Search

Introduction: Endoxifen—the principal metabolite of tamoxifen—is subject to a high inter-individual variability in serum concentration. Numerous attempts have been made to explain this, but thus far only with limited success. By applying predictive modeling, we aimed to identify factors that determine the inter-individual variability. Our purpose was to develop a prediction model for endoxifen concentrations, as a strategy to individualize tamoxifen treatment by model-informed dosing in order to prevent subtherapeutic exposure (endoxifen < 16 nmol/L) and thus potential failure of therapy. Methods: Tamoxifen pharmacokinetics with demographic and pharmacogenetic data of 303 participants of the prospective TOTAM study were used. The inter-individual variability in endoxifen was analyzed according to multiple regression techniques in combination with multiple imputations to adjust for missing data and bootstrapping to adjust for the over-optimism of parameter estimates used for internal model validation. Results: Key predictors of endoxifen concentration were CYP2D6 genotype, age and weight, explaining altogether an average-based optimism corrected 57% (95% CI 0.49–0.64) of the inter-individual variability. CYP2D6 genotype explained 54% of the variability. The remaining 3% could be explained by age and weight. Predictors of risk for subtherapeutic endoxifen (< 16 nmol/L) were CYP2D6 genotype and age. The model showed an optimism-corrected discrimination of 90% (95% CI 0.86–0.95) and sensitivity and specificity of 66% and 98%, respectively. Consecutively, there is a high probability of misclassifying patients with subtherapeutic endoxifen concentrations based on the prediction rule. Conclusion: The inter-individual variability of endoxifen concentration could largely be explained by CYP2D6 genotype and for a small proportion by age and weight. The model showed a sensitivity and specificity of 66 and 98%, respectively, indicating a high probability of (misclassification) error for the patients with subtherapeutic endoxifen concentrations (< 16 nmol/L). The remaining unexplained inter-individual variability is still high and therefore model-informed tamoxifen dosing should be accompanied by therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Valid and reliable measurement of an individual's knowledge and risk perception is pivotal to monitor and evaluate the effectiveness of interventions aimed at preventing cardiovascular diseases (CVDs). The recently developed Attitudes and Beliefs about Cardiovascular Disease (ABCD) knowledge and risk questionnaire is shown to be valid in England. In this study, we evaluated the psychometric properties of the modified and Dutch (Flemish)-translated ABCD questionnaire using both the classical test and item response theory (IRT) analysis. We conducted a community-based survey among 525 adults in Antwerp city, Belgium. We assessed the item- and scale-level psychometric properties and validity indices of the questionnaire. Parameters of IRT, item scalability, monotonicity, item difficulty and discrimination, and item fit statistics were evaluated. Furthermore, exploratory and confirmatory factorial validity, and internal consistency measures were explored. Descriptive statistics showed that both the knowledge and risk scale items have sufficient variation to differentiate individuals' level of knowledge and risk perception. The overall homogeneity of the knowledge and risk subscales was within the acceptable range (> 0.3). The exploratory and confirmatory factor analyses of the risk scale supported a three-factor solution corresponding to risk perception (F1), perceived benefits and intention to change physical activity (F2), and perceived benefit and intention to change healthy dietary habit (F3). The two parametric logistic (2—PL) and rating scale models showed that the item infit and outfit values for knowledge and risk subscales were within the acceptable range (0.6 to 1.4) for most of the items. In conclusion, this study investigated the Dutch (Flemish) version of the ABCD questionnaire has good psychometric properties to assess CVD related knowledge and risk perception in the adult population. Based on the factor loadings and other psychometric properties, we suggested a shorter version, which has comparable psychometric properties. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic caused many governments to impose policies restricting social interactions. A controlled and persistent release of lockdown measures covers many potential strategies and is subject to extensive scenario analyses. Here, we use an individual-based model (STRIDE) to simulate interactions between 11 million inhabitants of Belgium at different levels including extended household settings, i.e., "household bubbles". The burden of COVID-19 is impacted by both the intensity and frequency of physical contacts, and therefore, household bubbles have the potential to reduce hospital admissions by 90%. In addition, we find that it is crucial to complete contact tracing 4 days after symptom onset. Assumptions on the susceptibility of children affect the impact of school reopening, though we find that business and leisure-related social mixing patterns have more impact on COVID-19 associated disease burden. An optimal deployment of the mitigation policies under study require timely compliance to physical distancing, testing and self-isolation. The COVID-19 pandemic caused many governments to impose policies restricting social interactions. Here, the authors implement an age-specific, individual-based model with data on social contacts for the Belgian population and investigate the effect of non-pharmaceutical interventions. [ABSTRACT FROM AUTHOR]

The cross ratio function (CRF) is a commonly used tool to describe local dependence between two correlated variables. Being a ratio of conditional hazards, the CRF can be rewritten in terms of (first and second derivatives of) the survival copula of these variables. Bernstein estimators for (the derivatives of) this survival copula are used to define a nonparametric estimator of the cross ratio, and asymptotic normality thereof is established. We consider simulations to study the finite sample performance of our estimator for copulas with different types of local dependency. A real dataset is used to investigate the dependence between food expenditure and net income. The estimated CRF reveals that families with a low net income relative to the mean net income will spend less money to buy food compared to families with larger net incomes. This dependence, however, disappears when the net income is large compared to the mean income. [ABSTRACT FROM AUTHOR]

Vitamin D is a key nutrient for both healthy children and those with chronic illnesses. Understanding its roles in health and disease has become one of the most important issues in the nutritional management of children. Formal guidelines related to nutrient requirements for vitamin D in healthy children, recommending dietary intakes of 400IU per day for infants and 600IU per day for children over 1 year of age, were released by the Institute of Medicine in November 2010. However, application of these guidelines to children with acute and chronic illnesses is less clear. In this Review, we consider major illness categories and specific examples of conditions in children that might be affected by vitamin D. This information can be used in developing both model systems of investigation and clinical trials of vitamin D in children with acute and chronic illnesses. [ABSTRACT FROM AUTHOR]

Some patients with hypercalciuria are thought to have enhanced enteric calcium absorption, with a major component of recent diet contributing to urinary calcium. This mechanism has been difficult to test with the usual calcium loading procedures. We employed dual stable calcium isotope tracers to quantitate the components of urinary calcium excretion in 38 healthy female children. The mean urinary calcium excretion in these girls was 2.4 mg/kg per day. The contribution of recent diet to this total was a mean of 0.2 mg/kg per day. The maximum dietary contribution to urinary calcium excretion was 0.86 mg/kg per day. Recent diet contributes a mean of 8% to total dietary calcium excretion. This novel method permits precise quantitation of the contributions of recent diet and tissue stores to urinary calcium excretion. In these healthy girls, the fraction of urinary calcium derived from diet is trivial. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "The demise of calcium-based phosphate binders—is this appropriate for children?" by L. Rees and colleagues that was published in the previous issue.