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The effect of sleep disturbances on the incidence of dementia for varying lag times.
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317645.pdf (Publisher’s version ) (Open Access)BACKGROUND: Few studies have addressed the association of sleep disturbances with incident dementia with long lag times. We add to this literature by investigating how lag times varying from 2.2 to 23.8 years affect the relationship between sleep disturbance and incident dementia in a Dutch cohort study on aging. METHODS: Using eight waves of data from the Longitudinal Aging Study Amsterdam, we investigated the association of hours of sleep, difficulty falling asleep, interrupted sleep, and waking up early with incident dementia. For dementia an algorithm was used based on repeated measurements of cognitive tests and other data sources that provide strong indications of dementia. Sleep disturbances were assessed with a self-report questionnaire. RESULTS: Of 2,218 participants, 237 (11%) developed dementia in the period 1992/3 to 2015/6. Participants ≥70 years more often reported sleep disturbances compared to those <70. Only for a short lag time (3 years), sleeping ≥9 h was associated with incident dementia. Sleeping ≤6 h, interrupted sleep and waking up early were associated with incident dementia, particularly for lag times ≥15 years. DISCUSSION: We found that the association of sleep disturbances with incident dementia becomes stronger with longer lag times (particularly ≥15 years). Studies with lag times <15 years may suffer from reverse causation due to the changes in sleep patterns caused by the prodromal phase of neurodegenerative disease. The association of sleeping ≥9 h and the incidence of dementia in analyses with a short lag time seem to be the result of reverse causation.01 februari 202
Changes in participatory and societal outcomes during the waiting period for cochlear implantation - an observational study.
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316388.pdf (Publisher’s version ) (Open Access)INTRODUCTION: Various factors, including an aging population and expanding eligibility criteria, may increase the demand for cochlear implants (CIs), potentially resulting in longer waiting times. In most Dutch CI centers, the time between referral and surgery exceeds 6 months. Clinical experience suggests that during the waiting period for cochlear implantation, hearing and communication difficulties increase. Simultaneously, there is an interest in outcomes more closely aligned with patient values and needs, which resulted in the SMILE (Societal Merit of Interventions on hearing Loss Evaluation) study. This paper presents results on observed changes in societal and participatory outcomes during waiting time in participants with a time to CI surgery exceeding 6 months. METHODS: SMILE is a prospective multi-center study including 232 individuals who were referred for unilateral CI. Continuous and nominal data from multiple questionnaires, sent immediately after referral and shortly before surgery, were analyzed by computing differences, Cohen's D, and odds ratios. RESULTS: Of the total 232 participants, 102 had a time between inclusion and surgery exceeding 6 months. Of these, 89 had (partially) filled out surveys at both time points. Of all the domain scores 55% did not show differences between timepoints. All Cohen's D estimates were relatively small, ranging from - 0.298 to 0.388 for those outcomes that showed noteworthy changes. CONCLUSION: Waiting time from referral to surgery, even though exceeding 6 months, was observed to not seriously affect non-clinically-prioritized patients in an adverse way. Future investigations should identify subgroups on tolerable waiting times regarding short- and long-term outcomes. TRIAL REGISTRATION: Trial registration number at ClinicalTrials.gov: NCT05525221, 25-8-2022.01 februari 202
MIP4IBD: An Easy and Rapid Genotyping-by-Sequencing Assay for the Inflammatory Bowel Diseases Risk Loci.
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317352.pdf (Publisher’s version ) (Open Access)BACKGROUND: Inflammatory bowel diseases (IBD) are polygenic, with many genetic variants contributing to disease risk. Knowing the genotype of specific variants or calculating a combined genetic risk score benefits translational and functional research. To address this, we developed MIP4IBD, a flexible and cost-effective genotyping-by-sequencing assay using molecular inversion probes (MIPs). METHODS: The assay targets 463 IBD risk variants, and 77 additional relevant variants. Molecular inversion probes capture and library preparation were optimized using 15 IBD DNA samples, comparing genotypes with immunochip. A custom GitHub pipeline was created for data processing, performance testing, and genotype calling. The final design was validated on a larger scale (149 IBD patients, 104 non-IBD controls, and 3 external cell lines), incorporating post hoc quality control criteria. RESULTS: The assay achieved a 3.5-day turnaround time at €15 per sample with optimal sample throughput, demonstrating a 92.6% success rate in variant capture and genotype concordance rates of 99.3% and 99.6% with Infinium Global Screening Array24 BeadChip and WGS, respectively. A downstream application involved the calculation of a weighted IBD polygenic risk score (PRS), which was significantly higher in IBD patients than controls (mean 0.42 vs -0.49, P = 1.95E-11). Individuals in the highest PRS quartile had a 15.7-fold (95% CI: 6.5-38.3) risk of developing IBD and an earlier age of onset (26 vs 37 years, P = 0.02), compared to the lowest quartile. CONCLUSIONS: MIP4IBD is a validated, scalable genotyping assay targeting IBD risk loci, with an integrated bioinformatics pipeline from sequencing data to genotypes and PRS calculation. Its cost-effectiveness and flexibility for additional variants make it particularly appealing for translational and clinical applications
PARP inhibition preserves cone photoreceptors in rd2 retina.
