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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The present study compares two approaches to evaluate the effects of inter-individual differences in the biotransformation of chlorpyrifos (CPF) on the sensitivity towards in vivo red blood cell (RBC) acetylcholinesterase (AChE) inhibition and to calculate a chemical-specific adjustment factor (CSAF) to account for inter-individual differences in kinetics (HKAF). These approaches included use of a Supersome™ cytochromes P450 (CYP)-based and a human liver microsome (HLM)-based physiologically based kinetic (PBK) model, both combined with Monte Carlo simulations. The results revealed that bioactivation of CPF exhibits biphasic kinetics caused by distinct differences in the Km of CYPs involved, which was elucidated by Supersome™ CYP rather than by HLM. Use of Supersome™ CYP-derived kinetic data was influenced by the accuracy of the intersystem extrapolation factors (ISEFs) required to scale CYP isoform activity of Supersome™ to HLMs. The predicted dose–response curves for average, 99th percentile and 1st percentile sensitive individuals were found to be similar in the two approaches when biphasic kinetics was included in the HLM-based approach, resulting in similar benchmark dose lower confidence limits for 10% inhibition (BMDL10) and HKAF values. The variation in metabolism-related kinetic parameters resulted in HKAF values at the 99th percentile that were slightly higher than the default uncertainty factor of 3.16. While HKAF values up to 6.9 were obtained when including also the variability in other influential PBK model parameters. It is concluded that the Supersome™ CYP-based approach appeared most adequate for identifying inter-individual variation in biotransformation of CPF and its resulting RBC AChE inhibition.
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Inleiding en praktijkvraag De groeiende wereldbevolking gecombineerd met de klimaatverandering zorgt voor een de noodzaak tot een duurzame voedselvoorziening (KIA missie Landbouw, voedsel & water). Een significante reductie van gewasbestrijdingsmiddelen is daarbinnen een belangrijke doelstelling. Robotica maakt als technologie motor van de precisielandbouw plant specifieke precisie-bestrijding mogelijk. Het projectconsortium onderzoekt een semiautonoom samenwerkend grond-luchtrobot platform voor de precisielandbouw. Projectdoelstelling De doelstelling van het project AGRobot Platform is dan ook: “Onderzoek de mogelijkheden van een semi-autonoom samenwerkend grond-lucht robotplatform voor de precisielandbouw”. De hoofddoelstelling wordt binnen dit project beantwoordt door de deliverables uit de volgende subdoelstellingen: 1. Case studie onderzoek naar de mogelijke voordelen van het grond-luchtrobotplatform 2. Onderzoek naar de benodigde technologieën voor een grond-luchtrobotplatform 3. Ontwikkelen van een eerste (mogelijk case-specifieke) demonstrator 4. Ontwikkelen van (nieuwe) samenwerkingsvormen. Vraagsturing & Netwerkvorming Riwo Engineering is een industriële automatiseeerder die met zijn grondrobots en control-besturingssytemen actief is in de veeteelt. DRONEXpert gebruikt hyperspectrale camera’s onder drones voor het bemeten van gewassen. Saxion mechatronica onderzoekt met de onderzoekslijn unmanned robotic systems hoe de nieuwste robotica technologieën systemen mogelijk maakt voor ongestructureerde omgevingen. De partners bezitten gezamenlijk een enorm netwerk (TValley, Space53, euRobotics) en klanten om via de case studies de kansen te achterhalen en te realiseren. Innovatie Nergens ter wereld is een samenwerkend grond-luchtrobot platform actief in de precisielandbouw. Voor OostNederland, met naast veel robotica kennis ook veel Agro-kennis, zal het project letterlijk de KIEM zijn voor nieuwe projecten waaruit de valorisatie kansen richting heel Europa gaan. Activiteitenplan & Projectorganisatie Het project wordt geleid door de lector Dr. Ir. D.A.Bekke en uitgevoerd door Abeje Mersha en Mark Reiling samen met het deelnemend MKB. Het project bestaat uit 4 werkpakketten die achtereenvolgens antwoordt geven op de gestelde subdoelstellingen. Aan elk werkpakket zijn deliverables gekoppeld.
The pressure on the European health care system is increasing considerably: more elderly people and patients with chronic diseases in need of (rehabilitation) care, a diminishing work force and health care costs continuing to rise. Several measures to counteract this are proposed, such as reduction of the length of stay in hospitals or rehabilitation centres by improving interprofessional and person-centred collaboration between health and social care professionals. Although there is a lot of attention for interprofessional education and collaborative practice (IPECP), the consortium senses a gap between competence levels of future professionals and the levels needed in rehabilitation practice. Therefore, the transfer from tertiary education to practice concerning IPECP in rehabilitation is the central theme of the project. Regional bonds between higher education institutions and rehabilitation centres will be strengthened in order to align IPECP. On the one hand we deliver a set of basic and advanced modules on functioning according to the WHO’s International Classification of Functioning, Disability and Health and a set of (assessment) tools on interprofessional skills training. Also, applications of this theory in promising approaches, both in education and in rehabilitation practice, are regionally being piloted and adapted for use in other regions. Field visits by professionals from practice to exchange experiences is included in this work package. We aim to deliver a range of learning materials, from modules on theory to guidelines on how to set up and run a student-run interprofessional learning ward in a rehabilitation centre. All tested outputs will be published on the INPRO-website and made available to be implemented in the core curricula in tertiary education and for lifelong learning in health care practice. This will ultimately contribute to improve functioning and health outcomes and quality of life of patients in rehabilitation centres and beyond.
The pace of technology advancements continues to accelerate, and impacts the nature of systems solutions along with significant effects on involved stakeholders and society. Design and engineering practices with tools and perspectives, need therefore to evolve in accordance to the developments that complex, sociotechnical innovation challenges pose. There is a need for engineers and designers that can utilize fitting methods and tools to fulfill the role of a changemaker. Recognized successful practices include interdisciplinary methods that allow for effective and better contextualized participatory design approaches. However, preliminary research identified challenges in understanding what makes a specific method effective and successfully contextualized in practice, and what key competences are needed for involved designers and engineers to understand and adopt these interdisciplinary methods. In this proposal, case study research is proposed with practitioners to gain insight into what are the key enabling factors for effective interdisciplinary participatory design methods and tools in the specific context of sociotechnical innovation. The involved companies are operating at the intersection between design, technology and societal impact, employing experts who can be considered changemakers, since they are in the lead of creative processes that bring together diverse groups of stakeholders in the process of sociotechnical innovation. A methodology will be developed to capture best practices and understand what makes the deployed methods effective. This methodology and a set of design guidelines for effective interdisciplinary participatory design will be delivered. In turn this will serve as a starting point for a larger design science research project, in which an educational toolkit for effective participatory design for socio-technical innovation will be designed.
