International Migration, Integration and Social Cohesion online publications
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Fracture behavior of contemporary ceramics produced by digital manufacturing
Get PDFContinuous efforts have been made to enhance the quality of dental ceramics to improve the longevity of permanent restorations, which is the key to achieving long-term success for prosthetic treatment. When a failure occurs, restoration replacement often necessitates additional costs and supplementary interventions accompanied by sacrificing healthy dental tissues. Therefore, reducing the failure rate and improving the lifetime of ceramic restorations have always been the common goal for dental clinicians and technicians. With the development of new ceramic materials and digital manufacturing techniques, it is vital to have sufficient scientific knowledge of the materials and manufacturing to make the proper clinical decision and manufacture the restorations using appropriate techniques with optimized design to minimize fracture risk. This thesis aims to provide valuable insights into the understanding and application of contemporary dental ceramics and manufacturing techniques, as well as the optimization of manufacturing processes for enhancing their mechanical properties, reliability, and longevity
Artificial intelligence for intelligent care:How machine learning algorithms can enhance the personalised treatment of patients with haemophilia A
Get PDFThis thesis explores the integration of machine learning with pharmacometrics to enhance the treatment of haemophilia A, a rare X-linked bleeding disorder characterized by an increased risk of spontaneous bleeding. The introduction provides an overview of the disorder, the history of prophylactic treatment, and the role of pharmacokinetics (PK) in personalized care, concluding with a discussion of future therapies such as non-factor replacement. The potential of machine learning is introduced, emphasizing algorithms like random forests, neural networks, and Gaussian Processes, alongside challenges specific to pharmacometrics such as data sparsity and interpretability. Recent ML applications in pharmacometrics are reviewed, discussing usage as part of data preparation, hypothesis generation, and predictive modelling. The thesis then presents deep compartment models (DCMs), a hybrid framework combining neural networks with differential equations, which simplifies PK modelling, handles sparse data effectively, and outperforms traditional methods in speed and accuracy. Variational inference (VI) is proposed as an alternative to conventional mixed-effects estimation, yielding stable and precise results. Applications of machine learning algorithms for improving haemophilia A treatment are detailed, including models for predicting factor VIII (FVIII) pharmacokinetics in prophylactic and perioperative settings and for optimizing dosing based on bleeding risk using repeated time-to-event (RTTE) models. The OPTI-CLOT web-portal is introduced as a platform for personalized dosing recommendations. The thesis concludes by advocating for hybrid machine learning approaches to address challenges in personalized treatment, offering insights for broader adoption in rare disease management
De laatste heer van Amerongen, een Europees edelman in een Nederlandse dorpsgemeenschap:Godard John George Charles Godard graaf van Aldenburg Bentinck 1857-1940, edelman laverend tussen dynastieke, lokale en internationale belangen
Get PDFAristocraten kunnen zich in verschillende Europese landen verheugen in de belangstelling van historici. Ook in Nederland speelden aristocraten een belangrijke rol in het publieke leven. Nederland is in de geschiedenis geregeld neergezet als de burgerlijke natie bij uitstek. Vaak wordt daarbij verwezen naar het werk van de historicus Johan Huizinga. Daardoor werd minder aandacht geschonken aan de adellijke en patricische families en hun invloed op de zich ontwikkelende Nederlandse Staat. Deze studie naar het leven van de (Europese) edelman Godard Bentinck geeft een aanzet tot inzicht in adellijke families vanuit het perspectief van een individuele edelman binnen zijn omgeving. Het is een bijzonder onderzoek vanwege de biografische component zowel als de bredere betekenis voor de moderne Nederlandse geschiedenis in de Europese context. Kastelen en buitenplaatsen kunnen op een brede publieke belangstelling rekenen, er verschijnen diverse publicaties over huizen en tuinen, maar deze hebben over het algemeen een toeristische, of tuin- en architectuurhistorische insteek. Maar weinig studies belichten de historische relatie tussen dergelijke huizen en hun eigenaren, en vrijwel nooit wordt daarbij uitgezoomd naar de (inter)nationale, en ingezoomd op de lokaal-regionale context waartoe deze zich verhielden. De voormalige woning van deze edelman, kasteel Amerongen, is inmiddels een museum. De Nederlandse samenleving investeerde vele miljoenen in de metamorfose van dit Huis. Onderzoek naar de betekenis ervan dient een publieke zaak: inzicht en duiding geven aan de geschiedenis van de Nederlandse adel
Mechanistic insights and novel treatments for trauma-induced coagulopathy
