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.
MULTIFILE
The improvement of passive fire protection of storage vessels is a key factor to enhance safety among the LPG distribution chain. A thermal and mechanical model based on finite elements simulations was developed to assess the behaviour of full size tanks used for LPG storage and transportation in fire engulfment scenarios. The model was validated by experimental results. A specific analysis of the performance of four different reference coating materials was then carried out, also defining specific key performance indicators (KPIs) to assess design safety margins in near-miss simulations. The results confirmed the wide influence of coating application on the expected vessel time to failure due to fire engulfment. Aquite different performance of the alternative coating materialswas evidenced. General correlationswere developed among the vessel time to failure and the effective coating thickness in full engulfment scenarios, providing a preliminary assessment of the coating thickness required to prevent tank rupture for a given time lapse. The KPIs defined allowed the assessment of the available safety margins in the reference scenarios analyzed and of the robustness of thermal protection design.
MULTIFILE
4.1 IntroductionThe use of coercive measures generally has negative effects on patients. To help prevent its use, professionals need insight into what nurses believe about coercion and which staff determinants may influence its application. There is need for an integrated review on both attitude and influence of nurses on the use of coercion.4.2 AimTo summarize literature concerning attitude of nurses towards coercive measures and the influence of staff characteristics on the use of coercive measures.4.3 MethodSystematic review.4.4 ResultsThe attitude of nurses changed during the last two decades from a therapeutic to a safety paradigm. Nurses currently view coercive measures as undesirable, but necessary to deal with aggression. Nurses express the need for less intrusive interventions, although familiarity probably influences its perceived intrusiveness. Literature on the relation between staff characteristics and coercive measures is inconclusive.4.5 DiscussionNurses perceive coercive measures as unwanted but still necessary to maintain safety on psychiatric wards. Focussing on the determinants of perception of safety might be a promising direction for future research.4.6 Implications for practiceMental health care could improve the focus on the constructs of perceived safety and familiarity with alternative interventions to protect patients from unnecessary use of coercive interventions.
MULTIFILE
