Cost-effectiveness of obinutuzumab for chronic lymphocytic leukaemia in The Netherlands.

BACKGROUND: Obinutuzumab combined with chlorambucil (GClb) has shown to be superior to rituximab combined with chlorambucil (RClb) and chlorambucil (Clb) in newly diagnosed patients with chronic lymphocytic leukaemia (CLL). This study evaluates the cost-effectiveness per life-year and quality-adjusted life-year (QALY) of GClb compared to RClb, Clb, and ofatumumab plus chlorambucil (OClb) in The Netherlands. METHODS: A Markov model was developed to assess the cost-effectiveness of GClb, RClb, Clb and other treatments in the United Kingdom. A country adaptation was made to estimate the cost-effectiveness of these therapies in The Netherlands using Dutch unit costs and Dutch data sources for background mortality and post-progression survival. RESULTS: An incremental gain of 1.06 and 0.64 QALYs was estimated for GClb compared to Clb and RClb respectively, at additional costs of €23,208 and €7254 per patient. Corresponding incremental cost-effectiveness ratios (ICERs) were €21,823 and €11,344 per QALY. Indirect treatment comparisons showed an incremental gain varying from 0.44 to 0.77 QALYs for GClb compared to OClb and additional costs varying from €7041 to €5028 per patient. The ICER varied from €6556 to €16,180 per QALY. Sensitivity analyses showed the robustness of the results. CONCLUSION: GClb appeared to be a cost-effective treatment strategy compared to RClb, OClb and Clb.

Famine in the young and risk of later hospitalization for COPD and asthma.

BACKGROUND: Undernutrition during critical periods of growth and development may permanently affect lung physiology and function. OBJECTIVES: To investigate whether acute undernutrition in childhood or young adulthood increases the risk of later hospitalization for obstructive airways disease, chronic obstructive pulmonary disease (COPD), or asthma. METHODS: We studied 7,841 women from Prospect-EPIC who experienced the 1944-45 Dutch famine between ages 0 and 21. Pulmonary outcomes were measured by registered hospital admissions and exposure-blinded computed tomography (CT) in a subgroup of 295 women. With Cox proportional hazard regression we explored effects of famine exposure on risk of hospitalization for obstructive airways disease, COPD, and asthma. With logistic regression we explored effects of famine on risk of CT evidence of pulmonary disease. RESULTS: Risks of hospitalization for obstructive airways disease, copd, and asthma were increased after moderate famine exposure, and significantly increased after severe famine exposure: hazard ratios for obstructive airways disease were 1.31 (95% CI: 0.97 to 1.77) and 1.57 (95% CI: 1.10 to 2.23) respectively. Associations between famine exposure and hospitalization for COPD were stronger in ever-smokers than in never-smokers. CONCLUSIONS: Acute undernutrition in childhood or young adulthood is associated with an increased risk of later COPD and asthma hospitalization, possibly through increased sensitivity for tobacco smoke.

Famine in childhood and postmenopausal coronary artery calcification: a cohort study.

OBJECTIVE: To assess the effects of famine exposure during childhood on coronary calcium deposition and, secondarily, on cardiac valve and aortic calcifications. DESIGN: Retrospective cohort. SETTING: Community. PATIENTS: 286 postmenopausal women with individual measurements of famine exposure during childhood in the Netherlands during World War II. INTERVENTION/EXPOSURE: Famine exposure during childhood. MAIN OUTCOME MEASURES: Coronary artery calcifications measured by CT scan and scored using the Agatston method; calcifications of the aorta and cardiac valves (mitral and/or aortic) measured semiquantitatively. Logistic regression was used for coronary Agatston score of >100 or ≤100, valve or aortic calcifications as the dependent variable and an indicator for famine exposure as the independent variable. These models were also used for confounder adjustment and stratification based on age groups of 0-9 and 10-17 years. RESULTS: In the overall analysis, no statistically significant association was found between severe famine exposure in childhood and a high coronary calcium score (OR 1.80, 95% CI 0.87 to 3.78). However, when looking at specific risk periods, severe famine exposure during adolescence was related to a higher risk for a high coronary calcium score than non-exposure to famine, both in crude (OR 3.47, 95% CI 1.00 to 12.07) and adjusted analyses (OR 4.62, 95% CI 1.16 to 18.43). No statistically significant association was found between childhood famine exposure and valve or aortic calcification (OR 1.66, 95% CI 0.69 to 4.10). CONCLUSIONS: Famine exposure in childhood, especially during adolescence, seems to be associated with a higher risk of coronary artery calcification in late adulthood. However, the association between childhood famine exposure and cardiac valve/aortic calcification is less clear.

