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Regulation of the innate immune phenotype in atherosclerosis: navigating the inflammatory landscape
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313563.pdf (Publisher’s version ) (Open Access)Radboud University, 30 januari 2025Promotores : Riksen, N.P., Joosten, L.A.B. Co-promotor : Bekkering, S.236 p
mHealth Intervention for Dementia Prevention through lifestyle Optimisation (MIND-PRO) in a primary care setting: protocol for a randomised controlled trial in people with low SES and/or migration background.
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316994.pdf (Publisher’s version ) (Open Access)INTRODUCTION: The Mobile Health (mHealth) Intervention for Dementia Prevention through lifestyle Optimisation (MIND-PRO) study addresses the increasing prevalence of dementia among populations with lower socio-economic status (SES) and/or a migration background. The study aims to evaluate the effectiveness and implementation of an mHealth intervention designed for self-managing lifestyle modifications with remote coaching to reduce dementia risk factors. METHODS AND ANALYSIS: This prospective randomised open-label blinded end point (PROBE) trial follows a type 2 hybrid effectiveness-implementation design with a 12-month intervention period. It aims to recruit 692 participants in Dutch primary care. Entry criteria include age 50-75 years, low SES and/or migration background, one or more dementia risk factors (hypertension, dyslipidaemia, diabetes mellitus, physical inactivity, smoking, depression and overweight) or manifest cardiovascular disease and possession of a smartphone. Participants are randomised to a coach-supported, interactive app facilitating self-management of dementia risk factors or to a control app with static health information. The primary effectiveness outcome is a composite score of systolic blood pressure, non-high-density lipoprotein cholesterol and body mass index. Implementation outcomes include coverage, adoption, acceptability, appropriateness, feasibility, fidelity, costs and sustainability of the intervention. Secondary outcomes include the Cardiovascular Risk Factors, Ageing and Dementia risk score and its individual risk factors, and disability, physical activity, depressive symptoms, cognitive functioning and daily distance moved. ETHICS AND DISSEMINATION: The MIND-PRO trial is funded by the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10510032120004) and approved by the Ethics Committee of Amsterdam UMC (reference: METC 2023.0770). Results are expected in 2026 and will be submitted for publication in a peer-reviewed journal, and presented at scientific conferences. TRIAL REGISTRATION NUMBER: ISRCTN92928122
Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.
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315974.pdf (Publisher’s version ) (Open Access)AIMS: Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. METHODS: This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10(-8) was considered significant and a P-value between 5 × 10(-8) and 5 × 10(-6) was considered suggestive. RESULTS: Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10(-19)). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10(-6)). CONCLUSIONS: While rs6923761 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. [Corrections made on 23 September 2024, after first online publication: In the preceding sentence, identifier rs6923671 has been changed to rs6923761 in this version.] We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.01 februari 202
Faraday moments of the Southern Twenty-centimeter All-sky Polarization Survey (STAPS)
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317941.pdf (Publisher’s version ) (Open Access)15 p
ProRail als privaatrechtelijk ZBO: Reflecties op een wetsvoorstel
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315498.pdf (Author’s version preprint ) (Open Access)Tweede Kamer: Ronde Tafel ProRail, 23 januari 202
Development and validation of a machine learning-based, point-of-care risk calculator for post-ERCP pancreatitis and prophylaxis selection.
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315829.pdf (Publisher’s version ) (Closed access)BACKGROUND AND AIMS: A robust model of post-ERCP pancreatitis (PEP) risk is not currently available. We aimed to develop a machine learning-based tool for PEP risk prediction to aid in clinical decision making related to periprocedural prophylaxis selection and postprocedural monitoring. METHODS: Feature selection, model training, and validation were performed using patient-level data from 12 randomized controlled trials. A gradient-boosted machine (GBM) model was trained to estimate PEP risk, and the performance of the resulting model was evaluated using the area under the receiver operating curve (AUC) with 5-fold cross-validation. A web-based clinical decision-making tool was created, and a prospective pilot study was performed using data from ERCPs performed at the Johns Hopkins Hospital over a 1-month period. RESULTS: A total of 7389 patients were included in the GBM with an 8.6% rate of PEP. The model was trained on 20 PEP risk factors and 5 prophylactic interventions (rectal nonsteroidal anti-inflammatory drugs [NSAIDs], aggressive hydration, combined rectal NSAIDs and aggressive hydration, pancreatic duct stenting, and combined rectal NSAIDs and pancreatic duct stenting). The resulting GBM model had an AUC of 0.70 (65% specificity, 65% sensitivity, 95% negative predictive value, and 15% positive predictive value). A total of 135 patients were included in the prospective pilot study, resulting in an AUC of 0.74. CONCLUSIONS: This study demonstrates the feasibility and utility of a novel machine learning-based PEP risk estimation tool with high negative predictive value to aid in prophylaxis selection and identify patients at low risk who may not require extended postprocedure monitoring.01 januari 202
Direct oral anticoagulants versus vitamin K antagonists for cerebral venous thrombosis (DOAC-CVT): an international, prospective, observational cohort study.
