Cost-utility analysis of expanding the colorectal cancer screening policy in Flanders.

OBJECTIVE: Since 2013, Flanders has introduced a screening programme for colorectal cancer for all citizens aged between 50 and 74 years. The objective of this study was to assess the cost-utility of an expansion of the colorectal cancer screening policy in Flanders (Belgium) and to place these findings in the international context. METHODS: Cost-utility analysis using high-detail data about screening participation, screening results, and epidemiological data, a Markov cohort model has been constructed to study long-term costs and effects. A cost-utility analysis was performed as a three-way comparison between current, expanded (from age 45 years), and no screening scenarios, from a societal and healthcare perspective. Robustness was assessed by both one-way and probabilistic sensitivity analyses. RESULTS: Analyses show that both current and expanded screening result in quality-adjusted life years (QALY) gains and are mostly cost-saving. Overall, 97.5% of Incremental Cost-Effectiveness Ratios (ICERs) remained well below € 2000 per QALY for all comparisons. Parameters related to the colonoscopy that follows a positive test result such as compliance and cost are especially impactful on the cost-effectiveness. CONCLUSIONS: Screening participation and screening costs have remained comparatively stable, making colorectal cancer screening a cost-effective (dominant) policy. Expanding the screen age to 45 years is also cost-effective (dominant) compared with current screening, albeit with a slimmer margin.

The role of the 2D-to-3D transition in x-ray diffraction analysis of crystallite size.

The diffraction behaviour of stacked layers of graphene and hexagonal boron nitride are studied computationally by direct calculation of the diffraction pattern using the Debye scattering equation. Analysis of the position and profile of the diffraction peaks show that while single-layer graphene is unambiguously a 2D material, ordered stacks of three or more layers diffract as bulk material. Following the Scherrer equation, we correlate the known crystallite size with the diffraction peak parameters and observe strong affine relationships which exist separately for single-layer, bi-layer and three or more layer (bulk) structures. We determine a series of expressions to calculate the crystallite size which do not suffer the well-known size-dependence or rely on assumptions about the shape. We present a detailed workflow showing how these expressions can be applied to experimental data.

Factors associated with costs of care in community-dwelling persons with dementia from a third party payer and societal perspective: a cross-sectional study.

BACKGROUND: Besides the importance of estimating the global economic impact of care for persons with dementia, there is an emerging need to identify the key factors associated with this cost. The aim of this study was to analyze associations between the cost of care in community-dwelling persons with dementia and caregiver characteristics from both the healthcare third party payer perspective and the societal perspective. METHODS: Several characteristics based on the cross-sectional data of 355 dyads of informal caregivers and persons with dementia living in Belgium were identified to include in a log-gamma generalized linear model and were used in a multiple linear regression model with bootstrapping to test robustness. RESULTS: The mean monthly cost of care for a community-dwelling person with dementia was estimated at € 2339 (95% CI € 2133 - € 2545) per person from a societal perspective and at € 968 (95% CI € 825 - € 1111) per person from a third party payer viewpoint. Informal care accounted for the majority of the monthly costs from the societal perspective. Community based healthcare resource use represented the largest cost from the third party perspective. According to the regression analyses, a higher level of functional dependency of the person with dementia and a higher educational level of the caregiver were associated with a higher monthly cost from both a third party payer perspective and a societal perspective. In addition, being retired and a higher quality of life in the caregivers were associated with a lower monthly cost of care from the societal perspective. CONCLUSIONS: Several characteristics of the caregiver and the person with dementia were associated with the monthly costs of care from a third party payer and a societal perspective. Despite the lack of clear causal relationships, the results of this study can assist policy makers in planning and financing future dementia care. TRIAL REGISTRATION: Clinicaltrials.gov NCT02630446, December 15, 2015.

Health economic analysis of a cluster-randomised trial (OptiBIRTH) designed to increase rates of vaginal birth after caesarean section.

