Background: Adverse outcome pathway (AOP) networks are versatile tools in toxicology and risk assessment that capture and visualize mechanisms driving toxicity originating from various data sources. They share a common structure consisting of a set of molecular initiating events and key events, connected by key event relationships, leading to the actual adverse outcome. AOP networks are to be considered living documents that should be frequently updated by feeding in new data. Such iterative optimization exercises are typically done manually, which not only is a time-consuming effort, but also bears the risk of overlooking critical data. The present study introduces a novel approach for AOP network optimization of a previously published AOP network on chemical-induced cholestasis using artificial intelligence to facilitate automated data collection followed by subsequent quantitative confidence assessment of molecular initiating events, key events, and key event relationships. Methods: Artificial intelligence-assisted data collection was performed by means of the free web platform Sysrev. Confidence levels of the tailored Bradford-Hill criteria were quantified for the purpose of weight-of-evidence assessment of the optimized AOP network. Scores were calculated for biological plausibility, empirical evidence, and essentiality, and were integrated into a total key event relationship confidence value. The optimized AOP network was visualized using Cytoscape with the node size representing the incidence of the key event and the edge size indicating the total confidence in the key event relationship. Results: This resulted in the identification of 38 and 135 unique key events and key event relationships, respectively. Transporter changes was the key event with the highest incidence, and formed the most confident key event relationship with the adverse outcome, cholestasis. Other important key events present in the AOP network include: nuclear receptor changes, intracellular bile acid accumulation, bile acid synthesis changes, oxidative stress, inflammation and apoptosis. Conclusions: This process led to the creation of an extensively informative AOP network focused on chemical-induced cholestasis. This optimized AOP network may serve as a mechanistic compass for the development of a battery of in vitro assays to reliably predict chemical-induced cholestatic injury.
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Although systematic reviews are considered as central components in evidence-based practice, they currently face an important challenge to keep up with the exponential publication rate of clinical trials. After initial publication, only a minority of the systematic reviews are updated, and it often takes multiple years before these results become accessible. Consequently, many systematic reviews are not up to date, thereby increasing the time-gap between research findings and clinical practice. A potential solution is offered by a living systematic reviews approach. These types of studies are characterized by a workflow of continuous updates which decreases the time it takes to disseminate new findings. Although living systematic reviews are specifically designed to continuously synthesize new evidence in rapidly emerging topics, they have also considerable potential in slower developing domains, such as rehabilitation science. In this commentary, we outline the rationale and required steps to transition a regular systematic review into a living systematic review. We also propose a workflow that is designed for rehabilitation science.
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Summary: Xpaths is a collection of algorithms that allow for the prediction of compound-induced molecular mechanisms of action by integrating phenotypic endpoints of different species; and proposes follow-up tests for model organisms to validate these pathway predictions. The Xpaths algorithms are applied to predict developmental and reproductive toxicity (DART) and implemented into an in silico platform, called DARTpaths.
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The 'Media Battle' is a concept for a competitive one-week pressure-cooker contest, in which students develop a creative product for companies or other organisations. It brings together education, research and professional practice, with benefits for all parties involved. We guide participating organisations to develop a detailed problem description ensuring that descriptions are sufficiently clear and focused for students to work on during a week. Students spend the week developing their concept such that it can be pitched to their client organisation. Students are trained in pitching and are coached in developing creative concepts. Several groups have the same client. On the last day, clients select their favourite concept, while a jury selects a winner among the concepts of different clients. Most concepts are further developed in 'regular courses', while some concepts, usually the winning ones, are subject of further development in the curriculum. In this article we will describe our experiences with media battles and discuss critical success and failure factors.
