The first aim of this thesis was to evaluate the Late Effects Comprehensive Care & Follow-up (LEEF) program after pediatric stem cell transplantation for nonmalignant diseases at the LUMC, and... Show moreThe first aim of this thesis was to evaluate the Late Effects Comprehensive Care & Follow-up (LEEF) program after pediatric stem cell transplantation for nonmalignant diseases at the LUMC, and includes the assessment of various late effects and health-related quality of life. The second aim was to implement and evaluate aspects of VBHC at the LEEF program. This thesis describes lessons learned from the VBHC implementation in the Late Effects Comprehensive Care & Follow-up (LEEF) program and suggests possible future directions for VBHC implementation in similar comprehensive care programs. In this thesis, patient-reported outcomes (PROs) have demonstrated their value in research, such as long-term quality of life studies, but they have also proven to be valuable when used in clinical practice. The evaluation of PROs for both research purposes and clinical use can be expanded within the broader care path of pediatric stem cell transplantation. Furthermore, when discussing long-term HSCT outcomes, it is not solely about survival rates, but PROs are integral to capturing these long-term outcomes. Show less
Understanding how galaxies form, interact, and evolve comes largely from comparing theory predictions with observational data. Numerical simulations of galaxies provide the most accurate approach... Show moreUnderstanding how galaxies form, interact, and evolve comes largely from comparing theory predictions with observational data. Numerical simulations of galaxies provide the most accurate approach to testing the theory, as they follow the non-linear evolution of gas and dark matter in great detail and incorporate numerous baryonic processes, among which are energy feedback from supernovae (SNe) and Active Galactic Nuclei (AGN). In this thesis, we show the results of the development of the new model COLIBRE for cosmological simulations of galaxy formation that include a cold interstellar medium. First, we present a new SN feedback recipe developed for COLIBRE, whereby SN energy is injected into the gas in thermal and kinetic forms, and the total energy and momentum of the system of gas and stars are exactly conserved. Second, we conduct a detailed comparison of different ways in which SN energy is distributed in the gas environment around young stellar populations. Third, by using our simulation setup originally developed to test COLIBRE’s SN feedback, we show that the radioactive isotope Fe60 that has been detected on Earth is likely of SN origin. Finally, we present the calibration of the SN and AGN feedback of the COLIBRE model using machine learning. Show less
This book is about three West African sign languages with different time-depths, community sizes and patterns of social interactions. Adamorobe Sign Language (AdaSL), Ghana, is an old village sign... Show moreThis book is about three West African sign languages with different time-depths, community sizes and patterns of social interactions. Adamorobe Sign Language (AdaSL), Ghana, is an old village sign language used by 33 deaf people. Langue des Signes de Bouakako (LaSiBo), Côte d'Ivoire, is a new village sign language, used by six deaf people. Língua Gestual Guineense, Guinea-Bissau, is an emerging school-based sign language used by around 500 deaf people.In the three sign languages, 45 narratives of personal experiences were analysed to better understand how the time depth, the community size and the socialisation frequency influenced the three sign languages. Four different descriptive analyses of the narratives were carried out. Study 1 analysed the structure of the narratives, following Labov & Waletzky's model (1967) and Freytag's dramatic pyramid (1894). Studies 2, 3 and 4 focus on specific narrative devices that work to make narratives more convincing, as part of Labov's (1972) "evaluation" component. These devices refer to the moments when storytellers give dramatic prominence to narratives through the incorporation of characters, such as the use of different signing perspectives (Study 2), the use of role shifting between characters and constructed dialogues (Study 3) and the use of different types of descriptions of the animal (Study 4).These studies show that AdaSL and male LGG signers use devices that reflect a greater ability to capture the audience's attention, while LaSiBo and female LGG signers tend to show similar patterns in using simpler or reduced devices.This study shows that the frequency of social interaction between deaf peers is the most crucial factor in language change over time. Show less
