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
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
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
Background: Measures against COVID-19 in nursing homes affected not only clients but also staff. However, staff perspectives on the importance of these measures remain underexplored. Objective: To... Show moreBackground: Measures against COVID-19 in nursing homes affected not only clients but also staff. However, staff perspectives on the importance of these measures remain underexplored. Objective: To investigate measures related to staff during the COVID-19 pandemic, staff perspectives of important measures and the involvement of staff in deciding on these measures. Design: A qualitative study. Setting(s): We analysed minutes of nursing home outbreak teams in the Netherlands and conducted group meetings with Dutch nursing home staff in different positions, prioritizing measures and discussing staff' involvement in deciding on the measures. Participants were recruited purposefully. Participants: The minutes of 41 nursing home organizations were collected during March-November, 2020. Four group meetings were organized in the same period, each with 5 to 7 participants, resulting in 23 participants. Methods: The meeting minutes were analysed using qualitative content analysis, whereas reflexive thematic analysis was used for the group meeting data. The group meetings were conducted online and structured by the Nominal Group Technique to discuss the importance of measures for staff. Results: Measures implemented for staff focused on prevention of COVID-19 transmission, (suspension of) educational activities, testing, additional tasks and staffing capacity, promoting wellbeing, and other means of support. The implemented measures overlapped with the measures considered important by staff. In addition, staff considered measures on decision-making support and communication to be important. Staff prioritized the measures in the group meetings because they affected their well-being, workforce scheduling, decision-making, or infection prevention. Furthermore, the group meetings revealed that decision-making shifted from mainly implementing national measures to more context-adjusted decision-making in the staff's or clients' situations. Conclusions: We showed that although nursing home staff were not always involved in decisionmaking during the first COVID-19 wave, there was overlap between the measures implemented by the organizations and measures considered important by staff. We suggest that organizations Show less
Predicting the development of rheumatoid arthritis (RA) in an early stage through magnetic resonance imaging (MRI) can initiate timely treatment and improve long-term patient outcomes. Although... Show morePredicting the development of rheumatoid arthritis (RA) in an early stage through magnetic resonance imaging (MRI) can initiate timely treatment and improve long-term patient outcomes. Although manual prediction is time-consuming and requires expert knowledge, automatic RA prediction has not been fully investigated. While standard models fail to achieve acceptable performance, we present a consistency-based deep learning framework to classify and predict RA automatically and precisely, including an output-standardized model, customized self-supervised pretraining and a loss function that is based on label consistency between original and augmented inputs. For training and evaluation, we used a database, containing 5945 MRI scans of carpal, metacarpophalangeal (MCP), and metatarsophalangeal (MTP) joints, from 2151 subjects obtained over a period of ten years. Four (three classification- and one prediction-) tasks were defined to distinguish two patient groups (with recent-onset arthritis and clinically suspect arthralgia) from healthy controls and RA from other arthritis patients within the recent-onset arthritis group, and predict RA development in a period of two years within the clinically suspect arthralgia group. The proposed method was evaluated with the area under the receiver operating curve (AUROC) on a separate test set, achieving mean AUROCs of 83.6%, 83.3%, and 69.7% in the three classification tasks, and 67.8% in the prediction task. This proves the existence of early signs of RA in MRI and the potential of a consistency-based deep learning model to detect these early signs and predict RA Show less
Oratie uitgesproken door Prof. dr. E.P.M. (Bart) Joosen bij de aanvaarding van het ambt van hoogleraar Financieel recht aan de Universiteit Leiden op vrijdag 24 mei 2024
Malaria continues to wreak havoc in tropical regions, due largely to the lack of an effective vaccine. Vaccine candidates based on whole parasites have shown promising results in malaria-naïve... Show moreMalaria continues to wreak havoc in tropical regions, due largely to the lack of an effective vaccine. Vaccine candidates based on whole parasites have shown promising results in malaria-naïve individuals, but their potency in malaria-exposed individuals is considerably lower. This dissertation described the development of a chemical strategy for boosting such parasites’ potency in pursuit of more efficacious malaria vaccines for use in endemic areas.Chapter 2 outlined the adaptation of a method for chemically modifying microbial cell surfaces.Chapter 3 showed the chemistry underlying this modification system to be stably compatible with in vivo usage.Chapter 4 demonstrated that when the chemical modification system was used to introduce immune-potentiating agents onto bacteria, better immune responses ensued.Chapter 5 tied it all together by using the chemical modification system to potentiate malaria parasites, and showed that doing so markedly improved immune responses in an in vivo immunization model.Chapter 6 summarized these findings in the context of malaria vaccine development and posited next steps forward. Show less
