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Remarks on ghost resonances
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317579.pdf (Publisher’s version ) (Open Access
Model-informed development of a cost-saving dosing regimen for enfortumab vedotin.
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317333.pdf (Publisher’s version ) (Open Access)AIM: Enfortumab vedotin is an antibody-drug conjugate (ADC) that has been approved for locally advanced or metastatic urothelial cancer, as monotherapy and in combination with pembrolizumab, and has shown significant benefit in progression-free survival and overall survival for these patients. The economic burden of enfortumab vedotin hampers widespread patient access. The aim of this study was to develop a model-informed alternative dosing regimen that results in equivalent drug exposure while reducing the costs and prevent drug spillage. METHODS: Population pharmacokinetic modelling was used to simulate a dosing regimen leading to equivalent exposure by using the published population pharmacokinetic model in the registration reports. The alternative dosing regimen was based on weight-bands derived from the established non-linear relationship between body weight and systemic exposure, and the usage of whole vials based on fixed doses to prevent spillage. Equivalent exposure compared to the approved body weight-based dosing regimen was defined as conservative equivalent boundaries of 90-111% for the calculated geometric mean ratios (GMRs) of area under the concentration-time curve and trough concentration. RESULTS: A weight-band based dosing regimen for each dose level of enfortumab vedotin was developed. The GMRs for all pharmacokinetic outcomes were within the predefined equivalence boundaries. In addition, a more even exposure distribution was observed across the body weight quartiles. The average costs savings across all dose levels and per weight-band were approximately 15%. CONCLUSION: The proposed alternative dosing regimen shows that drug costs and spillage of enfortumab vedotin can be reduced while maintaining an equivalent and more evenly distributed exposure in treated patients
The Tree of Biologics. Branching out into the Future of Psoriasis Treatment
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316595.pdf (Publisher’s version ) (Open Access)Psoriasis is a chronic skin condition that can significantly impact a patient's quality of life. When biologics were developed as a treatment for psoriasis, there was already a solid foundation of other treatment options. Over the past 20 years, the "tree" of treatment options, including various biologics, has grown further. During this time, we’ve gained many insights, but some questions remain unanswered. For instance: What is the most effective biologic? And which biologic is best suited for which patient? Using data collected at Radboud university medical center and 23 other hospitals, we investigated these questions. Some key findings include that biologics from specific treatment classes achieved excellent results linked to their mechanisms of action. Additionally, we found that biologics were effective for both older adults and children. Lastly, the research methods we used offer directions for future studies.Radboud University, 06 maart 2025Promotor : Jong, E.M.G.J. de Co-promotores : Reek, J.M.P.A. van den, Seyger, M.M.B.274 p
De dynamiek van goed koopmansgebruik, de gevolgen van het omgaan van de Hoge Raad
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314842.pdf (Publisher’s version ) (Open Access)10 p
Comparing organ and effective dose of various CT localizer acquisition strategies: A Monte Carlo study.
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314981.pdf (Publisher’s version ) (Open Access)BACKGROUND: CT examinations commonly start with the acquisition of one or two localizer radiographs (2D localizers). Recently, a manufacturer introduced the option to perform a heavily filtrated low-dose helical scan as a localizer acquisition. To compare the dose of one or two 2D localizer acquisitions to the dose of a 3D localizer acquisition, one cannot simply compare the CTDIs of the different acquisition techniques, because of the use of different geometries and spectra. PURPOSE: To compare the organ and effective dose for various CT localizer acquisition techniques. METHODS: A Geant4-based Monte Carlo simulation, replicating a clinical wide-area CT scanner was developed and validated. Various localizer acquisition strategies were simulated: Anterior-posterior (AP) alone, PA alone, combined AP+lateral (LAT), and PA+LAT 2D localizers, and an Ag-filtered 3D localizer acquisition. Validation was performed by measuring and simulating CTDI(100) in both the periphery and the center of a CTDI phantom. The software was subsequently used to estimate organ and effective doses for localizers for chest, abdomen + pelvis, and the combined chest, abdomen, and pelvis exams. As representations of patients, eight ICRP computational phantoms (adult, 15-, 10-, and 5-year, both male and female) and five female and five male XCAT phantoms with various BMIs were used. The dose of the various strategies was compared to the current clinically-implemented AP+LAT localizers. RESULTS: CTDI(100)-measurements and simulations within the CTDI-phantom differs by a maximum of 8.1% and by an average of 0.9%. For chest, the average effective doses for AP, PA, AP+LAT, and the 3D localizer are 0.10, 0.07, 0.32, and 0.22 mSv, respectively. The organ dose to the breast varies the most across the various localizer strategies and is, on average, 0.17, 0.03, 0.44, and 0.33 mGy, in the same order. For abdomen, the average effective doses are 0.11, 0.07, 0.36, and 0.25 mSv for the AP, PA, AP+LAT and the 3D localizer, respectively. The organ dose to the stomach varies the most across the various localizers and is on average 0.14, 0.08, 0.58, and 0.30 mGy, in the same order. The PA-only localizer results in the lowest organ dose to the most radiosensitive organs and the lowest effective dose. For the chest exam, compared to AP+LAT, the PA+LAT results in a 7 ± 2% effective dose reduction (mean ± standard deviation), while the 3D localizer results in a 21 ± 3% effective dose reduction. Using AP or PA only would result in 69 ± 2% and 76 ± 2% reduction, respectively. For the abdomen exam, also compared to AP+LAT, PA+LAT results in 6 ± 2% effective dose reduction, while the 3D localizer results in a 20 ± 5% reduction. Using AP or PA only would result in 69 ± 5% and 76 ± 4% reduction, respectively. CONCLUSIONS: Using a PA localizer results in a lower or equivalent organ dose in the most radiosensitive organs, and a lower effective dose compared to an AP localizer for both chest and abdomen+pelvis exams. Compared to a two-localizer strategy, the 3D localizer results in a lower effective dose in both the chest and abdomen+pelvis region.01 januari 202
Graph neural networks for assessing the reliability of the medium-voltage grid☆
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317068.pdf (Publisher’s version ) (Open Access
Targeting oxidative stress-induced lipid peroxidation enhances podocyte function in cystinosis.