Get PDFBleeding after trauma is a leading cause of mortality worldwide and is exacerbated by trauma-induced coagulopathy (TIC). Early on, TIC is characterised by platelet dysfunction, coagulation factor depletion and hyperfibrinolysis. Despite its clinical importance, the pathophysiology of TIC is not fully understood, and effective treatment options are limited. Therefore, we aimed to investigate the mechanisms underlying TIC and explore novel treatments using a translational approach.First, we studied the effect of shock duration on TIC, using a murine trauma model. Next, we reviewed the mechanisms and treatment options for trauma-induced platelet dysfunction. Using an experimental model of trauma and shock, we explored the relationship between high mobility group box 1 (HMGB1) and TIC. We investigated whether inhibition of HMGB1 would improve platelet dysfunction and TIC.Reduced coagulation factor activity is one of the key features of TIC. Previously it was shown that Factor V activity is most severely depleted. In an international cohort of trauma patients, we explored the relationship between Factor V activity and mortality. Next, we used an in vitro model of TIC to investigate whether supplementing FV(a) would improve coagulation. TIC with hyperfibrinolysis has the highest mortality when compared to other TIC phenotypes. The mechanisms are however incompletely understood. In the final part of this thesis, we studied the effect of ADAMTS13 degradation in hyperfibrinolytic trauma patients and explored whether ADAMTS13 has a causal role in hyperfibrinolysis. In this study, we combined clinical data from severely injured trauma patients, with a mechanistic in vitro study. These results were further supported in an experimental trauma model, using ADAMTS13 knock-out mice
Molecular profiling of intestinal cancers:Towards clinical implementation
Get PDFGastrointestinal (GI) cancers are molecularly heterogeneous, resulting in pronounced intertumoral differences in disease progression and treatment response. The diversity of GI malignancies complicates estimation of prognosis and optimal timing and selection of treatment regimens for individual patients. In recent years, it has become clear that gene expression (transcriptomic) profiling of GI tumors reflects key elements of tumor heterogeneity, and as such, is capable of stratifying patients based on molecular tumor properties. Often, these molecular tumor subgroups contain prognostic and predictive value. The Consensus Molecular Subtypes (CMSs) of colorectal cancer (CRC) are an example of such a taxonomy. Although biologically highly informative, clinical usage of transcriptomic taxonomies remains challenging, due to unclear clinical consequence, high costs, the required expertise and technical limitations. As an illustration, tumor classification on low-quality RNA-data from formalin-fixed paraffin-embedded (FFPE) tissue samples, which are widely used in the clinic, remains complicated.In this thesis, we set out to further explore and expand the clinical potential of transcriptomic subtyping of GI malignancies. We did so by optimally making use of the available literature regarding transcriptomic tumor stratification and clinical management, by performing in-depth molecular characterization of GI malignancies, and by studying large retrospective cohorts of patients. First, we focused on CRC, which is a commonly occurring and well-studied example of a GI malignancy with clinically relevant transcriptomic subgroups (the CMSs), and used this cancer type as a source of inspiration for studies on small intestinal adenocarcinomas (SIAs), a rare cancer type for which molecular profiling efforts are scarce
Clinical dilemmas in diagnosis and treatment of breast disease
Get PDFThis thesis explores various clinical dilemmas in the treatment of breast disease, focusing on the phyllodes tumor and early-stage breast cancer. The first section of this thesis focuses on the phyllodes tumor. The second section addresses challenges in early breast cancer treatment, including the use of FDG-PET/CT, selecting patients for neoadjuvant systemic treatment and selection for delayed oncoplastic surgery. The thesis concludes with the DESCARTES study protocol, investigating whether radiotherapy can be omitted for patients with pCR after neoadjuvant therapy. Overall, the thesis emphasizes the need for individualized treatment strategies to improve outcomes and address persistent clinical challenges in breast cancer care
Transient spectroscopy of color centers in semiconductors and their application