In this dissertation we investigate the emotional and psychiatric effects of glucocorticoids (e.g. cortisol, dexamethasone and prednisone). Glucocorticoids are widely used and their possible... Show moreIn this dissertation we investigate the emotional and psychiatric effects of glucocorticoids (e.g. cortisol, dexamethasone and prednisone). Glucocorticoids are widely used and their possible psychiatric side effects are well known. It is still unclear who is susceptible to side effects and what mechanism is behind this. In this thesis we try to better understand the underlying causes. For example, we use a relatively new static method in this research field, which can analyze changes over time better than the usual methods. In a study, we show that in depressed study participants, changes in certain affect items preceded changes in cortisol levels, while in control participants this was the other way around. Furthermore, we explore a hypothesis that may explain the mechanism of the psychiatric side effects of glucocorticoids. This mechanism is also used for a strategy to prevent the psychiatric side effects. The strategy is based on the fact that synthetic glucocorticoids are very similar to the body's own hormone cortisol, but their binding to the two cortisol receptor proteins and their effects may be different. By achieving a balanced activation of the two cortisol proteins when using glucocorticoids, the psychiatric side effects could possibly be prevented. In summary, this thesis provides further insight into the emotional and psychiatric side effects of glucocorticoids, but the search for a better understanding of the neuropsychiatric side effects remains a pressing concern, which will hopefully benefit patient care in the future. Show less
The lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier function. The three main SC lipid classes are ceramides (CER), cholesterol and... Show moreThe lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier function. The three main SC lipid classes are ceramides (CER), cholesterol and free fatty acids. In inflammatory skin diseases, such as atopic dermatitis and psoriasis, the SC lipid composition is altered compared to the healthy SC composition. The studies presented in this thesis focused on the effect of the CER subclass composition on the lipid organization, molecular arrangement and barrier function of the skin. First, the CER compositional changes were examined in the SC of seborrheic dermatitis patients, an inflammatory skin disease. A particular emphasis was paid to the ratio of two important CER subclasses, sphingosine CER (CER NS) and phytosphingosine CER (CER NP), and its correlation to the skin barrier. In the subsequent chapters lipid model systems with a simple CER subclass composition were used to study the influence of the CER NS: CER NP molar ratio on the barrier function and lipid organization. Show less
The dissertation investigates the role of lexical tone in spoken word recognition and production. In particular, it focuses on three groups of speakers: native speakers of Standard Chinese, bi... Show moreThe dissertation investigates the role of lexical tone in spoken word recognition and production. In particular, it focuses on three groups of speakers: native speakers of Standard Chinese, bi-dialectal speakers of Standard Chinese and Xi’an Mandarin, and bilingual speakers of Standard Chinese and English. Through a series of experiments employing the eye-tracking visual world paradigm and the picture-word interference paradigm, four key issues were explored: the role of lexical tone in Mandarin spoken word recognition; tonal interference in bi-dialectal spoken word recognition; the activation of lexical tone in bilingual spoken word production; and the influence of lexical tone on the bilingual mental lexicon. The findings of this dissertation not only showed how Mandarin listeners utilize tonal information during tone word recognition but also revealed dynamic tonal interaction between language systems. Overall, this dissertation contributes to a deeper understanding of lexical access by highlighting the significant role of lexical tone in both monolingual and bilingual contexts, shedding light on the intricate processes involved in spoken word recognition and production across languages. Show less
Manumission is the release from slavery, and therefore, a transition from the most extreme form of subjugation into another position and status in society. Some historians have defined manumission... Show moreManumission is the release from slavery, and therefore, a transition from the most extreme form of subjugation into another position and status in society. Some historians have defined manumission as a formal act, often understood as a gift that severed the bond between slave and master. More recently researchers have emphasized that it was a lengthy process that involved pre-existing dependencies and resulted in new hierarchies. This article takes a fresh look at the process and tries to gain a fuller understanding of manumission by examining it from the position of the manumitted and their social relations. Taking into consideration a wide range of documentary sources from colonial, notarial and Dutch governmental archives, we reconstruct the dependencies that were created in the process of manumission. The dependencies that evolved during manumission processes were related to family and other kinship ties, but also had an urban, communal, religious, economic and institutional logic. Manumission was not only an act at a specific moment, but also a process, and it was not a bilateral, but a multilateral one. With the instrument of manumission and within the limits set by economic reality and the colonial government, the manumittees tried to make meaningful life choices that transformed slave society profoundly. We find that they created complex dependencies across boundaries of status and racial categorization. Show less
