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Dissolved Mn(III) is a key redox intermediate in sediments of a seasonally euxinic coastal basin
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316725.pdf (Publisher’s version ) (Open Access
X-Linked autism type 9 caused by a hemizygote pathogenic variant in the TMLHE gene: Etiological diagnosis in an adult male with moderate intellectual disability
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315532.pdf (Publisher’s version ) (Open Access)INTRODUCTION: Levocarnitine is essential for brain functioning and fatty acid metabolism and stems largely from dietary sources. The Epsilon-Trimethyllysine Hydroxylase (TMLHE) gene encodes the enzyme N-Trimethyllysine hydroxylase (TMLH) which catalyses the first step in the biosynthesis of carnitine. Lack of TMLH enzyme activity is associated with developmental delay and autistic behaviours described as X-linked recessive autism, type 6 (OMIM#300872). PATIENT AND METHODS: Here, an institutionalized adult male patient with intellectual disability, autism, and challenging behaviours is presented in whom genetic analysis disclosed a novel pathogenic variant in the TMLHE gene. Extensive somatic, neurological, psychiatric, and neuropsychological investigations were performed next to examination of hematological and biochemical parameters including plasma carnitine status. Also, Whole Exome Sequencing (WES) and Next-Generation Metabolic Screening (NGMS) were performed. RESULTS: Moderate intellectual disability along with obsessive and aggressive behaviour in the context of autism spectrum disorders was established as well as symptoms from the catatonic spectrum. With WES, a novel variant in the TMHLE gene was identified and using NGMS, increased concentration of trimethyllysine and decreased concentration of γ-butyrobetaine were found resulting in a significantly decreased BB/TML ratio, confirming the pathogenicity of this variant. CONCLUSION: X-linked autism type 6 is characterized by moderate intellectual disability and symptoms from the autism spectrum in the absence of any dysmorphisms. To prevent regressive autistic episodes in young children, it is highly recommended to consider next-generation sequencing techniques as the first step in the differential diagnostic process of autism.6 p
Classification of Fibro-Osseous Tumors in the Craniofacial Bones Using DNA Methylation and Copy Number Alterations
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317566.pdf (Publisher’s version ) (Open Access)11 p
Endothelial-Ercc1 DNA repair deficiency provokes blood-brain barrier dysfunction.
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315833.pdf (Publisher’s version ) (Open Access)Aging of the brain vasculature plays a key role in the development of neurovascular and neurodegenerative diseases, thereby contributing to cognitive impairment. Among other factors, DNA damage strongly promotes cellular aging, however, the role of genomic instability in brain endothelial cells (EC) and its potential effect on brain homeostasis is still largely unclear. We here investigated how endothelial aging impacts blood-brain barrier (BBB) function by using excision repair cross complementation group 1 (ERCC1)-deficient human brain ECs and an EC-specific Ercc1 knock out (EC-KO) mouse model. In vitro, ERCC1-deficient brain ECs displayed increased senescence-associated secretory phenotype expression, reduced BBB integrity, and higher sprouting capacities due to an underlying dysregulation of the Dll4-Notch pathway. In line, EC-KO mice showed more P21(+) cells, augmented expression of angiogenic markers, and a concomitant increase in the number of brain ECs and pericytes. Moreover, EC-KO mice displayed BBB leakage and enhanced cell adhesion molecule expression accompanied by peripheral immune cell infiltration into the brain. These findings were confined to the white matter, suggesting a regional susceptibility. Collectively, our results underline the role of endothelial aging as a driver of impaired BBB function, endothelial sprouting, and increased immune cell migration into the brain, thereby contributing to impaired brain homeostasis as observed during the aging process
Characterization of nonlinear stress relaxation of the femoral and tibial trabecular bone for computational modeling.
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318179.pdf (Publisher’s version ) (Open Access)Computational models of orthopedic reconstructions are reliant on bone material properties, but viscoelastic behavior of trabecular bone is often ignored in numerical simulations. The inclusion of stress relaxation could be of importance for the accuracy of models simulating the primary stability of cementless implants. In this study, a material model to describe the nonlinear viscoelastic behavior of human trabecular bone was constructed based on uniaxial stress relaxation experiments. The relationship of bone mineral density (BMD) and stress relaxation was explored, and the material model was implemented in sample-specific finite element (FE) simulations. Cylindrical trabecular human bone specimens, from the distal femur and proximal tibia, were subjected to stress relaxation tests, undergoing compression with strains from 0.2 % to 0.8 % for 30 min on four consecutive days. The experimental data were extrapolated to 24 h. Similar levels of stress relaxation were found for femoral and tibial specimens, with an average 54.4 % stress relaxation and a maximum level of 81.6 %. Using a modified superposition model, the specimen-specific nonlinear stress relaxation behavior was captured. However, when the samples were considered collectively, no correlation was found between applied strain, BMD and the viscoelastic response. Therefore, the average level of stress relaxation in combination with existing BMD-stiffness relationships were implemented in FE simulations for each individual specimen. While the FE models, on average, overestimated the overall stiffness by 64 %, they were able to adequately capture the stress relaxation response.01 april 202
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