OBJECTIVE: To perform a health economic analysis of an intervention designed to increase rates of vaginal birth after caesarean, compared with usual care. DESIGN: Economic analysis alongside the cluster-randomised OptiBIRTH trial (Optimising childbirth by increasing vaginal birth after caesarean section (VBAC) through enhanced women-centred care). SETTING: Fifteen maternity units in three European countries - Germany (five), Ireland (five), and Italy (five) - with relatively low VBAC rates. POPULATION: Pregnant women with a history of one previous lower-segment caesarean section; sites were randomised (3:2) to intervention or control. METHODS: A cost-utility analysis from both societal and health-services perspectives, using a decision tree. MAIN OUTCOME MEASURES: Costs and resource use per woman and infant were compared between the control and intervention group by country, from pregnancy recognition until 3 months postpartum. Based on the caesarean section rates, and maternal and neonatal morbidities and mortality, the incremental cost-utility ratios were calculated per country. RESULTS: The mean difference in costs per quality-adjusted life years (QALYs) gained from a societal perspective between the intervention and the control group, using a probabilistic sensitivity analysis, was: €263 (95% CI €258-268) and 0.008 QALYs (95% CI 0.008-0.009 QALYs) for Germany, €456 (95% CI €448-464) and 0.052 QALYs (95% CI 0.051-0.053 QALYs) for Ireland, and €1174 (95% CI €1170-1178) and 0.006 QALYs (95% CI 0.005-0.007 QALYs) for Italy. The incremental cost-utility ratios were €33,741/QALY for Germany, €8785/QALY for Ireland, and €214,318/QALY for Italy, with a 51% probability of being cost-effective for Germany, 92% for Ireland, and 15% for Italy. CONCLUSION: The OptiBIRTH intervention was likely to be cost-effective in Ireland and Germany. TWEETABLE ABSTRACT: The OptiBIRTH intervention (to increase VBAC rates) is likely to be cost-effective in Germany and Ireland.

Cost-effectiveness and budget impact analysis of a population-based screening program for colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer mortality in Belgium. In Flanders (Belgium), a population-based screening program with a biennial immunochemical faecal occult blood test (iFOBT) in women and men aged 56-74 has been organised since 2013. This study assessed the cost-effectiveness and budget impact of the colorectal population-based screening program in Flanders (Belgium). METHODS: A health economic model was conducted, consisting of a decision tree simulating the screening process and a Markov model, with a time horizon of 20years, simulating natural progression. Predicted mortality and incidence, total costs, and quality-adjusted life-years (QALYs) with and without the screening program were calculated in order to determine the incremental cost-effectiveness ratio of CRC screening. Deterministic and probabilistic sensitivity analyses were conducted, taking into account uncertainty of the model parameters. RESULTS: Mortality and incidence were predicted to decrease over 20years. The colorectal screening program in Flanders is found to be cost-effective with an ICER of 1681/QALY (95% CI -1317 to 6601) in males and €4,484/QALY (95% CI -3254 to 18,163). The probability of being cost-effective given a threshold of €35,000/QALY was 100% and 97.3%, respectively. The budget impact analysis showed the extra cost for the health care payer to be limited. CONCLUSION: This health economic analysis has shown that despite the possible adverse effects of screening and the extra costs for the health care payer and the patient, the population-based screening program for CRC in Flanders is cost-effective and should therefore be maintained.

Comparison of two approaches of INR-follow-up and determinants of INR-stability.

INTRODUCTION: Patients with atrial fibrillation (AF) and treated with coumarins need a close follow-up of the international normalized ratio (INR)-values. This can be done by the general practitioner (GP) or by a haematologist in an outpatient hospital clinic. OBJECTIVE: To compare both ways of follow-up and to investigate determinants of stable INR-patterns. METHODS: Cross-sectional single-centre study in patients with AF treated at the UZ Brussel, a university hospital in Brussels. Of the 113 patients included in the study, 71 had their INR followed-up by their GP and 42 similar patients were followed-up by a haematologist. Data of these 113 patients were further analysed to identify possible determinants for stable INR-values. RESULTS: The time in therapeutic range (TTR) did not significantly differ between both groups. However, patients in the GP-group had significantly more INR-values under 2.0 compared to patients from the haematologist-group (P = 0.044), whereas patients in the haematologist-group had significantly more INR-values above 3.0 compared to patients from the GP-group (P = 0.038). Reimbursement costs of both ways of follow-up were comparable, but the out-of-pocket costs for the patient were lower in the GP-group. The time since AF diagnosis was the only significant determinant predicting a higher TTR. CONCLUSION: Both approaches of follow-up seem to lead to the same TTR, yielding no reason to advocate one approach above the other. However, the patient costs were lower when followed-up by the GP.