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318184.pdf (Publisher’s version ) (Open Access)The rd2 mouse model, characterized by a mutation in the Prph2 gene, exhibits abnormal development of photoreceptor outer segments, resulting in progressive retinal degeneration. While the correlation between poly-ADP-ribose polymerase (PARP) activity and the degeneration of rod photoreceptors is established in the rd2 model, the specific mechanism driving cone degeneration in this model remains unclear. Furthermore, it is yet to be determined whether inhibiting PARP activity can effectively impede the degeneration of cone photoreceptors in this context. We demonstrated that PARP inhibitors Olaparib, BMN-673, and 3-aminobenzamide (3AB), effectively reduced photoreceptor cell loss in the rd2 retina. Notably, rd2 retinas exhibited decreased cone density, but treatment with PARP inhibitors significantly protected cone photoreceptors. The PARP inhibitors, particularly BMN-673, demonstrated a significant protective effect as evidenced by increased rhodopsin expression within the outer segment and a concurrent decrease in Müller cell activity indicated by GFAP expression. The treatment also resulted in significant changes for markers of oxidative stress, such as glutathione (GSH), and oxidized glutathione (GSSG). Notably, the administration of PARP inhibitors also reduced CD9 expression (extracellular vesicle marker), which were significantly increased within the outer nuclear layer (ONL) in the rd2 retinas. Among PARP inhibitors, BMN-673 demonstrated the highest efficacy in preserving photoreceptors, particularly benefiting cone cells
Guiding Automated Theorem Proving with Machine Learning
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317236.pdf (Publisher’s version ) (Open Access)Mathematics can be formalised so that computers can perform proof steps and recognise when a theorem has been proved. Computer systems that automate mathematics are called automated theorem provers (ATPs). ATPs have rules for valid inference, which prescribe how axioms and statements may be treated when searching for a proof. The number of possible choices at any point in the process can become very large, making it difficult to navigate the search towards a proof. It would be useful to have a system that could predict which choices are better than others, so that a proof can be found earlier in the search process.
In this PhD thesis, ATPs are combined with machine learning, a technique that learns patterns in data. The machine learning component learns to predict which choices in the proof search process are useful and which are not. This information can be learned from established proofs. The overall goal is to improve the power of ATP systems, reflected in the number of theorems that can be proven in a given period of time. The findings demonstrate that systems based on instantiation and rewriting can be controlled with machine learning and that their performance can be improved on specific datasets.Radboud University, 11 maart 2025Promotor : Heskes, T.M. Co-promotores : Janota, M., Urban, Josefx, 145 p
The Effect of Lifestyle on the Quality of Life of Vulvar Cancer Survivors.