The fetal origins of hypertension: a systematic review and meta-analysis of the evidence from animal experiments of maternal undernutrition.

OBJECTIVE: Numerous experiments in animals have been performed to investigate the effect of prenatal undernutrition on the development of hypertension in later life, with inconclusive results. We systematically reviewed animal studies examining the effects of maternal undernutrition on SBP, DBP, and mean arterial blood pressure (BP) in offspring. METHODS: A search was performed in Medline and Embase to identify articles that reported on maternal undernutrition and hypertension in experimental animal studies. Summary estimates of the effect of undernutrition on SBP, DBP, and mean arterial BP were obtained through meta-analysis. RESULTS: Of the 6151 articles identified, 194 were considered eligible after screening titles and abstracts. After detailed evaluation, 101 met the inclusion criteria and were included in the review. Both maternal general and protein undernutrition increased SBP [general undernutrition: 14.5 mmHg, 95% confidence interval (CI) 10.8-18.3; protein undernutrition: 18.9 mmHg, 95% CI 16.1-21.8] and mean arterial BP (general undernutrition: 5.0 mmHg, 95% CI 1.4-8.6; protein undernutrition: 10.5 mmHg, 95% CI 6.7-14.2). There was substantial heterogeneity in the results. DBP was increased by protein undernutrition (9.5 mmHg, 95% CI 2.6-16.3), whereas general undernutrition had no significant effect. CONCLUSION: The results of this meta-analysis generally support the view that in animals, maternal undernutrition--both general and protein--results in increased SBP and mean arterial BP. DBP was only increased after protein undernutrition. The results depended strongly on the applied measurement technique and animal model.

Famine exposure in the young and the risk of type 2 diabetes in adulthood.

The developmental origins hypothesis proposes that undernutrition during early development is associated with an increased type 2 diabetes risk in adulthood. We investigated the association between undernutrition during childhood and young adulthood and type 2 diabetes in adulthood. We studied 7,837 women from Prospect-EPIC (European Prospective Investigation Into Cancer and Nutrition) who were exposed to the 1944-1945 Dutch famine when they were between age 0 and 21 years. We used Cox proportional hazards regression models to explore the effect of famine on the risk of subsequent type 2 diabetes in adulthood. We adjusted for potential confounders, including age at famine exposure, smoking, and level of education. Self-reported famine exposure during childhood and young adulthood was associated with an increased type 2 diabetes risk in a dose-dependent manner. In those who reported moderate famine exposure, the age-adjusted type 2 diabetes hazard ratio (HR) was 1.36 (95% CI [1.09-1.70]); in those who reported severe famine exposure, the age-adjusted HR was 1.64 (1.26-2.14) relative to unexposed women. These effects did not change after adjustment for confounders. This study provides the first direct evidence, using individual famine exposure data, that a short period of moderate or severe undernutrition during postnatal development increases type 2 diabetes risk in adulthood.

Postnatal acute famine and risk of overweight: the dutch hungerwinter study.

Objective. To examine the association between undernutrition during postnatal periods of development and the risk of overweight in adulthood. Methods. We studied 8,091 women from Prospect-EPIC, exposed to the Dutch famine at ages between 0 and 21 years, recruited at ages between 49 and 70 years. We used linear and logistic regression models to explore the effect of famine on BMI, waist circumference, and the risk of overweight. Results. Overall, postnatal famine exposure was associated with increased BMI and waist circumference in a dose-dependent manner (P for trend < 0.01). Furthermore, risk of overweight was increased following famine exposure (P for trend = 0.01), with those severely exposed at ages 0-9 years having 25% (95% CI 1.05 to 1.50) higher risk compared to unexposed women. Conclusions. This study is the first to directly show a positive association between short and transient undernutrition during postnatal development and BMI, waist circumference, and overweight in adulthood.

Cardiovascular consequences of famine in the young.

Aims The developmental origins hypothesis proposes that undernutrition during foetal life, infancy, or childhood is associated with an increased risk of cardiovascular disease in adulthood. As data on postnatal developmental programming are scarce, we investigated whether exposure to undernutrition during childhood, adolescence, or young adulthood is related to coronary heart disease (CHD) and stroke in adult life. Methods and results We studied 7845 women from the Prospect-EPIC cohort who had been exposed at various degrees to the 1944-45 Dutch famine when they were aged between 0 and 21 years. We used Cox proportional hazard regression models to explore the effect of famine on the risk of CHD and stroke, overall and within exposure age categories (0-9, 10-17, ≥18 years). We adjusted for potential confounders, including age at famine exposure, smoking, and level of education as a proxy for socio-economic status. Overall, stronger famine exposure was associated with higher CHD risk. Among those who experienced the famine between ages 10 and 17 years, CHD risk was significantly higher among severely exposed women compared with unexposed women (HR 1.38; 95% CI 1.03-1.84), which only slightly attenuated after adjustment for confounding (HR 1.27; 95% CI 0.94-1.71). We observed a lower stroke risk among famine exposed women (HR 0.79; 95% CI 0.61-1.02). Adjustment for potential confounders produced similar results (HR 0.77; 95% CI 0.59-0.99). Conclusion Exposure to undernutrition during postnatal periods of development, including adolescence, may affect cardiovascular health in adult life.