Predictors of late initiation for prenatal care in a metropolitan region in Belgium. A cohort study.

OBJECTIVES: Timely initiation of prenatal care (PNC) in the first pregnancy trimester allows prevention, identification and treatment of risk factors. However, not all women initiate PNC timely, especially women in a deprived situation. The aim of this study was to measure the prevalence of late initiation, defined as initiation after 14 weeks of gestational age. Secondly the authors wanted to identify predictors for late PNC onset. STUDY DESIGN: Observational cohort study. METHODS: Pregnant women (n = 1750) were recruited in all four hospitals in Ghent (Belgium), a metropolitan region. A socio-economic deprivation ranking was measured by using a General Deprivation Index (GDI), which consists of six criteria to assess a socio-economic situation as deprived. A univariate analysis and a forward conditional multivariate logistic regression model were used analysing the association between deprivation and the likelihood to initiate PNC late. RESULTS: 1115 women were included of whom 6.1% (n = 68) initiated PNC late. A foreign maternal country of birth (OR 2.10; 95% CI 1.15-3.83) and a total GDI ≥3 (OR 4.40; 95% CI 2.36-8.21) were good predictors for late initiation. More specifically, the GDI criteria education (OR 4.02; 95% CI 2.00-8.08) and unemployment (OR 2.40; 95% CI 1.17-4.90) were significantly associated with higher likelihood for late initiation. CONCLUSIONS: A small group of women initiates PNC late. Vulnerable groups, at risk for late initiation can be identified through assessing their deprivation status. Priority for additional support should be given to women with low educational attainment or women in uncertain employment situations.

Predicting sickness impact profile at six months after stroke: further results from the European multi-center CERISE study.

PURPOSE: To develop prognostic models and equations for predicting participation at six months after stroke. METHODS: This European prospective cohort study recruited 532 consecutive patients from four rehabilitation centers. Participation was assessed at six months after stroke with the Sickness Impact Profile (SIP), which consists of a physical, psychosocial and independent dimension. Twenty-six independent variables on admission to the rehabilitation center and 13 additional variables measured at two months post stroke were included in the analysis. A multiple logistic regression analysis was conducted predicting good participation (SIP < 20%). Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: The prognostic models for the three dimensions provided independent predictors containing demographics, complications, diagnostic, and disability measures. Sensitivity ranged from 64-84%, specificity 66-85%, positive predictive value 70-78%, and negative predictive value 76-87%. Barthel Index on admission, Euroqol Health State at two months and Caregiver Strain Index at two months were retained in all prediction models. CONCLUSIONS: A combination of variables was found in the prognostic models of the three dimensions of the SIP at six months after stroke. Already from the early beginning of stroke rehabilitation it seems important to focus on personal activities of daily living as well as caregivers' strain. IMPLICATIONS FOR REHABILITATION: Prognostic factors predicting participation, measured by the three dimensions of the Sickness Impact Profile at six months post stroke include demographic variables, post-stroke complications, diagnostic parameters and disability measures. Significant prognostic variables for all three dimensions of the Sickness Impact Profile were a higher Barthel Index score on admission to the rehabilitation center, a higher Euroqol Health State score at two months post stroke and a lower Caregiver Strain Index score at two months post stroke. Early stroke therapy should therefore further emphasize rehabilitation of personal activities of daily living such as mobility, walking, feeding, dressing, and toilet use, as well as considering strategies to reduce caregiver strain such as giving support, providing information and training carers.

Establishing a method to estimate the cost-effectiveness of a kindergarten-based, family-involved intervention to prevent obesity in early childhood. The ToyBox-study.

