ObjectiveTo assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.BackgroundMigraine has been linked to IBD and celiac... Show moreObjectiveTo assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.BackgroundMigraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition.MethodsLinkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed.ResultsMigraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99–1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99–1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96–1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79–1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00–1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92–0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02–1.29, p = 0.025). However, the results were not significant after multiple testing correction.ConclusionsWe found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes. Show less
Khidir, S.J.H.; Jong, P.H.P. de; Willemze, A.; Helm -van Mil, A.H.M. van der; Mulligen, E. van 2024
ObjectivesClinically suspect arthralgia (CSA) is an at-risk stage of rheumatoid arthritis (RA), in which patients experience symptoms and physical limitations. Perceptions of CSA-patients have... Show moreObjectivesClinically suspect arthralgia (CSA) is an at-risk stage of rheumatoid arthritis (RA), in which patients experience symptoms and physical limitations. Perceptions of CSA-patients have remained largely unknown. Therefore, we aimed to map perceptions of CSA-patients and compare these to RA-patients. Additionally, we studied changes in perceptions in CSA over time.MethodsThree hundred and ninety-nine consecutively included CSA-patients from the Leiden and Rotterdam CSA-cohorts and 100 recently diagnosed RA-patients from the Leiden Early Arthritis Clinic were included. Patients’ illness perceptions (IP) were assessed using the Brief Illness Perception Questionnaire (BIPQ), consisting of 8 questions (scale 0–10; higher score indicating more negative IP) covering cognitive, emotional and comprehensibility domains, and one open question about causes of disease. IP were measured at baseline in both populations and during 2 years follow-up in the CSA-cohorts.ResultsTotal BIPQ-scores were comparable at CSA-presentation and RA-diagnosis (40 ± 11 and 40 ± 10; range 0–80). Comparing dimensions separately revealed that CSA-patients were less worried about physical complaints compared to RA-patients. However, CSA-patients were more negative about expected treatment-effect on symptoms. IP over time in CSA improved in patients without development of clinical arthritis (from 38 ± 11 to 34 ± 14; P = 0.005) but remained similar in CSA-patients who progressed to arthritis/RA (mean 40 at both timepoints). CSA-patients mainly perceived physical strain and heredity as causes of their complaints.ConclusionsAlthough CSA-patients have not developed clinical arthritis, illness perceptions at CSA-presentation and RA-diagnosis are equally severe. Knowledge on worries and expectations may contribute to improving patient-contact and care in patients at risk of RA. Show less
Shalgunov, V.; Broek, S.L. van den; Andersen, I.V.; Raval, N.R.; Schäfer, G.; Barz, M.; ... ; Battisti, U.M. 2024
Brain pretargeted nuclear imaging for the diagnosis of various neurodegenerative diseases is a quickly developing field. The tetrazine ligation is currently the most explored approach to achieve... Show moreBrain pretargeted nuclear imaging for the diagnosis of various neurodegenerative diseases is a quickly developing field. The tetrazine ligation is currently the most explored approach to achieve this goal due to its remarkable properties. In this work, we evaluated the performance of F-537-Tetrazine, previously developed by Biogen, and N-(3-[18F]fluoro-5-(1,2,4,5-tetrazin-3-yl)benzyl)propan-1-amine, previously developed in our group, thereby allowing for the direct comparison of these two imaging probes. The evaluation included synthesis, radiolabeling and a comparison of the physicochemical properties of the compounds. Furthermore, their performance was evaluated by in vitro and in vivo pretargeting models. This study indicated that N-(3-[18F] fluoro-5-(1,2,4,5-tetrazin-3-yl)benzyl)propan-1-amine might be more suited for brain pretargeted imaging. Show less
