Sustainability-focused research networks and communities of practice have emerged as a key response and strategy to build capacity and knowledge to support transformation towards more sustainable,... Show moreSustainability-focused research networks and communities of practice have emerged as a key response and strategy to build capacity and knowledge to support transformation towards more sustainable, just and equitable futures. This paper synthesises insights from the development of a community of practice on social-ecological systems (SES) research in southern Africa over the past decade, linked to the international Programme on Ecosystem Change and Society (PECS). This community consists of a network of researchers who carry out place-based SES research in the southern African region. They interact through various cross-cutting working groups and also host a variety of public colloquia and student and practitioner training events. Known as the Southern African Program on Ecosystem Change and Society (SAPECS), its core objectives are to: (1) derive new approaches and empirical insights on SES dynamics in the southern African context; (2) have a tangible impact by mainstreaming knowledge into policy and practice; and (3) grow the community of practice engaged in SES research and governance, including researchers, students and practitioners. This paper reflects on experiences in building the SAPECS community, with the aim of supporting the development of similar networks elsewhere in the world, particularly in the Global South. Show less
Sustainability-focused research networks and communities of practice have emerged as a key response and strategy to build capacity and knowledge to support transformation towards more sustainable,... Show moreSustainability-focused research networks and communities of practice have emerged as a key response and strategy to build capacity and knowledge to support transformation towards more sustainable, just and equitable futures. This paper synthesises insights from the development of a community of practice on social-ecological systems (SES) research in southern Africa over the past decade, linked to the international Programme on Ecosystem Change and Society (PECS). This community consists of a network of researchers who carry out place-based SES research in the southern African region. They interact through various cross-cutting working groups and also host a variety of public colloquia and student and practitioner training events. Known as the Southern African Program on Ecosystem Change and Society (SAPECS), its core objectives are to: (1) derive new approaches and empirical insights on SES dynamics in the southern African context; (2) have a tangible impact by mainstreaming knowledge into policy and practice; and (3) grow the community of practice engaged in SES research and governance, including researchers, students and practitioners. This paper reflects on experiences in building the SAPECS community, with the aim of supporting the development of similar networks elsewhere in the world, particularly in the Global South. Show less
Jong, L.M. de; Boussallami, S.; Sánchez-López, E.; Giera, M.; Tushuizen, M.E.; Hoekstra, M.; ... ; Manson, M.L. 2023
Introduction: Pharmacogenetics-informed drug prescribing is increasingly applied in clinical practice. Typically, drug metabolizing phenotypes are determined based on genetic test results,... Show moreIntroduction: Pharmacogenetics-informed drug prescribing is increasingly applied in clinical practice. Typically, drug metabolizing phenotypes are determined based on genetic test results, whereupon dosage or drugs are adjusted. Drug-drug-interactions (DDIs) caused by concomitant medication can however cause mismatches between predicted and observed phenotypes (phenoconversion). Here we investigated the impact of CYP2C19 genotype on the outcome of CYP2C19-dependent DDIs in human liver microsomes. Methods: Liver samples from 40 patients were included, and genotyped for CYP2C19*2, *3 and *17 variants. S-mephenytoin metabolism in microsomal fractions was used as proxy for CYP2C19 activity, and concordance between genotype-predicted and observed CYP2C19 phenotype was examined. Individual microsomes were subsequently co-exposed to fluvoxamine, voriconazole, omeprazole or pantoprazole to simulate DDIs. Results: Maximal CYP2C19 activity (Vmax) in genotype-predicted intermediate metabolizers (IMs; *1/*2 or *2/*17), rapid metabolizers (RMs; *1/*17) and ultrarapid metabolizers (UMs; *17/*17) was not different from Vmax of predicted normal metabolizers (NMs; *1/*1). Conversely, CYP2C19*2/*2 genotyped-donors exhibited Vmax rates ∼9% of NMs, confirming the genotype-predicted poor metabolizer (PM) phenotype. Categorizing CYP2C19 activity, we found a 40% concordance between genetically-predicted CYP2C19 phenotypes and measured phenotypes, indicating substantial phenoconversion. Eight patients (20%) exhibited CYP2C19 IM/PM phenotypes that were not predicted by their CYP2C19 genotype, of which six could be linked to the presence of diabetes or liver disease. In subsequent DDI experiments, CYP2C19 activity was inhibited by omeprazole (-37% ± 8%), voriconazole (-59% ± 4%) and fluvoxamine (-85% ± 2%), but not by pantoprazole (-2 ± 4%). The strength of CYP2C19 inhibitors remained unaffected by CYP2C19 genotype, as similar percental declines in CYP2C19 activity and comparable metabolism-dependent inhibitory constants (Kinact/KI) of omeprazole were observed between CYP2C19 genotypes. However, the consequences of CYP2C19 inhibitor-mediated phenoconversion were different between CYP2C19 genotypes. In example, voriconazole converted 50% of *1/*1 donors to a IM/PM phenotype, but only 14% of *1/*17 donors. Fluvoxamine converted all donors to phenotypic IMs/PMs, but *1/*17 (14%) were less likely to become PMs than *1/*1 (50%) or *1/*2 and *2/*17 (57%). Conclusion: This study suggests that the differential outcome of CYP2C19-mediated DDIs between genotypes are primarily dictated by basal CYP2C19 activity, that may in part be predicted by CYP2C19 genotype but likely also depends on disease-related factors. Show less
Audebert, M.; Assmann, A.S.; Azqueta, A.; Babica, P.; Benfenati, E.; Bortoli, S.; ... ; Oelgeschläger, M. 2023
Carcinogenic chemicals, or their metabolites, can be classified as genotoxic or non-genotoxic carcinogens (NGTxCs). Genotoxic compounds induce DNA damage, which can be detected by an established in... Show moreCarcinogenic chemicals, or their metabolites, can be classified as genotoxic or non-genotoxic carcinogens (NGTxCs). Genotoxic compounds induce DNA damage, which can be detected by an established in vitro and in vivo battery of genotoxicity assays. For NGTxCs, DNA is not the primary target, and the possible modes of action (MoA) of NGTxCs are much more diverse than those of genotoxic compounds, and there is no specific in vitro assay for detecting NGTxCs. Therefore, the evaluation of the carcinogenic potential is still dependent on long-term studies in rodents. This 2-year bioassay, mainly applied for testing agrochemicals and pharmaceuticals, is time-consuming, costly and requires very high numbers of animals. More importantly, its relevance for human risk assessment is questionable due to the limited predictivity for human cancer risk, especially with regard to NGTxCs. Thus, there is an urgent need for a transition to new approach methodologies (NAMs), integrating human-relevant in vitro assays and in silico tools that better exploit the current knowledge of the multiple processes involved in carcinogenesis into a modern safety assessment toolbox. Here, we describe an integrative project that aims to use a variety of novel approaches to detect the carcinogenic potential of NGTxCs based on different mechanisms and pathways involved in carcinogenesis. The aim of this project is to contribute suitable assays for the safety assessment toolbox for an efficient and improved, internationally recognized hazard assessment of NGTxCs, and ultimately to contribute to reliable mechanism-based next-generation risk assessment for chemical carcinogens. Show less
Nagy, N.A.; Lozano Vigario, F.; Sparrius, R.; Capel, T.M.M. van; Ree, R. van; Tas, S.W.; ... ; Jong, E.C. de 2023
Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for... Show moreImiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [-26.4%, -4.3%], p = 0.0111 and 95% CI [-7.96, -2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [-79.7%, -16.3%], p = 0.0165), NK and dendritic cells (95% CI [-68.7%, -5.2%], p = 0.0333, 95% CI [-76.9%, -13.9%], p = 0.0184), and classical monocytes (95% CI [-76.7%, -26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark. Show less
Jansen, A.J.G.; Mcdonald, V.; Newland, A.; Morgan, M.; Bastiaanse, M.; Wilson, K.; ... ; Zwaginga, J.J. 2023
Objective:Identify patient experience and preference towards thrombopoietin-receptor agonists (TPO-RAs) in treatment of immune thrombocytopenia (ITP) in the Netherlands.Methods:The Thrombopoietin... Show moreObjective:Identify patient experience and preference towards thrombopoietin-receptor agonists (TPO-RAs) in treatment of immune thrombocytopenia (ITP) in the Netherlands.Methods:The Thrombopoietin-Receptor Agonist Patient experience (TRAPeze) survey used a discrete choice experiment (DCE) to elicit patient preferences and a patient burden survey (PBS) to evaluate the clinical and social impact of ITP. TRAPeze collected responses from 6th October to 19th November 2021.Results:Seventy-six respondents completed the DCE: treatment preference appeared to be driven by method of administration (odds ratio [OR] 4.33; 95% confidence interval [CI] 2.88–6.52), frequency of dosing (OR 2.33; 95% CI 1.86–2.92) and drug–food interactions (OR 1.91; 95% CI 1.54–2.37). Respondents preferred therapies delivered orally over subcutaneous injection (OR 4.22; 95% CI 2.76–6.46), dosed once weekly over once daily (OR 2.37; 95% CI 1.58–3.54) and without food restrictions over with restrictions (OR 1.90; 95% CI 1.52–2.38). Sixty-nine respondents completed the DCE and PBS (mean [range] age 53 [19–83] years, 65% female). Seven incomplete PBS responses were excluded from analysis. Respondents were currently, or most recently, receiving eltrombopag (n = 43) or romiplostim (n = 26), of which 30% (n = 21/69) had previously received another TPO-RA. Loss (29%, n = 6/21) and lack (29%, n = 6/21) of response were the most common reasons for switching TPO-RA. Only 28% (n = 18/65) of respondents felt their TPO-RA increased energy levels.Conclusion:Patients preferred therapies delivered orally, dosed less frequently and without food restrictions. QoL of ITP patients on TPO-RAs can be improved; the burden analyses presented can inform future efforts towards this. Show less