Overweight and obesity in children are recognized as a major health problem. The ToyBox-intervention was developed with the aim of preventing obesity in pre-schoolers. Because it is increasingly important to inform policy makers not only on the effects of prevention interventions, but also on their costs and cost-effectiveness, our purpose was to establish a method to estimate the cost-effectiveness of the ToyBox-intervention. In order to estimate the long-term impact of the ToyBox-intervention on health and societal costs, extrapolations of the intervention effect will be conducted to predict children's weight status (based on the body mass index) at adult age. Effects of the adult weight status on the prevalence of obesity-related complications will be modelled through a Markov model, with a total time horizon of 70 years and a cycle length of 1 year. The model will be conducted in six European countries participating in the ToyBox-intervention, based on country-specific economic and epidemiological data. This study describes the methodological rationale and implementation of an analytic model to examine the cost-effectiveness of the ToyBox-intervention for six European countries, in order to inform decision-makers on the value for money of this intervention in the prevention of obesity in pre-schoolers.

Physician's expectations regarding prescribing clinical decision support systems in a Belgian hospital.

OBJECTIVES: Developing and implementing clinical decision support systems (CDSSs) is time-consuming and costly. Therefore, prioritization of the most relevant systems is warranted. The physician's perceived usefulness has been identified as a decisive reason for using CDSSs. The objective of this study was to investigate the physician's perceived usefulness of different types of CDSSs and to identify the user needs and expectations regarding future CDSSs. METHODS: Cross-sectional single-centre survey among physicians with a clinical assignment in a university hospital. Physicians were questioned about their current experiences with drug prescribing and the perceived usefulness and desired features of future CDSSs. RESULTS: One hundred and sixty-four physicians completed the survey (52·6%). The majority acknowledged that it is very difficult to take all relevant information into account when prescribing drugs. Drug-drug interaction checking, drug-allergy checking, and dosing guidance were considered as most useful. Automated clinical guidelines and adverse drug event monitoring were considered as least useful. The user-friendliness of the systems, clinical relevance of the alerts, and prevention of alert fatigue were perceived as important aspects for a successful implementation. CONCLUSIONS: From the physicians' perspective drug-drug interaction checking, drug-allergy checking, and dosing guidance should receive the highest priority for development and implementation. Because the perceived usefulness has been identified as a decisive reason for using CDSSs, it seems feasible to take into account this prioritization when developing and implementing CDSSs. In order to overcome the physicians' perceived disadvantages, attention should go to the development of user-friendly systems that deliver clinical relevant alerts.

Anxiety and depression after stroke: a 5 year follow-up.

PURPOSE: The aim was to document the prevalence and predictors of anxiety and depression 5 years after stroke, across four European centres. METHOD: A cohort of 220 stroke patients was assessed at 2, 4 and 6 months and 5 years after stroke. Patients were assessed on the Hospital Anxiety and Depression Scale and measures of motor function and independence in activities of daily living. RESULTS: At 5 years, the prevalence of anxiety was 29% and depression 33%, with no significant differences between centres. The severity of anxiety and depression increased significantly between 6 months and 5 years. Higher anxiety at 6 months and centre were significantly associated with anxiety at 5 years, but not measures of functional recovery. Higher depression scores at 6 months, older age and centre, but not measures of functional recovery, were associated with depression at 5 years. CONCLUSIONS: Anxiety and depression were more frequent at 5 years after stroke than at 6 months. There were significant differences between four European centres in the severity of anxiety and depression. Although the main determinant of anxiety or depression scores at 5 years was the level of anxiety or depression at 6 months, this accounted for little of the variance. Centre was also a significant predictor of mood at 5 years. There needs to be greater recognition of the development of mood disorders late after stroke and evaluation of variation in management policies across centres.

Effect of a therapeutic intervention for the hemiplegic upper limb in the acute phase after stroke: a single-blind, randomized, controlled multicenter trial.