Background: The Plaque At RISK (PARISK) study demonstrated that patients with a carotid plaque with intraplaque hemorrhage (IPH) have an increased risk of recurrent ipsilateral ischemic... Show moreBackground: The Plaque At RISK (PARISK) study demonstrated that patients with a carotid plaque with intraplaque hemorrhage (IPH) have an increased risk of recurrent ipsilateral ischemic cerebrovascular events. It was previously reported that symptomatic carotid plaques with IPH showed higher IPH signal intensity ratios (SIR) and larger IPH volumes than asymptomatic plaques. We explored whether IPH SIR and IPH volume are associated with future ipsilateral ischemic cerebrovascular events beyond the presence of IPH. Methods: Transient ischemic attack and ischemic stroke patients with mild-to-moderate carotid stenosis and an ipsilateral IPH-positive carotid plaque (n = 89) from the PARISK study were included. The clinical endpoint was a new ipsilateral ischemic cerebrovascular event during 5 years of follow-up, while the imaging-based endpoint was a new ipsilateral brain infarct on brain magnetic resonance imaging (MRI) after 2 years (n = 69). Trained observers delineated IPH, a hyperintense region compared to surrounding muscle tissue on hyper T1-weighted magnetic resonance images. The IPH SIR was the maximal signal intensity in the IPH region divided by the mean signal intensity of adjacent muscle tissue. The associations between IPH SIR or volume and the clinical and imaging-based endpoint were investigated using Cox proportional hazard models and logistic regression, respectively. Results: During 5.1 (interquartile range: 3.1–5.6) years of follow-up, 21 ipsilateral cerebrovascular ischemic events were identified. Twelve new ipsilateral brain infarcts were identified on the 2-year neuro MRI. There was no association for IPH SIR or IPH volume with the clinical endpoint (hazard ratio (HR): 0.89 [95% confidence interval: 0.67–1.10] and HR: 0.91 [0.69–1.19] per 100-µL increase, respectively) nor with the imaging-based endpoint (odds ratio (OR): 1.04 [0.75–1.45] and OR: 1.21 [0.87–1.68] per 100-µL increase, respectively). Conclusion: IPH SIR and IPH volume were not associated with future ipsilateral ischemic cerebrovascular events. Therefore, quantitative assessment of IPH of SIR and volume does not seem to provide additional value beyond the presence of IPH for stroke risk assessment. Show less
Hazard assessment (HA) requires toxicity tests to allow deriving protective points of departure (PoDs) for risk assessment irrespective of a compound's mode of action (MoA). The scope of in vitro... Show moreHazard assessment (HA) requires toxicity tests to allow deriving protective points of departure (PoDs) for risk assessment irrespective of a compound's mode of action (MoA). The scope of in vitro test batteries (ivTB) thereby necessitated for systemic toxicity is still unclear. We explored the protectiveness regarding systemic toxicity of an ivTB with a scope, which was guided by previous findings from rodent studies, where examining six main targets, including liver and kidney, was sufficient to predict the guideline scope-based PoD with high probability. The ivTB comprises human in vitro models representing liver, kidney, lung and the neuronal system covering transcriptome, mitochondrial dysfunction and neuronal outgrowth. Additionally, 32 CALUX®- and 10 HepG2 BAC-GFP reporters cover a broad range of disturbance mechanisms. Eight compounds were chosen for causing adverse effects such as immunotoxicity or anemia in vivo, i.e., effects not directly covered by assays in the ivTB. PoDs derived from the ivTB and from oral repeated dose studies in rodents were extrapolated to maximum unbound plasma concentrations for comparison. The ivTB-based PoDs were one to five orders of magnitude lower than in vivo PoDs for six of eight compounds, implying that they were protective. The extent of in vitro response varied across test compounds. Especially for hematotoxic substances, the ivTB showed either no response or only cytotoxicity. Assays better capturing this type of hazard would be needed to complement the ivTB. This study highlights the potentially broad applicability of ivTBs for deriving protective PoDs of compounds with unknown MoA. Show less
Kunnen, S.J.; Arnesdotter, E.; Willenbockel, C.T.; Vinken, M.; Water, B. van de 2024
Next generation risk assessment of chemicals revolves around the use of mechanistic information without animal experimentation. In this regard, toxicogenomics has proven to be a useful tool to... Show moreNext generation risk assessment of chemicals revolves around the use of mechanistic information without animal experimentation. In this regard, toxicogenomics has proven to be a useful tool to elucidate the underlying mechanisms of adverse effects of xenobiotics. In the present study, two widely used human in vitro hepatocyte culture systems, namely primary human hepatocytes (PHH) and human hepatoma HepaRG cells, were exposed to liver toxicants known to induce liver cholestasis, steatosis or necrosis. Benchmark concentration-response modelling was applied to transcriptomics gene co-expression networks (modules) to derive benchmark concentrations (BMCs) and to gain mechanistic insight into the hepatotoxic effects. BMCs derived by