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317490.pdf (Publisher’s version ) (Open Access)BACKGROUND: Cystinosis is a rare, incurable lysosomal storage disease caused by mutations in the CTNS gene encoding the cystine transporter cystinosin, which leads to lysosomal cystine accumulation in all cells of the body. Patients with cystinosis display signs of podocyte damage characterized by extensive loss of podocytes into the urine at early disease stages, glomerular proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) lesions. Although standard treatment with cysteamine decreases cellular cystine levels, it neither reverses glomerular injury nor prevents the loss of podocytes. Thus, pathogenic mechanisms other than cystine accumulation are involved in podocyte dysfunction in cystinosis. METHODS: We used immortalized patient-derived cystinosis, healthy, and CTNS knockdown podocytes to investigate podocyte dysfunction in cystinosis. The results were validated in our newly in-house developed fluorescent ctns(-/-)[Tg(fabp10a:gc-EGFP)] zebrafish larvae model. To understand impaired podocyte functionality, static and dynamic permeability assays, tracer-metabolomic analysis, flow cytometry, western blot, and chemical and dynamic redox-sensing fluorescent probes were used. RESULTS: In the current study, we discovered that cystinosis podocytes demonstrate increased ferroptotic cell death caused by mitochondrial reactive oxygen species (ROS)-driven membrane lipid peroxidation. Moreover, cystinosis cells present a fragmented mitochondrial network with impaired tricarboxylic acid cycle (TCA) cycle and energy metabolism. Targeting mitochondrial ROS and lipid peroxidation improved podocyte function in vitro and rescued proteinuria in vivo in cystinosis zebrafish larvae. CONCLUSIONS: Mitochondrial ROS contribute to podocyte injury in cystinosis by driving lipid peroxidation and ferroptosis, which in turn lead to podocyte detachment. This finding adds cystinosis to the list of podocytopathies associated with mitochondrial dysfunction. The identified mechanisms reveal new therapeutic targets and highlight lipid peroxidation as an exploitable vulnerability of cystinosis podocytes
Predicting reading comprehension in Creole Papiamento and Dutch in a post-colonial context
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317116.pdf (Publisher’s version ) (Open Access)In postcolonial contexts, children usually learn to read in a language other than their main socialization language, usually a creole. To understand how this affects reading acquisition we examined the early Creole Papiamento (L1) and Dutch (L2) reading skills of 128 Caribbean children. We investigated the impact of instructional order, first Papiamento then Dutch (Papiamento-first group), and vice versa (Dutch-first group), and cognitive and linguistic predictors on grade 2 reading comprehension. The study also explored linguistic interdependence. Results showed a significant positive effect of instructional order on Dutch reading comprehension for the Dutch-first group, but no differences between groups on Papiamento reading comprehension. Both linguistic and cognitive precursors predicted reading comprehension in Papiamento and Dutch. We found that reading comprehension in Papiamento and Dutch is interdependent, influenced by instruction language, especially in the Dutch-first group. This underlines the crucial role of L1 in shaping reading comprehension in both L1 and L2.24 februari 202534 p
A voice-enabled intelligent virtual agent for people with memory impairments: Thematic analysis of focus group results
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315748.pdf (Author’s version preprint ) (Open Access)8th International Workshop, CONVERSATIONS 2024 (Thessaloniki, Greece, December 4-5, 2024
Quality of life of women with a screen-detected versus clinically detected breast cancer in the Netherlands: a prospective cohort study.
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317478.pdf (Publisher’s version ) (Open Access)PURPOSE: Breast cancer (BC) screening enables early detection of BC, which may lead to improved quality of life (QoL). We aim to compare QoL between women with a screen-detected and clinically detected BC in the Netherlands. METHODS: We used data from the 'Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation' (UMBRELLA) between October 2013 and March 2022. Patients were categorized as screen-detected or clinically detected. We analysed three questionnaires, namely EORTC QLQ C-30, BR23, and HADS (Hospital Anxiety and Depression Scale) completed by BC patients shortly after diagnosis (T1) and one-year after treatment (T2). Independent t-tests were performed to compare QoL average differences between the two groups. Bonferroni-corrected p-value significance threshold of 0.00057 was used. The magnitude of differences was calculated using Cohen's d. The clinical relevance of QLQ-C30 differences was assessed based on interpretation guideline of EORTC-QLQ-C30 results. RESULTS: After applying inclusion and exclusion criteria, there were 691 women with screen-detected BC and 480 with clinically detected BC. Generally, screen-detected BC patients reported a better QoL. At T1, their average QLQ-C30 summary score was higher (86.1) than clinically detected BC patients (83.0) (p < 0.0001). Cohen's d for all items ranged between 0.00 and 0.39. A few QLQ-C30 score differences were clinically relevant, indicating better outcomes in emotional functioning, general health, constipation, and fatigue for women with screen-detected BC. CONCLUSIONS: In the Netherlands, women with screen-detected BC reported statistically significant and better QoL than women with clinically detected BC. However, clinical relevance of the differences is limited.01 januari 202