BACKGROUND AND PURPOSE: Arm function recovery is notoriously poor in stroke patients. The effect of treatment modalities, particularly those directed at improving upper limb function, has been studied primarily in chronic stroke patients. The purpose of this study was to investigate the effect of a specific therapeutic intervention on arm function in the acute phase after stroke. METHODS: In a single-blind, randomized, controlled multicenter trial, 100 consecutive patients were allocated to either an experimental group that received an additional treatment of sensorimotor stimulation or to a control group. The intervention was applied for 6 weeks. Patients were evaluated for level of impairment (Brunnström-Fugl-Meyer test) and disability (Action Research Arm test, Barthel Index) before, midway, and after the intervention period and at follow-up 6 and 12 months after stroke. RESULTS: Patients in the experimental group performed better on the Brunnström-Fugl-Meyer test than those in the control group throughout the study period, but differences were significant only at follow-up. Results on the Action Research Arm test and Barthel Index revealed no effect at the level of disability. The effect of the therapy was attributed to the repetitive stimulation of muscle activity. The treatment was most effective in patients with a severe motor deficit and hemianopia or hemi-inattention. No adverse effects due to the intervention were found. CONCLUSIONS: Adding a specific intervention during the acute phase after stroke improved motor recovery, which was apparent 1 year later. These results emphasize the potential beneficial effect of therapeutic interventions for the arm.

Formation and persistence of safrole-DNA adducts over a 10,000-fold dose range in mouse liver.

The spice constituent safrole (1-allyl-3,4-methylenedioxybenzene) and related allylbenzenes form DNA adducts and are rodent carcinogens. This study examined both dose and time dependence of hepatic safrole-DNA adduct formation over a 10,000-fold dose range up to 30 days after single administration. Female CD-1 mice were treated with safrole i.p. at 0.001, 0.01, 0.1, 1.0, and 10.0 mg/mouse in 0.2 ml tricaprylin or with vehicle alone. Liver DNA was analyzed at 0.5, 1, 2, 3, 7, 15 and 30 days via the dinucleotide/monophosphate version of the 32P-postlabeling assay. An approximately 10-fold increase in total safrole adduct levels with each successive 10-fold increase in dose was observed, giving relative adduct labeling (RAL) values of 10(-9)-10(-5). Each dose elicited identical kinetics of adduct formation, showing peak levels at 2 days and only slight decreases thereafter. The time course of adduct persistence was independent of the dose (0.01-10 mg/mouse). An in vitro experiment established that the assay responded in strictly linear fashion to adduct concentration over a 10,000-fold range, and thus was suitable for in vivo dosimetry. DNA synthesis, as measured by [3H]thymidine incorporation, was enhanced only for the 10.0 mg dose at 2, 3 and 7 days. These results indicate a linear response of safrole-DNA adduct formation and persistence in mouse liver following administration of minute (0.001 mg/mouse) to high (10.0 mg/mouse) doses of the carcinogen.

Flavor constituents in cola drinks induce hepatic DNA adducts in adult and fetal mice.

Mice given one of several widely consumed cola drinks in place of drinking water for up to 8 weeks developed significant levels of covalent liver DNA adducts in a time dependent manner, as measured by 32P-postlabeling. These adducts were not detected in mice given tap water or one of 3 non-cola beverages. Adducts chromatographically identical to those induced by cola drinks were detected in mice treated with extracts of nutmeg or mace, spices from the nutmeg tree (Myristica fragrans Houttuyn), or with myristicin (1-allyl-5-methoxy-3,4-methylenedioxybenzene), the major spice constituent of nutmeg. In addition, small amounts of adducts derived from the hepatocarcinogen safrole (1-allyl-3,4-methylenedioxybenzene), a minor constituent of nutmeg, were observed. Liver DNA adducts were also detected in fetal liver when pregnant mice were intubated with myristicin. Possible implications of these findings for human health are discussed.

Age-dependent increases of DNA adducts (I-compounds) in human and rat brain DNA.

Brain DNA from 20 humans ranging in age from neonatal to 100 years was analyzed by the nuclease P1-enhanced version of the 32P-postlabeling assay for bulky covalently modified nucleotides. A reproducible pattern of three 32P-labeled spots was obtained by thin-layer chromatography followed by autoradiography. Two of these spots increased with age (Mann-Whitney U-test; P < 0.001; comparison of ages < or = 60 years and ages > 60 years). Thus, these spots met the definition of I-compounds. Rat brain DNA exhibited the same two I-spots, whose intensities also increased with animal age (1, 4, and 10 months). In humans, considerable individual variation of brain I-compound levels was observed, especially at ages > 60 years, presumably reflecting environmental, life-style, or genetic factors. This variation was not noted for brain DNA of laboratory rats. Thus, human brain DNA undergoes progressive covalent modifications with aging.