concentration-response modelling of gene co-expression modules recapitulated concentration-response modelling of individual genes. Although PHH and HepaRG cells showed overlap in deregulated genes and modules by the liver toxicants, PHH demonstrated a higher responsiveness, based on the lower BMCs of co-regulated gene modules. Such BMCs can be used as transcriptomics point of departure (tPOD) for assessing module-associated cellular (stress) pathways/processes. This approach identified clear tPODs of around maximum systemic concentration (Cmax) levels for the tested drugs, while for cosmetics ingredients the BMCs were 10-100-fold higher than the estimated plasma concentrations. This approach could serve next generation risk assessment practice to identify early responsive modules at low BMCs, that could be linked to key events in liver adverse outcome pathways. In turn, this can assist in delineating potential hazards of new test chemicals using in vitro systems and used in a risk assessment when BMCs are paired with chemical exposure assessment. Show less
BackgroundThe 2022 consensus statement of the European Atherosclerosis Society (EAS) on lipoprotein(a) (Lp(a)) recognizes the role of Lp(a) as a relevant genetically determined risk factor and... Show moreBackgroundThe 2022 consensus statement of the European Atherosclerosis Society (EAS) on lipoprotein(a) (Lp(a)) recognizes the role of Lp(a) as a relevant genetically determined risk factor and recommends its measurement at least once in an individual's lifetime. It also strongly urges that Lp(a) test results are expressed as apolipoprotein (a) (apo(a)) amount of substance in molar units and no longer in confounded Lp(a) mass units (mg/dL or mg/L). Therefore, IVD manufacturers should transition to molar units. A prerequisite for this transition is the availability of an Lp(a) Reference Measurement Procedure (RMP) that allows unequivocal molecular detection and quantification of apo(a) in Lp(a). To that end an ISO 17511:2020 compliant LC-MS based and IFCC-endorsed RMP has been established that targets proteotypic peptides of apolipoprotein(a) (apo(a)) in Lp(a). The RMP is laborious and requires highly skilled operators. To guide IVD-manufacturers of immunoassay-based Lp(a) test kits in the transition from mass to molar units, a Designated Comparison Method (DCM) has been developed and evaluated.MethodsTo assess whether the DCM provides equivalent results compared to the RMP, the procedural designs were compared and the analytical performance of DCM and RMP were first evaluated in a head-to-head comparison. Subsequently, apo(a) was quantified in 153 human clinical serum samples. Both DCM and RMP were calibrated using external native calibrators that produce results traceable to SRM2B. Measurement uncertainty (MU) was checked against predefined allowable MU.ResultsThe major difference in the design of the DCM for apo(a) is the use of only one enzymatic digestion step. The analytical performance of the DCM and RMP for apo(a) is highly similar. In a direct method comparison, equivalent results were obtained with a median regression slope 0.997 of and a median bias of - 0.2 nmol/L (- 0.2%); the intermediate imprecision of the test results was within total allowable error (TEa) (CVa of 10.2% at 90 nmol/L).ConclusionsThe semi-automated, higher throughput, LC-MS-based method for Lp(a) meets the predefined analytical performance specifications and allowable MU and is hence applicable as a higher order Designated Comparison Method, which is ideally suited to guide IVD manufacturers in the transition from Lp(a) mass to molar units. Show less
Senjor, E.; Pirro, M.; Svajger, U.; Prunk, M.; Sabotic, J.; Jewett, A.; ... ; Kos, J. 2024
Cystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell... Show moreCystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell stage, called split-anergy. We show that N-glycosylation determines the localization and cellular function of cystatin F. Cystatin F mostly exhibited high-mannose glycosylation in U-937 cells, both high-mannose and complex glycosylation in NK-92 and primary NKs, and predominantly complex glycosylation in super-charged NKs. Manipulating N-glycosylation with kifunensine increased high-mannose glycosylation of cystatin F and lysosome localisation, which decreased cathepsin C activity and reduced NK cytotoxicity. Mannose-6-phosphate could significantly reduce the internalization of extracellular cystatin F. By comparing NK cells with different cytotoxic potentials, we found that high-mannose cystatin F was strongly associated with lysosomes and cathepsin C in NK-92 cell line. In contrast, in highly cytotoxic super-charged NKs, cystatin F with complex glycosylation was associated with the secretory pathway and less prone to inhibit cathepsin C. Modulating glycosylation to alter cystatin F localisation could increase the cytotoxicity of NK cells, thereby enhancing their therapeutic potential for treating cancer patients. Show less
