New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose–response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals.
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PURPOSE: To investigate the reliability and validity of the SQUASH physical activity (PA) questionnaire in a multi-ethnic population living in the Netherlands.METHODS: We included participants from the HELIUS study, a population-based cohort study. In this study we included Dutch (n = 114), Turkish (n = 88), Moroccan (n = 74), South-Asian Surinamese (n = 98) and African Surinamese (n = 91) adults, aged 18-70 years. The SQUASH was self-administered twice to assess test-re-test reliability (mean interval 6-7 weeks) and participants wore an accelerometer and heart rate monitor (Actiheart) to enable assessment of construct validity.RESULTS: We observed low test-re-test reliability; Intra class correlation coefficients ranged from low (0.05 for moderate/high intensity PA in African Surinamese women) to acceptable (0.78 for light intensity PA in Moroccan women). The discrepancy between self-reported and measured PA differed on the basis of the intensity of activity: self-reported light intensity PA was lower than measured but self-reported moderate/high intensity PA was higher than measured, with wide limits of agreement. The discrepancy between questionnaire and Actiheart measures of moderate intensity PA did not differ between ethnic minority and Dutch participants with correction for relevant confounders. Additionally, the SQUASH overestimated the number of participants meeting the Dutch PA norm; Cohen's kappas for the agreement were poor, the highest being 0.30 in Dutch women.CONCLUSION: We found considerable variation in the test-re-test reliability and validity of self-reported PA with no consistency based on ethnic origin. Our findings imply that the SQUASH does not provide a valid basis for comparison of PA between ethnic groups.
Optimizing protein intake is a novel strategy to prevent age associated loss of muscle mass and strength in older adults. Such a strategy is still missing for older adults from ethnic minority populations. Protein intake in these populations is expected to be different in comparison to the majority of the population due to several socio-cultural factors. Therefore, the present study examined the dietary protein intake and underlying behavioral and environmental factors affecting protein intake among older adults from ethnic minorities in the Netherlands. We analyzed frequency questionnaire (FFQ) data from the Healthy Life in an Urban Setting (HELIUS) cohort using ANCOVA to describe dietary protein intake in older adults from ethnic minorities in the Netherlands (N = 1415, aged >55 years, African Surinamese, South Asian Surinamese, Moroccan, and Turkish). Additionally, we performed focus groups among older adults from the same ethnic minority populations (N = 69) to discover behavioral and environmental factors affecting protein intake; 40-60% of the subjects did not reach minimal dietary protein recommendations needed to maintain muscle mass (1.0 g/kg bodyweight per day (BW/day)), except for Turkish men (where it was 91%). The major sources of protein originated from animal products and were ethnic specific. Participants in the focus groups showed little knowledge and awareness about protein and its role in aging. The amount of dietary protein and irregular eating patterns seemed to be the major concern in these populations. Optimizing protein intake in these groups requires a culturally sensitive approach, which accounts for specific protein product types and sociocultural factors.