Survival effects of prenatal famine exposure.

BACKGROUND: Adverse intrauterine conditions are known to be associated with an increased risk of chronic diseases in adult life. Previously, we showed that prenatal famine exposure increased the incidence of cardiovascular and metabolic disease in adulthood. OBJECTIVE: We examined the association between prenatal famine exposure and adult mortality. DESIGN: We studied adult mortality among 1991 term singletons from the Dutch Famine Birth Cohort. We compared overall and cause-specific adult mortality among people exposed to famine in late, mid, and early gestation with those unexposed to famine in utero by using Cox proportional hazard models. RESULTS: A total of 206 persons (10%) had died by the end of follow-up. Compared with unexposed women, women exposed to famine in early gestation had a significantly higher risk of overall adult mortality (HR: 1.9; 95% CI: 1.1, 3.4), cardiovascular mortality (HR: 4.6; 95% CI: 1.2, 17.7), cancer mortality (HR: 2.3; 95% CI: 1.1, 4.7), and breast cancer mortality (HR: 8.3; 95% CI: 1.1, 63.0). In men exposed to famine in early gestation, these associations were as follows compared with unexposed men: overall adult mortality (HR: 0.4; 95% CI: 0.2, 1.1), cardiovascular mortality (HR: 0.9; 95% CI: 0.3, 3.1), and cancer mortality (HR: 0.3; 95% CI: 0.0, 1.9). CONCLUSIONS: Women exposed to famine in early gestation had a higher overall adult, cardiovascular, cancer, and breast cancer mortality risk than did women not exposed to famine. No such effects were observed in men exposed to famine in early gestation.

Hungry in the womb: what are the consequences? Lessons from the Dutch famine.

An increasing body of evidence suggests that poor nutrition at the very beginning of life - even before birth - leads to large and long term negative consequences for both mental and physical health. This paper reviews the evidence from studies on the Dutch famine, which investigated the effects of prenatal undernutrition on later health. The effects of famine appeared to depend on its timing during gestation, and the organs and tissues undergoing critical periods of development at that time. Early gestation appeared to be the most vulnerable period. People who were conceived during the famine were at increased risk of schizophrenia and depression, they had a more atherogenic plasma lipid profile, were more responsive to stress and had a doubled rate of coronary heart disease. Also, they performed worse on cognitive tasks which may be a sign of accelerated ageing. People exposed during any period of gestation had more type 2 diabetes. Future investigation will expand on the finding that the effects of prenatal famine exposure may reach down across generations, possibly through epigenetic mechanisms. Recent evidence suggests that similar effects of prenatal undernutrition are found in Africa, where many are undernourished. Hunger is a major problem worldwide with one in seven inhabitants of this planet suffering from lack of food. Adequately feeding women before and during pregnancy may be a promising strategy in preventing chronic diseases worldwide.

Variations in the uncoupling protein-3 gene are associated with specific obesity phenotypes.

OBJECTIVE: Uncoupling protein 3 (UCP-3) uncouples oxidative metabolism from ATP synthesis, resulting in the production of heat instead of energy storage. Single nucleotide polymorphisms (SNPs) in UCP-3 might result in a reduced function or expression of UCP-3 and therefore lead to an increased capacity to store energy as fat. DESIGN: We conducted a population-based, cross-sectional single-center study among 400 Dutch men between 40 and 80 years. METHODS: Seven SNPs in the UCP-3 gene were genotyped by means of an allele-specific real-time TaqMan PCR. Linear regression analyses were performed to examine the independent effects of these SNPs on obesity phenotypes. RESULTS: We found a significant association between homozygosity for the minor allele of rs647126, rs1685356, and rs2075577 and an increase in body mass index (BMI; P=0.033, P=0.016, and P=0.019 respectively). Heterozygosity for rs1685354 was associated with a significant decrease in visceral fat mass (P=0.030). CONCLUSIONS: Our results suggest that genetic variations in the UCP-3 gene are associated with an increase in BMI. A plausible mechanism by which these SNPs lead to an increase in BMI is that due to these SNPs, the UCP-3 activity might be decreased. As a result, uncoupling activity may also decrease, which will lead to an increase in body weight and BMI.