Previous studies have demonstrated the common occurrence of constituency focus in parliamentary questions, which is most often attributed to electoral incentives. If an electoral system makes use... Show morePrevious studies have demonstrated the common occurrence of constituency focus in parliamentary questions, which is most often attributed to electoral incentives. If an electoral system makes use of a single nationwide district, however, these district-oriented electoral incentives do not apply. MPs may still substantively represent a geographical region, because they are motivated to stand up for a specific region for other reasons. This article explores the extent to which Dutch MPs pay attention in parliamentary questions and debates to specific regions. We find that those with stronger ties to a region, and especially MPs who reside in a region, are more likely to mention it in parliamentary questions and speeches. In addition, we find that this effect is stronger for provinces where regional attachment among residents is relatively stronger. Show less
Gomon, D.; Sijmons, J.; Putter, H.; Dekker, J.W.; Tollenaar, R.; Wouters, M.; ... ; Signorelli, M. 2024
During the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of care... Show moreDuring the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of care provided at each hospital is essential to improve patient outcomes. It is unclear which methods should be used to generate most informative output for the identification of potential quality issues. Our aim is to compare the commonly employed funnel plot with existing cumulative sum (CUSUM) methodology for the evaluation of postoperative survival and hospital stay outcomes of patients who underwent colorectal surgery in the Netherlands. Data from the Dutch ColoRectal Audit on 25367 patients in the Netherlands who underwent surgical resection for colorectal cancer in 71 hospitals between 2019 and 2021 is used to compare four methods for the detection of deviations in the quality of care. Two methods based on binary outcomes (funnel plot, binary CUSUM) and two CUSUM charts based on survival outcomes (BK-CUSUM and CGR-CUSUM) are considered. A novel approach for determining hospital specific control limits for CUSUM charts is proposed. The ability to detect deviations as well as the time until detection are compared for the four methods. Charts were constructed for the inspection of both postoperative survival and hospital stay. Methods using survival outcomes always yielded faster detection times compared to approaches employing binary outcomes. Detections between methods mostly coincided for postoperative survival. For hospital stay detections varied strongly, with methods based on survival outcomes signalling over half the hospitals. Further pros and cons as well as pitfalls of all methods under consideration are discussed. Methodology for the continuous inspection of the quality of care should be tailored to the specific outcome. Properly understanding how the mechanism of a control chart functions is crucial for the correct interpretation of results. This is particularly true for CUSUM charts, which require the choice of a parameter that greatly influences the results. When applying CUSUM charts, consideration of these issues is strongly recommended. Show less
Baca, M.; Popović, D.; Agadzhanyan, A.K.; Baca, K.; Conard, N.J.; Fewlass, H.; ... ; Nadachowski, A. 2024
The narrow-headed vole, collared lemming and common vole were the most abundant small mammal species across the Eurasian Late Pleistocene steppe-tundra environment. Previous ancient DNA studies of... Show moreThe narrow-headed vole, collared lemming and common vole were the most abundant small mammal species across the Eurasian Late Pleistocene steppe-tundra environment. Previous ancient DNA studies of the collared lemming and common vole have revealed dynamic population histories shaped by climatic fluctuations. To investigate the extent to which species with similar adaptations share common evolutionary histories, we generated a dataset comprised the mitochondrial genomes of 139 ancient and 6 modern narrow-headed voles from several sites across Europe and northwestern Asia covering approximately the last 100 thousand years (kyr). We inferred Bayesian time-aware phylogenies using 11 radiocarbon-dated samples to calibrate the molecular clock. Divergence of the main mtDNA lineages across the three species occurred during marine isotope stages (MIS) 7 and MIS 5, suggesting a common response of species adapted to open habitat during interglacials. We identified several time-structured mtDNA lineages in European narrow-headed vole, suggesting lineage turnover. The timing of some of these turnovers was synchronous across the three species, allowing us to identify the main drivers of the Late Pleistocene dynamics of steppe- and cold-adapted species. Show less