This thesis has studied several modalities how to increase the organ utilisation rate. The results in this thesis indicate that the acceptance of kidneys with acute kidney injury stage 1 or 2 will... Show moreThis thesis has studied several modalities how to increase the organ utilisation rate. The results in this thesis indicate that the acceptance of kidneys with acute kidney injury stage 1 or 2 will significantly contribute to the donor pool as AKI kidneys have comparable outcomes and should therefore not be discarded. Clinically relevant biomarkers such as cell-free unmethylated-INS DNA, FMN, GSN, IGFBP3 and IGF2R were identified or explored in the first part of this thesis and may, if analysed and/or validated thoroughly, contribute to a better assessment of organ viability supporting the justified decision whether to accept or decline the donor organ.The second part of this thesis describes different aspects of the organ preservation technique of abdominal normothermic regional perfusion (aNRP). This relatively new machine perfusion technique has been shown to be feasible and safe, however, consensus regarding assessment parameters during perfusion, protocols and outcome measurements is still lacking. Despite of an inspiring surgical enthusiasm and keeninterest to accept this modality as a new standard, a randomised clinical trial is still required and entirely ethically justifiable in order to scientifically demonstrate superiority of this method for each individual abdominal organ comparing it to other successful (ex-situ) preservation and perfusion strategies. If aNRP can be shown to obtain better post transplantation outcomes whilst increasing organ utilisation, it may be the least complex and most cost-effective strategy in organ preservation. On the other hand, aNRP will only be used in DCD donors. As such, uncertainty regarding the quality of higher risk organs from DBD donors will still be evaluated ex-situ during cold and/or warm machine perfusion with the potential to repair or even regenerate injured organs and making them ‘transplantable’ again. Show less
Emotions significantly influence our perceptions and interactions with the environment, yet the impact of our emotional states on judging and responding to others remains underexplored. In this... Show moreEmotions significantly influence our perceptions and interactions with the environment, yet the impact of our emotional states on judging and responding to others remains underexplored. In this thesis, I examined how (romantic) attraction influences our attention (Part I), how we judge others’ intentions (Part II), and whether mimicking another facilitates bond formation (Part III). In two empirical chapters, I demonstrate that people have a strong attentional bias towards visual attractiveness and a tendency to indicate interest in establishing a romantic connection to attractive others. In the subsequent empirical chapter, I show that men are more likely to judge women they find attractive as more sexually aroused. Crucially, in a real-life dating study, I show that men who are attracted to another are more likely to assume mutual interest. Further, I introduce a framework suggesting that people align their actions and emotional states with others to foster romantic relationships. The final empirical chapter suggests that mimicking the attraction cues of others enhances bond formation. Overall, this dissertation sheds light on how attractiveness and attraction affect our attention, our social cognition, and the synchronization of actions and emotions, offering insights into the mechanisms underlying romantic connections. Show less
Cancer immunotherapies utilizing immune checkpoint blockade (ICB) therapy targeting CTLA-4 and PD-1/PD-L1 relieve tumor-induced immune suppression and induce durable tumor regression. The use of... Show moreCancer immunotherapies utilizing immune checkpoint blockade (ICB) therapy targeting CTLA-4 and PD-1/PD-L1 relieve tumor-induced immune suppression and induce durable tumor regression. The use of ICB therapy have demonstrated remarkable therapeutic efficacy in a proportion of patients with melanoma. However, still a substantial percentage of patients does not respond (durable) to ICB treatment and many questions remain. Therefore, in this thesis, the aim is to improve our understanding of ICB efficacy. We demonstrate the promise of neoadjuvant ICB therapy (approach in which ICB therapy is applied before surgery) and analyze different cohorts of melanoma patients. This results in the identification of several markers that are associated with prognosis, including IFN-y related gene signature score, Batf3 dendritic cell associated gene signature score, tumor mutational burden and systemic LRG1 expression. These markers can potentially be targeted and might facilitate rational combination therapies that can boost the efficacy of ICB therapy. For this purpose, we perform a repurposing compound screen that targets antigen cross-presentation. Togethers, this work increases our understanding of factors that determine ICB therapy efficacy and toxicity, with the goal to identify novel strategies to improve outcome of melanoma patients in a rationale and personal manner. Show less