DNA adducts in human environmentally exposed to aromatic compounds in an industrial area of Poland.

The effect of environmental pollution on DNA adducts in humans was analysed in a highly industrialized area of Poland. Coded samples of white blood cell DNA were analysed by 32P-postlabelling and immunoassay from three populations: coke workers, exposed occupationally to high levels of polycyclic aromatic hydrocarbons (PAHs); residents of the towns around cokeries (local controls); and residents from rural Poland (countryside controls). Local controls exhibited adduct levels and patterns similar to those of coke workers, while the levels in rural controls were 2-3 times lower. The results, based on coded samples and two different assays, suggest that environmental pollution is likely to contribute to the adduct levels in local controls. Furthermore, the results show that the levels of aromatic adducts in white blood cell DNA do not linearily relate to ambient air levels of PAHs but other sources such as food may be important contributors.

Postlabeling and immunoassay analysis of polycyclic aromatic hydrocarbons--adducts of deoxyribonucleic acid in white blood cells of foundry workers.

Blood samples were obtained from volunteers who were occupationally exposed to polycyclic aromatic hydrocarbons in a Finnish iron foundry and from referents not known to be occupationally exposed to this class of chemical carcinogens. Aromatic adducts were determined in the deoxyribonucleic acid of white blood cells from the exposed workers with the 32P-postlabeling and immunologic techniques. There was a correlation between the estimated exposure in a particular job and the adduct levels. Jobs of men with high adduct levels (greater than 1 adduct/10(7) nucleotides in the postlabeling assay) included sand preparation, molding, shake-out, and transport. The adduct levels were low in men in pattern making, melting, and fettling. This study suggests that 32P-postlabeling and immunoassay may be useful in monitoring human exposure to known and previously unidentified environmental genotoxic agents.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on I-compounds in hepatic DNA of Sprague-Dawley rats: sex-specific effects and structure-activity relationships.

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds on the specific patterns of age-dependent I-compound DNA adducts in the liver of male and female Sprague-Dawley rats were determined by the 32P-postlabeling assay. In female rats, TCDD causes a dose-dependent decrease of several individual and total hepatic I-compound levels after administration of 1 and 5 micrograms/kg per week for 4 weeks. In contrast, no such effects were observed in male Sprague-Dawley rats treated with the 5 micrograms/kg dose level of TCDD. The relative effects of TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD) and 1,2,4,7,8-PCDD on hepatic I-compound levels in the susceptible female Sprague-Dawley rats were determined using a dose of 5 micrograms/kg per week for 4 weeks. The two compounds which are substituted in all four lateral positions, namely TCDD and 1,2,3,7,8-PCDD, caused a significant decrease in hepatic I-compound levels, whereas 1,2,4,7,8-PCDD which is substituted in only three lateral positions was inactive. The structure-activity relationships observed for the effects of these compounds on hepatic I-compounds correlated with their corresponding structure-Ah receptor binding and structure-toxicity relationships. The results are therefore consistent with a role for the Ah receptor in the TCDD-mediated reduction in hepatic I-compound levels in female Sprague-Dawley rats. These results and data from previous studies demonstrate a correlation between the susceptibility of an organ/species to the carcinogenic effects of TCDD and the reduction of I-compound levels. The significance of this correlation in the development of TCDD-induced carcinogenesis has not been delineated.

DNA adducts in humans related to occupational and environmental exposure to aromatic compounds.

White blood cell DNA adducts were measured in coke workers, local controls and countryside controls using the 32P-postlabelling technique and immunoassay. The methods detected aromatic adducts, including those formed by polycyclic aromatic hydrocarbons. Coke workers are heavily exposed to aromatic compounds, which are also emitted in large amounts into the environment. The two techniques detected a large difference in adduct levels between the coke workers and the countryside controls. The adduct levels in the local controls were substantially higher than those in the countryside controls. As occupational exposure did not account for such a difference, the data suggest that the source of aromatic adducts in local controls is environmental pollution.