Children with intellectual disabilities have consistently occupied a marginalisedposition within the digital landscape. While they might reap benefits from usingdigital products and services, they... Show moreChildren with intellectual disabilities have consistently occupied a marginalisedposition within the digital landscape. While they might reap benefits from usingdigital products and services, they are also particularly vulnerable to online risks dueto cognitive deficiencies and lower critical literacy skills. As a result, children withintellectual impairments frequently encounter various predicaments, encompassingonline sexual solicitation, exposure to inaccurate information and manipulativebehavioural designs, as well as various privacy and data protection concerns.Regarding these challenges, utilising data protection by design under Article 25(1)GDPR can play a pivotal role in dismantling certain barriers. This approach allowsdigital service providers to take children’s evolving capacities into account andimplement technical and organisational measures appropriate for their age anddevelopmental stage. The aim of this article is to explore what challenges childrenwith intellectual disabilities might confront in the digital environment and examinehow data protection by design can help prevent or mitigate these challenges.Specifically, the article proposes a series of potential measures as the following: (1)presenting information transparently and in a manner accessible to children withintellectual disabilities; (2) crafting an inclusive user interface that enables thesechildren to actively and autonomously engage with the digital environment; (3)integrating interactive assistive tools, such as AI bots, to offer guidance and support;and (4) introducing parental control mechanisms that allow parents to provideassistance in alignment with their children's needs and preferences. Show less
In lieu of an abstract:In 2018, three anonymous and hitherto unpublished, unexhibited drawings of Istanbul by the same hand, previously part of Dr. Müfid Ekdal’s collection, were donated to the... Show moreIn lieu of an abstract:In 2018, three anonymous and hitherto unpublished, unexhibited drawings of Istanbul by the same hand, previously part of Dr. Müfid Ekdal’s collection, were donated to the Suna and İnan Kıraç Foundation by his son Oral Ekdal, upon Dr. Ekdal’s passing. One of them, a 360-degree, threeand- a-half-meter-long panorama, inspired researchers and curators working at the Istanbul Research Institute and Pera Museum to work on an exhibition on the history of Istanbul panoramas. Four years after preparations began, On the Spot: Panoramic Gaze on Istanbul, a History, curated by Çiğdem Kafescioğlu, K. Mehmet Kentel, and M. Baha Tanman, opened on October 26, 2023, at the Pera Museum, and greets its visitors with the aforementioned panorama. While the exhibition and its accompanying catalog explore various facets of Istanbul’s panoramic imaginaries through the centuries and firmly locate Istanbul as a crucial spot within the global history of panoramas, this short piece aims to briefly introduce these three recent additions to the Suna and İnan Kıraç Foundation collections to the scholarly community. Show less
Alberts, N.; Blanken, M. den; Bruinen, R.; Dammers, D.; Dijk, A.-C. van; Geboers, L.; ... ; Timorason, A. 2023
Purpose The purpose of this study was to explore the lived experience of dancing with Parkinson's and Multiple Sclerosis in an inclusive dance group called ReDiscoverMe (RDM). Methods Participatory... Show morePurpose The purpose of this study was to explore the lived experience of dancing with Parkinson's and Multiple Sclerosis in an inclusive dance group called ReDiscoverMe (RDM). Methods Participatory research approaches and interpretative phenomenological analysis were used to make sense of the lived experience captured in interviews and observations. Arthur Frank's conceptual framework on embodied storytelling from his book The Wounded Storyteller was the study's theoretical lens. Themes are both described and represented in images made by an RDM participant. Findings Dancing in a nonjudgmental environment was described by participants as a way to rediscover themselves while continually adapting to living with chronic illness. We interpreted this experience of rediscovery as an active, recursive process involving three "movements": escaping, expanding, and embracing. Through these movements, participants could rise above the self and illness. Conclusions The lived experience of dancing in this group was characterized by transformations of the body, self, and life. Through escaping, expanding, and embracing, participants could more easily embrace the body's contingency, integrate the self and body by becoming dancers, connect with others living with illness, and produce desire through passion. Participants could therefore experience illness as a journey and gain something from the experience. Show less