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318045.pdf (Publisher’s version ) (Open Access)Introduction: Vulvar cancer affects approximately 47,000 women annually worldwide. With most studies focusing on oncological outcomes, quality of life is often overlooked. There is a lack of knowledge on the influence of modifiable factors such as lifestyle on the quality of life of vulvar cancer survivors. This study evaluated the association between lifestyle factors and the quality of life of vulvar cancer survivors. Methods: This was a cross-sectional survey study of women who received surgical treatment for vulvar cancer ≥FIGO stage 1B at the Northern Gynecological Oncology Centre, UK, between 2013 and 2022. Baseline and clinical characteristics were collected from patient records. Godin Leisure-Time Exercise questionnaires were used to assess physical activity. BMI was assessed using self-reported height and weight. Quality of life was measured using the validated European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and the vulvar cancer-specific module (VU-34). An analysis was performed using Mann-Whitney-U and Kruskal-Wallis tests. Results: Of the 299 women, 139 were eligible for participation, of whom 58 participated (41.7%). Twenty participants had a sedentary (40.8%), eight a moderately active (16.3%), and seventeen an active (34.7%) lifestyle. Active participants reported higher overall quality of life and higher functioning in all domains but not for vulvar-related symptoms or sexual functioning. Forty-nine participants disclosed their BMI, which was not associated with quality of life outcomes. Conclusions: A higher level of physical activity was associated with higher quality of life. No association was found between BMI and quality of life
Insights from Univalent Foundations: A Case Study Using Double Categories
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317293.pdf (Publisher’s version ) (Open Access)CLS 202
Are contemporary antifungal doses sufficient for critically ill patients? Outcomes from an international, multicenter pharmacokinetics study for Screening Antifungal Exposure in Intensive Care Units-the SAFE-ICU study.
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317619.pdf (Publisher’s version ) (Closed access)PURPOSE: Appropriate antifungal therapy is a major determinant of survival in critically ill patients with invasive fungal disease. We sought to describe whether contemporary dosing of antifungals achieves therapeutic exposures in critically ill patients. METHODS: In a prospective, open-label, multicenter pharmacokinetic study, intensive care unit (ICU) patients prescribed azoles, echinocandins, or polyene antifungals for treatment or prophylaxis of invasive fungal disease were enrolled. Blood samples were collected on two occasions, with three samples taken during a single dosing interval on each occasion. Total concentrations were centrally measured using validated chromatographic methods. Pharmacokinetic parameters were estimated using noncompartmental methods. Antifungal dosing adequacy was assessed using predefined PK/PD targets. RESULTS: We included 339 patients from 30 ICUs across 12 countries. Median age 62 (interquartile range [IQR], 51-70) years, median APACHE II score 22 (IQR, 17-28), and 61% males. Antifungal therapy was primarily prescribed for treatment (80.8%). Fluconazole was the most frequently prescribed antifungal (40.7%). The most common indication for treatment was intra-abdominal infection (30.7%). Fungi were identified in 45% of patients, of which only 26% had a minimum inhibitory concentration available. Target attainment was higher for patients receiving prophylaxis (> 80% for most drugs). For patients receiving treatment, low target attainment was noted for voriconazole (57.1%), posaconazole (63.2%), micafungin (64.1%) and amphotericin B (41.7%). CONCLUSION: This study highlights the varying degrees of target attainment across antifungal agents in critically ill patients. While a significant proportion of patients achieved the predefined PK/PD targets, wide variability and subtherapeutic exposures persist. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03136926, 2017-04-21.01 februari 202
Arbitration in the Netherlands, in particular NAI arbitration
No full textItem does not contain fulltextXXIII, 665 p
Multisensory contextual cues and information affect plant-based food choices and taste perception
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314210.pdf (Publisher’s version ) (Open Access)The context in which food is selected and consumed is an important factor in its choice, consumption, and acceptability. This study assessed the effect of information and multisensory contexts on meat-related food choices and taste perception. In total, 224 participants first watched one of two pitches, either discussing the implications of consuming animal meat (sustainable pitch) or promoting body movement (control pitch). Participants were then exposed to one of three multisensory contexts: a 'sustainable' context with natural green colours, nature sounds and a flower fragrance, a 'meat' context with red colours, the sounds of country music and a smokey BBQ smell, and a monotone off-white ‘neutral’ context with neutral background music and no additional smell. Participants were instructed to choose one of two presented hotdogs (animal meat hotdog or plant-based meat hotdog) and to taste and rate the chosen one on liking and taste attributes. Results showed that multisensory sustainable contextual cues combined with information on sustainability beforehand increased the likelihood of choosing plant-based meat hotdogs over animal meat hotdogs. In addition, while tasting the plant-based meat hotdog, multisensory contextual cues that are inspired by a meat context appeared to enhance taste perception, even for vegans and vegetarians. These findings provide further evidence for the importance of context in food choice and acceptance: the context where people choose plant-based meat should preferably be separated and different from the context of consumption. The findings also imply that information can change behaviour, not just attitudes as previous research indicated, but only if combined with multisensory cues in the context.11 p