Kat, A.C. de; Roelofs, F.; Slagboom, P.E.; Broekmans, F.J.M.; Beekman, M.; Berg, N. van den 2024
Research questionAre age at last childbirth and number of children, as facets of female reproductive health, related to individual lifespan or familial longevity?DesignThis observational study... Show moreResearch questionAre age at last childbirth and number of children, as facets of female reproductive health, related to individual lifespan or familial longevity?DesignThis observational study included 10,255 female participants from a multigenerational historical cohort, the LINKing System for historical family reconstruction (LINKS), and 1258 female participants from 651 long-lived families in the Leiden Longevity Study (LLS). Age at last childbirth and number of children, as outcomes of reproductive success, were compared with individual and familial longevity using the LINKS dataset. In addition, the genetic predisposition in the form of a polygenic risk score (PRS) for age at menopause was studied in relation to familial longevity using the LLS dataset.ResultsFor each year increase in the age of the birth of the last child, a woman's lifespan increased by 0.06 years (22 days; P = 0.002). The yearly risk for having a last child was 9% lower in women who survived to the oldest 10% of their birth cohort (hazard ratio 0.91, 95% CI 0.86–0.95). Women who came from long-living families did not have a higher mean age of last childbirth. There was no significant association between familial longevity and genetic predisposition to age at menopause.ConclusionsFemale reproductive health associates with a longer lifespan. Familial longevity does not associate to extended reproductive health. Other factors in somatic maintenance that support a longer lifespan are likely to have an impact on reproductive health. Show less
Willemsen, R.F.; Versluis, A.; Aardoom, J.J.; Petrus, A.H.J.; Silven, A.V.; Chavannes, N.H.; Dijke, A. van 2024
Introduction: Depressive and anxiety disorders are common mental disorders ranking among the leading causes of global disease burden. Not all clients currently benefit from therapy and clients are... Show moreIntroduction: Depressive and anxiety disorders are common mental disorders ranking among the leading causes of global disease burden. Not all clients currently benefit from therapy and clients are looking for modern ways of therapy. Online psychotherapy is a promising option for better meeting clients’ needs. Recently, a new psychotherapy concept has emerged that combines videoconferencing sessions with support through a mobile application. The latter allows for ecological momentary assessments and interventions, facilitates communication between patients and therapists in between sessions through chat, and allows for incorporating feedbackinformed treatment principles. Material and methods: The study was a retrospective observational matched cohort study, comparing online psychotherapy with Therapy As Usual (TAU) for clients with depressive or anxiety disorders. Data were obtained via questionnaires, which are part of standard clinical care. Primary outcomes included general mental functioning, and symptoms of depression and anxiety. Secondary outcomes were efficiency, client satisfaction, and therapy costs. Primary endpoints were analyzed using linear mixed models analysis, with an interaction term between time and group. Secondary outcomes were analyzed using linear regression. Results: Larger improvements were observed in the online compared to the TAU group for general mental functioning and depressive disorder (i.e., General mental functioning: B = -8.50, 95 CI: − 15.01 − − 1.97, p = 0.011; Depressive disorder: B = − 3.66, 95 % CI: − 5.79 – -1.54p < 0.01). No significant differences in change over time between the two groups were observed for anxiety disorder (B = -3.64, 95 % CI: (− 13.10 – 5.82) p = 0.447). The total number of sessions was significantly higher in the online psychotherapy group than in TAU (B = 3.71, p < 0.01), although clients were matched on treatment time in weeks. Treatment session duration in minutes was comparable across the groups. Discussion: Online psychotherapy with app support showed to be a promising alternative to TAU for depressive and anxiety disorders. More research is needed to evaluate the effectiveness, cost-effectiveness and client satisfaction of online psychotherapy compared to TAU, such as randomized controlled trials or studies multiple baseline series designs, and in-depth qualitative research. Show less
