher CRP concentrations over a period of >15 years. An increase in CRP concentration with age was found in women, but not in men. Frailty was not associated with cytomegalovirus serostatus or with changes in lymphoid derived T-, B-, or NK-cell numbers. CONCLUSION: Frail elderly, compared to their age- and sex-matched peers, endure a chronic and stable low-grade inflammation, which is associated with a myeloid cell lineage expansion. These findings could help to monitor clinically significant immunological decline in the elderly.

Lifetime medical costs of obesity: prevention no cure for increasing health expenditure.

BACKGROUND: Obesity is a major cause of morbidity and mortality and is associated with high medical expenditures. It has been suggested that obesity prevention could result in cost savings. The objective of this study was to estimate the annual and lifetime medical costs attributable to obesity, to compare those to similar costs attributable to smoking, and to discuss the implications for prevention. METHODS AND FINDINGS: With a simulation model, lifetime health-care costs were estimated for a cohort of obese people aged 20 y at baseline. To assess the impact of obesity, comparisons were made with similar cohorts of smokers and "healthy-living" persons (defined as nonsmokers with a body mass index between 18.5 and 25). Except for relative risk values, all input parameters of the simulation model were based on data from The Netherlands. In sensitivity analyses the effects of epidemiologic parameters and cost definitions were assessed. Until age 56 y, annual health expenditure was highest for obese people. At older ages, smokers incurred higher costs. Because of differences in life expectancy, however, lifetime health expenditure was highest among healthy-living people and lowest for smokers. Obese individuals held an intermediate position. Alternative values of epidemiologic parameters and cost definitions did not alter these conclusions. CONCLUSIONS: Although effective obesity prevention leads to a decrease in costs of obesity-related diseases, this decrease is offset by cost increases due to diseases unrelated to obesity in life-years gained. Obesity prevention may be an important and cost-effective way of improving public health, but it is not a cure for increasing health expenditures.

Cost-effectiveness of a low-calorie diet and orlistat for obese persons: modeling long-term health gains through prevention of obesity-related chronic diseases.

OBJECTIVE: Our study estimated the cost-effectiveness of pharmacologic treatment of obesity in combination with a low-calorie diet in The Netherlands. METHODS: Costs and effects of a low-calorie diet-only intervention and of a low-calorie diet in combination with 1 year of orlistat were compared to no treatment. The RIVM Chronic Disease Model was used to project the differences in quality adjusted life years (QALYs) and lifetime health-care costs because of the effects of the interventions on body mass index (BMI) status. This was done by linking BMI status to the occurrence of obesity-related diseases and by relating quality of life to disease status. Probabilistic sensitivity analysis was employed to study the effect of uncertainty in the model parameters. In univariate sensitivity analysis, we assessed how sensitive the results were to several key assumptions. RESULTS: Incremental costs per QALY gained were Euro 17,900 for the low-calorie diet-only intervention compared to no intervention and Euro 58,800 for the low-calorie diet + orlistat compared to the low-calorie diet only. Assuming a direct relation between BMI and quality of life, these ratios decreased to Euro 6000 per QALY gained and Euro 24,100 per QALY gained. Costs per QALY gained were also sensitive to assumptions about long-term weight loss maintenance. CONCLUSIONS: Cost-effectiveness ratios of interventions aiming at weight reduction depend strongly on assumptions regarding the relation between BMI and quality of life. We recommend that a low-calorie diet should be the first option for policymakers in combating obesity.

[Undesirable medicalisation: on the nature and background of too much medicine]. / Ongewenste medicalisering.

Over recent years there has been renewed focus on medicalisation. Amongst other things, this is the result of the realisation that expansion of the medical domain can also have undesirable effects. However, the line between justified medical interventions and overdiagnosis is difficult to draw. The first step in regaining control of undesirable medicalisation is to identify and quantify the processes behind it and the situations in clinical practice in which it may occur. In this article we discuss different types of medicalisation and, on the basis of this, we give an indication of the frequency with which medicalisation occurs. Finally, we discuss the mechanisms that facilitate medicalisation.