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Incidence of Newly Diagnosed Cancer After Cerebral Venous Thrombosis.
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316635.pdf (Publisher’s version ) (Open Access)IMPORTANCE: Active cancer is a risk factor for cerebral venous thrombosis (CVT), but whether CVT is associated with occult cancer is unknown. OBJECTIVE: To evaluate the incidence of newly diagnosed cancer after CVT. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used data from the Dutch Hospital Discharge Registry from January 1, 1997, to July 1, 2020. Analyses were conducted between June 2023 and April 2024. Patients admitted with a first-ever CVT were included. Patients with a history of cancer or diagnosed with cancer during hospitalization for CVT were excluded. EXPOSURE: CVT was identified using International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes. MAIN OUTCOMES AND MEASURES: The main outcome was cumulative incidence of cancer after CVT. Standardized incidence ratios (SIRs) were calculated relative to a matched cohort from the general population using the Netherlands Cancer Registry. RESULTS: A total of 2649 patients with CVT (median [IQR] age, 44.5 [30.7-56.4] years; 1856 [70.1%] female) were included. Cancer was diagnosed in 119 patients during a median (IQR) follow-up of 4.7 (1.9-8.9) years, of whom 29 (24.4%) had hematologic cancer. The cumulative incidence of cancer was 5.9% (95% CI, 4.8%-7.2%) after 10 years and was highest in men aged 50 years or older (13.5%; 95% CI, 9.1%-18.7%). Patients with CVT had an increased rate of cancer compared with the reference cohort during the entire follow-up, but the difference narrowed over time (SIRs of 3.35 [95% CI, 2.41-4.55] and 1.40 [95% CI, 1.14-1.69] at 1 and 10 years, respectively). The rate was increased both in patients younger than 50 years (SIRs of 6.70 [95% CI, 3.97-10.59] and 1.72 [95% CI, 1.24-2.34] at 1 and 10 years, respectively) and those 50 years or older (SIRs of 2.41 [95% CI, 1.53-3.62] and 1.25 [95% CI, 0.96-1.60] at 1 and 10 years, respectively), as well as in male patients (SIRs of 3.59 [95% CI, 2.16-5.61] and 1.69 [95% CI, 1.25-2.23] at 1 and 10 years, respectively) and female patients (SIRs, 3.17 [95% CI, 1.99-4.80] and 1.22 [95% CI, 0.92-1.58] at 1 and 10 years, respectively). CONCLUSIONS AND RELEVANCE: This cohort study of patients with CVT found an increased risk of cancer during follow-up regardless of age or sex. Men 50 years or older had the highest absolute risk, whereas younger patients had the highest relative risk. Physicians should be vigilant for signs of cancer after CVT, and further research on screening for cancer after CVT is warranted
Cost-effectiveness of low-dose colchicine in patients with chronic coronary disease in The Netherlands
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315621.pdf (Publisher’s version ) (Open Access
Highlights of the Cardiovascular Magnetic Resonance 2024 Conference: the first joint European Association of Cardiovascular Imaging, European Society of Cardiovascular Radiology, and Society for Cardiovascular Magnetic Resonance conference.
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318068.pdf (Publisher’s version ) (Open Access)Cardiovascular Magnetic Resonance 2024 Conference (CMR2024) convened in London, UK, from 24 to 26 January 2024 and brought together 2705 learners and renowned cardiac imaging professionals to discuss and learn about the latest advancements. Organized by the Society for Cardiovascular Magnetic Resonance (SCMR) and the European Association of Cardiovascular Imaging (EACVI), in collaboration with the European Society of Cardiovascular Radiology (ESCR), CMR2024 was the largest international cardiac magnetic resonance conference to date. This conference underscored the collaboration between cardiologists, radiologists, scientists, and technologists by bringing together three major societies-SCMR, EACVI, and ESCR. Innovative session formats like 'Shark Tank' and 'Workflow, Innovations & Patients' facilitated expert opinion and practical experiences sharing in a 'TED-talk style'. With over 1168 abstract submissions and 75% acceptance rate, the programme featured multiple Early Career Award sessions, oral scientific sessions, oral case sessions, and rapid-fire sessions, all categorized by topic. Highlights included patient- and physician-centred imaging sessions, sharing referring physicians' and patients' insights of incremental value of cardiovascular magnetic resonance (CMR) in patient's management. The programme offered invited lectures in eight parallel tracks with three plenary and two keynote speakers. In addition, the interactive workshops and panel discussions provided a platform for knowledge exchange, support, and collaboration. A great emphasis was placed on collaboration between radiologists, cardiologists, scientists, and technologists, showcasing an ideal cardiac imaging marriage as a model for enhanced patient care around the globe. The event also featured exhibitions of the latest CMR technology and software, offering attendees a glimpse into the future cardiac imaging. CMR2024 emerged as a remarkable scientific, educational, and networking event, inspiring attendees to learn and collaborate within the global CMR community
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