No full textThis thesis investigates color centers in wide-bandgap semiconductors, which are crucial for quantum technologies. A transient absorption (TA) spectroscopy setup, spanning 400-2300 nm with nanosecond resolution, was developed for the investigation of their intricate electronic structures and dynamics over pump-probe delays reaching milliseconds and even seconds. The present study focused on the investigation of nitrogen-vacancy (NV) centers in diamond and silicon vacancy (VSi) centers in 4H-SiC. For NV centers, numerous previously unknown electronic states were discovered in both negatively and neutrally charged states (NV- and NV0, respectively), and their inter-charge conversion was documented. This also included the first direct observation of tunneling-mediated charge conversion. A magnetometer operating at room temperature, employing the NV-singlet absorption, has been demonstrated. This magnetometer demonstrated a noteworthy achievement, achieving a sensitivity of 18pT/√Hz, thereby eliminating the requirement for optical cavities. Subsequently, the photoexcitation dynamics of VSi centers were reported, and the initial transition energies between their spin-doublet electronic states were identified. These findings significantly advance our understanding of color centers, with direct implications for quantum sensors, providing a foundation for future research in wide-bandgap materials.</p
Molecular conversations with soluble adenylyl cyclase:A journey of serendipity
No full textAdenylyl cyclases are enzymes that produce cAMP. In contrast to the more well-known transmembrane adenylyl cyclases, soluble adenylyl cyclase (sAC) is found in the cytoplasm and in intracellular organelles. sAC is also not regulated by G-proteins or activated by forskolin; instead, it is regulated by intracellular bicarbonate, calcium, and ATP concentrations. Recent studies have demonstrated the role of sAC-specific cAMP in various tissue-specific and cell autonomous contexts. Despite these unique known properties and functions, not much is known about how cellular sAC protein levels are regulated or maintained. In this thesis, using the H69 cholangiocyte cell line as our model, we set out to investigate how sAC is regulated at the post-translational level and is involved in cholangiocyte-specific functions and physiology, such as cellular apoptosis and ciliogenesis. The observations presented in this thesis imply that sAC could potentially be therapeutically targeted to restore or maintain cholangiocyte physiology in diseases such as primary biliary cholangitis or polycystic liver disease
Minoritized citizens' perspectives on political representation
Get PDFThis dissertation examines how minoritized citizens with migration backgrounds in Western Europe experience political representation. While the number of minoritized politicians is gradually increasing, parliaments still fail to reflect society’s diversity. At the same time, debates on immigration, integration, and Islam shape the political landscape. These dynamics raise key questions: how do citizens with migration backgrounds perceive political representation, how do processes of minoritization influence these perceptions, and what opportunities do citizens see to influence political representation? This dissertation argues that examining citizen perspectives allows scholars to critically assess, integrate, and extend existing theoretical models. It highlights the persistent barriers minorities face in achieving equal political influence and shows that a growing number of minoritized politicians does not automatically result in feelings of adequate representation. The study underscores the importance of intersectional analysis in political representation research, providing insights into within- and between-group differences in how citizens want to be represented, in what ways, and by whom
When personal becomes relational:Investigating the role of personality traits in affective student-teacher relationships
Get PDFThe affective quality of dyadic student–teacher relationships (i.e., the emotional bond between teachers and individual students) has been found to be an important context for students’ academic and social development. This dissertation addresses the limited attention given to personality traits in this field by investigating the role of personality traits in the affective quality of dyadic student–teacher relationships. This overarching aim was pursued through both a systematic review of existing research and original empirical studies. These included the development of a new measurement tool, further exploration of the personality–relationship link, and testing a mediation model in which affective student–teacher relationships serve as an underlying mechanism linking personality traits to school engagement. Findings suggest that higher levels of agreeableness, conscientiousness, and openness, and lower levels of neuroticism, are associated with more positive student–teacher relationships. Importantly, not only students’ but also teachers’ personality traits matter. Beyond individual traits, personality match between students and teachers may also play a role in relationship quality and warrants further investigation. Finally, students who score high on agreeableness and low on neuroticism are likely to report more positive relationship quality (i.e., higher closeness and lower conflict), which, in turn, may promote their emotional engagement. Taken together, this dissertation contributes to a deeper understanding of how personality traits shape relational and academic outcomes in schools and suggests that attention to personality traits may be a promising avenue for understanding different aspects of students’ school experiences