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316813.pdf (Publisher’s version ) (Open Access)BACKGROUND: There is an unmet need for high-quality data from prospective studies on the safety and effectiveness of direct oral anticoagulants (DOACs) for the treatment of cerebral venous thrombosis (CVT). We aimed to compare the safety and effectiveness of DOACs versus vitamin K antagonists (VKAs) for the treatment of CVT in a setting that reflects daily clinical practice. METHODS: DOAC-CVT was an international, prospective, observational cohort study done in 65 hospitals in 23 countries across five continents. Eligible patients were adults (aged ≥18 years) with radiologically confirmed CVT starting oral anticoagulant treatment with either DOACs or VKAs, as per local practice, within 30 days after diagnosis. Exclusion criteria were previous use of anticoagulants at the time of CVT diagnosis or an absolute contraindication to DOACs (eg, pregnancy and lactation, or severe renal or liver disease). Data were collected during routine clinical visits or telephone consultations at CVT diagnosis (baseline) and at 3 months, 6 months, and 12 months after CVT diagnosis. The primary endpoint was a composite of symptomatic venous thromboembolism and major bleeding events (International Society on Thrombosis and Haemostasis criteria) at 6 months. Main outcomes were adjusted for the confounders age, renal function, active cancer, CNS infections, concomitant antiplatelet use, country of inclusion's income status, Glasgow Coma Scale score, intracranial haemorrhage, antiphospholipid antibodies, previous major bleeding, and previous venous thromboembolism using inverse probability-of-treatment weighting. This study is registered at ClinicalTrials.gov (NCT04660747) and is ongoing. FINDINGS: Between Jan 27, 2021, and Jan 15, 2024, 619 patients were included; 401 (65%) patients started DOAC treatment, and 218 (35%) patients started VKA treatment. 390 (63%) of 619 patients were female and 229 (37%) of 619 patients were male. Patients' median age was 41 years (IQR 28-51). 6-month follow-up data were available for 617 (>99%) of 619 patients. 12 (3%) of 401 patients in the DOAC group and seven (3%) of 218 patients in the VKA group had a primary outcome event (weighted odds ratio [OR] 0·99 [95% CI 0·37-3·38]). Three (1%) of 401 patients in the DOAC group died versus three (1%) of 218 patients in the VKA group (weighted OR 0·55 [95% CI 0·11-2·80]). INTERPRETATION: The rate of recurrent thrombosis and major bleeding did not differ between patients with CVT treated with DOACs versus VKAs. This study adds to the increasing evidence that DOACs are a reasonable treatment option for CVT alongside VKAs. FUNDING: Netherlands Thrombosis Foundation
Towards a sustainable future for plastics: A global material flow and life cycle assessment perspective
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310290.pdf (Publisher’s version ) (Open Access)
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310290 supplementary data.pdf (Publisher’s version ) (Open Access)Plastics are versatile, lightweight, inexpensive, and robust. Because of these properties, they are produced in large quantities and used in all industrial sectors. Despite their positive properties, the use of plastics is also sometimes associated with negative environmental impacts, such as climate change and pollution. Methods for quantifying these negative impacts include spatial pollution modelling, measurements, material flow analysis (MFA), and life cycle assessment (LCA). The advantages of plastics underline the importance of finding good solutions for the negative impacts of their use. First, the negative environmental impacts must be addressed in a comprehensive manner. This requires developing methods (MFA and LCA) for sources of plastic pollution and their impact on a global scale. Second, when applying these methods, the effectiveness of solutions to climate change and pollution must be assessed. This PhD thesis aims to contribute to the assessment of the environmental impact of plastics. This will support decisions for a sustainable future for plastics, where ‘sustainable’ means minimising negative environmental impact from both climate change and pollution.Radboud University, 13 januari 2025Promotor : Huijbregts, M.A.J. Co-promotor : Emmerik, T.H.M. va
Absolute membrane protein abundance of P-glycoprotein, breast cancer resistance protein, and multidrug resistance proteins in term human placenta tissue and commonly used cell systems: Application in physiologically based pharmacokinetic modeling of placental drug disposition.
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315908.pdf (Publisher’s version ) (Open Access)The placenta acts as a barrier, excluding noxious substances while actively transferring nutrients to the fetus, mediated by various transporters. This study quantified the expression of key placental transporters in term human placenta (n = 5) and BeWo, BeWo b30, and JEG-3 placenta cell lines. Combining these results with pregnancy physiologically based pharmacokinetic (PBPK) modeling, we demonstrate the utility of proteomic analysis for predicting placental drug disposition and fetal exposure. Using targeted proteomics with quantification concatemer standards, we found significant expression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, MRP4, and MRP6 in the human placenta (0.05-0.25 pmol/mg membrane protein) with only regional differences observed for P-gp. Unexpectedly, both P-gp and BCRP were below the limit of quantification in the regularly used BeWo cells, indicating that this cell line may not be suitable for the study of placental P-gp and BCRP-mediated transport. In cellular and vesicular overexpression systems, P-gp and BCRP were detectable as expected. Vesicle batches showed consistent P-gp expression correlating with functional activity (N-methyl-quinidine transport). However, BCRP activity (estrone 3-sulfate transport) did not consistently align with expression levels. Incorporating in vitro transporter kinetic data, along with placental transporter abundance, into a PBPK model enabled the evaluation of fetal exposure. Simulation with a hypothetical drug indicated that estimating fetal exposure relies on the intrinsic clearances of relevant transporters. To minimize interlaboratory discrepancies, expression data was generated using consistent proteomic methodologies in the same lab. Integration of this data in pregnancy PBPK modeling offers a promising tool to investigate maternal, placental, and fetal drug exposure. SIGNIFICANCE STATEMENT: This study quantified the expression of key placental transporters in human placenta and various placental cell lines, revealing significant expression variations. By integrating these data with physiologically based pharmacokinetic modeling, the study highlights the importance of transporter abundance data in understanding and predicting placental drug disposition, essential for maternal and fetal health during pregnancy.01 januari 202