Integrating in vitro testing and physiologically-based pharmacokinetic (PBPK) modelling for chemical liver toxicity assessment—A case study of troglitazone

In vitro to in vivo extrapolation (IVIVE) for next-generation risk assessment (NGRA) of chemicals requires computational modeling and faces unique challenges. Using mitochondria-related toxicity data of troglitazone (TGZ), a prototype drug known for liver toxicity, from HepaRG, HepG2, HC-04, and primary human hepatocytes, we explored inherent uncertainties in IVIVE, including cell models, cellular response endpoints, and dose metrics. A human population physiologically-based pharmacokinetic (PBPK) model for TGZ was developed to predict in vivo doses from in vitro point-of-departure (POD) concentrations. Compared to the 200–800 mg/d dose range of TGZ where liver injury was observed clinically, the predicted POD doses for the mean and top one percentile of the PBPK population were 28–372 and 15–178 mg/d respectively based on C_max dosimetry, and 185–2552 and 83–1010 mg/d respectively based on AUC. In conclusion, although with many uncertainties, integrating in vitro assays and PBPK modeling is promising in informing liver toxicity-inducing TGZ doses.     

Associations between heart rate variability and maximal fat oxidation in two different cohorts of healthy sedentary adults

Background and aimsResting heart rate variability (HRV) and maximal fat oxidation (MFO) during exercise are both considered as a noninvasive biomarkers for early detection of cardiovascular risk factors. Thus, this study aimed to analyze the relationship between resting HRV parameters and MFO during exercise, and the intensity of exercise that elicit MFO (Fat_max) in healthy sedentary adults.Methods and resultsA total of 103 healthy young adults (22.2 ± 2.3 years old, 67% female; from the ACTIBATE cohort) and 67 healthy middle-aged adults (53.1 ± 5.0 years old, 52% female; from the FIT-AGEING cohort) were included in this cross-sectional study. HRV was assessed using a Polar RS800CX heart rate monitor, while MFO and Fat_max were determined during a graded exercise treadmill test using indirect calorimetry. No significant associations were observed for healthy young adults (standardized β coefficients ranged from ?0.063 to 0.094, and all P ≥ 0.347) and for middle-aged adults (standardized β coefficients ranged from ?0.234 to 0.090, and all P ≥ 0.056). Nevertheless, only a weak association was observed between one HRV parameter in time-domain (the percentage of R-R intervals that shows a difference higher than 50 ms [pNN50]) and MFO in the cohort of middle-aged adults (β coefficient = ?0.279, and P = 0.033).ConclusionThe results of this study suggest that resting HRV parameters are not associated with MFO and Fat_max during exercise in two independent cohorts of healthy sedentary young and middle-aged adults, respectively.     

Effect of a multi-disciplinary program on anthropometric and biochemical parameters in obese and overweight elementary school girls: A randomized clinical trial

Background and aimsObesity and overweight in children are associated with an increased risk of several health issues. The present study aimed to assess the effects of a multi-disciplinary program (including nutrition education using a smartphone game, physical activity, and cognitive behavioral therapy [CBT]) on the management of obesity and overweight in elementary school girls.Methods and resultsSixty-two school girls above the 85th percentile of body mass index (BMI) for age were randomly assigned to two groups. During 10 weeks of study, the intervention group received a multi-disciplinary intervention, including nutrition education using a smartphone game, aerobic exercise, and CBT. The control group received usual traditional nutritional education. Biochemical and metabolic factors were assessed, including fasting blood sugar (FBS), lipid profile, serum leptin, and anthropometric measurements. The Dutch Eating Behavior Questionnaire (DEBQ) and metabolic equivalent test (MET) were also conducted. The intervention group showed more promising results in weight loss, waist circumference (WC), hip circumference (HC), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and FBS compared to the control group (P < 0.05). In addition, MET and DEBQ scores in all three sections of emotions, stimuli, and restriction were better in the intervention group than in the control group (P < 0.05). However, there was no significant difference between groups regarding the results of serum leptin and waist-to-hip ratio (WHR; p > 0.05).ConclusionsThe results indicated that education through smartphone games could possibly affect performance in real life. In addition, the multi-disciplinary approach to childhood obesity might have better performance in most areas than the single-intervention approach in obesity management.     

Stress Testing Versus CT Angiography in Patients With Diabetes and Suspected Coronary Artery Disease

Background

The optimal noninvasive test (NIT) for patients with diabetes and stable symptoms of coronary artery disease (CAD) is unknown.