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In the Netherlands, over 40% of nursing home residents are estimated to have visual impairments. This results in the loss of basic visual abilities. The nursing home environment fits more or less to residents’ activities and social participation. This is referred to as environmental fit. To raise professional awareness of environmental fit, an Environmental Observation tool for the Visually Impaired was developed. This tool targets aspects of the nursing home environment such as ‘light’, the use of ‘colours and contrasts’ and ‘furnishing and obstacles’. Objective of this study is to validate the content of the observation tool to have a tool applicable for practice. Based on the content validity approach, we invited a total of eight experts, six eye care professionals and two building engineering researchers, to judge the relevance of the items. The Item Content Validity approach was applied to determine items to retain and reject. The content validity approach led to a decrease in the number of items from 63 to 52. The definitive tool of 52 items contains 21 for Corridors, 17 for the Common Room, and 14 for the Bathroom. All items of the definite tool received an Item-Content Validity Index of 0.875 and a Scale-Content Validity Index of 0.71. The content validity index of the scale and per item has been applied, resulting in a tool that can be applied in nursing homes. The tool might be a starting point of a discussion among professional caregivers on environmental interventions for visually impaired older adults in nursing homes
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Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.
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Citizen participation in local renewable energy projects is often promoted as many suppose it to be a panacea for the difficulties that are involved in the energy transition process. Quite evidently, it is not; there is a wide variety of visions, ideologies and interests related to an ‘energy transition’. Such a variety is actually a precondition for a stakeholder participation process, as stakeholder participation only makes sense if there is ‘something at stake’. Conflicting viewpoints, interests and debates are the essence of participation. The success of stakeholder participation implies that these differences are acknowledged, and discussed, and that this has created mutual understanding among stakeholders. It does not necessarily create ‘acceptance’. Renewable energy projects often give rise to local conflict. The successful implementation of local renewable energy systems depends on the support of the local social fabric. While at one hand decisions to construct wind turbines in specific regions trigger local resistance, the opposite also occurs! Solar parks sometimes create a similar variation: Various communities try to prevent the construction of solar parks in their vicinity, while other communities proudly present their parks. Altogether, local renewable energy initiatives create a rather chaotic picture, if regarded from the perspective of government planning. However, if we regard the successes, it appears the top down initiatives are most successful in areas with a weak social fabric, like industrial areas, or rather recently reclaimed land. Deeply rooted communities, virtually only have successful renewable energy projects that are more or less bottom up initiatives. This paper will first sketch why participation is important, and present a categorisation of processes and procedures that could be applied. It also sketches a number of myths and paradoxes that might occur in participation processes. ‘Compensating’ individuals and/or communities to accept wind turbines or solar parks is not sufficient to gain ‘acceptance’. A basic feature of many debates on local renewable energy projects is about ‘fairness’. The implication is that decision-making is neither on pros and cons of various renewable energy technologies as such, nor on what citizens are obliged to accept, but on a fair distribution of costs and benefits. Such discussions on fairness cannot be short cut by referring to legal rules, scientific evidence, or to standard financial compensations. History plays a role as old feelings of being disadvantaged, both at individual and at group level, might re-emerge in such debates. The paper will provide an overview of various local controversies on renewable energy initiatives in the Netherlands. It will argue that an open citizen participation process can be organized to work towards fair decisions, and that citizens should not be addressed as greedy subjects, trying to optimise their own private interests, but as responsible persons.
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Report in English on the results of the international Master Class by Stadslab on intercultural park design. The case described is a design for for a park in Eastern Ukrainian city of Melitopol. A redevelopment strategy is proposed for its historic Gorky Park (1936). The book also contains essays by intercultural cities expert Phil Wood and introductions by Marc Glaudemans, Beatriz Ramo and Olexandr Butsenko.
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This article will discuss philosophical debates on economic growth and environmental sustainability, the role of management responsibility, and the risk of subversion to business as usual. This discussion will be framed using the concepts of Cradle to Cradle (C2C) and Circular Economy about sustainable production. The case study illustrating the danger of subversion of these progressive models discussed here is based on the assignments submitted by Masters students as part of a course related to sustainable production and consumption at Leiden University. The evaluation of the supposedly best practice cases placed on the website of the Ellen MacArthur Foundation or those awarded Cradle to Cradle certificate has led some students to conclude that these cases illustrated green-washing. Larger implications of identified cases of green-washing for the field of sustainable business and ecological management are discussed. “This is a post-peer-review, pre-copyedit version of an article published in 'Philosophy of Management'. The final authenticated version is available online at: https://doi.org/10.1007/s40926-019-00108-x LinkedIn: https://www.linkedin.com/in/helenkopnina/
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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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