The terrorist attacks of September 11th, 2001 represent a seminal event in American history, catalyzing a 20-year period in which counterterrorism was the top priority for US national security. Yet... Show moreThe terrorist attacks of September 11th, 2001 represent a seminal event in American history, catalyzing a 20-year period in which counterterrorism was the top priority for US national security. Yet, our understanding of US counterterrorism policy and the factors driving its evolution remains varied and unclear.In this dissertation, two dimensions of policy perspective and mode of thinking are integrated into a framework called the Policy Profile Code (PPC), a model that helps us understand the options policymakers have when confronted with crisis. Through the PPC, we metaphorically named the profiles of a policymaker: The Commander, The Prosecutor, The Negotiator, and The Doctor. When applying the PPC to each US presidential administration (Bush, Obama, and Trump) across the 20-year period following 9/11, we find overall change in US counterterrorism policy that included an evolution from The Commander, to The Prosecutor, to The Negotiator. We also find The Doctor policy profile was not adopted during this period. Show less
Corporate taxation has become an important topic of public debate and corporate tax planning has met with strong societal criticism. In response to these societal concerns, the Organization for... Show moreCorporate taxation has become an important topic of public debate and corporate tax planning has met with strong societal criticism. In response to these societal concerns, the Organization for Economic Co-operation and Development (OECD) launched the OECD/G20 BEPS project. In light of these developments, research on the professional practice of corporate tax planning has become more relevant. In this book, the author investigates tax professionals’ reactions to changing societal expectations of corporate tax planning. Taking a qualitative approach, the responses of different types of tax professionals of the Dutch corporate tax field were examined. Particular attention was paid to the manner in which tax professionals understand corporate tax planning and the public discussion, to what degree societal norms influence the professional practice of corporate taxation, and to what degree tax professionals have altered their role perceptions in response to public concerns of corporate tax planning. Show less
Prostate cancer (PCa) is the second most prevalent cancer among men worldwide when assessing age-standardized incidence rates. The primary method for early PCa diagnosis involves measuring the... Show moreProstate cancer (PCa) is the second most prevalent cancer among men worldwide when assessing age-standardized incidence rates. The primary method for early PCa diagnosis involves measuring the serum concentration of prostate-specific antigen (PSA), with elevated levels (> 3 ng/mL in the Netherlands) indicating the potential presence of PCa. However, the conventional PSA test exhibits a low specificity. Thus, clinical challenges persist, including the differentiation between PCa and benign prostatic hyperplasia and distinguishing indolent PCa from aggressive forms. This underscores the need for a more specific biomarker for early PCa detection and stratification. Previous studies have reported altered glycosylation features in two prostate-secreted glycoproteins, PSA and prostatic acid phosphatase (PAP) in PCa patients, e.g. variation in sialylation, fucosylation and the level of LacdiNAc . The aim of this thesis was to identify PCa biomarkers for early detection and to improve patient stratification, focusing specifically on the glycomic profiles of PSA and PAP. In addition, as PSA plays an important role with regard to fertility, its glycosylation -in relation to male infertility- was also touched upon. For this purpose, mass spectrometry (MS) based glycoproteomic methods were established to map the glycoprofiles of PSA and PAP derived from various biofluids. Show less
The research aims to explore the evolutionary adaptability of enzymes and the impact of temperature on protein evolution pathways, using M. tuberculosis β-lactamase BlaC as the object of study.... Show moreThe research aims to explore the evolutionary adaptability of enzymes and the impact of temperature on protein evolution pathways, using M. tuberculosis β-lactamase BlaC as the object of study. Enzymes inherently embody a delicate balance between activity and stability, and the acquisition of new enzymatic functions is often accompanied by trade-offs, such as decreased stability or reduction of the original activity. Probing evolutionary adaptability of BlaC with laboratory evolution in combination with structural characterization can provide information about the mechanisms of rapid adaptations observed for β-lactamases in the clinic. The role of temperature as a conventional selection pressure in such evolutionary adaptation is unclear. The cooperative nature of enzyme unfolding over a narrow temperature trajectory raises the question whether evolution at temperatures well below the melting point is influenced by temperature. The approach used in this work to answer these questions is by simulating evolution under different selection pressures and characterize the variant enzymes in terms of activity, structure, dynamics and melting temperature. The research makes clear how enzyme kinetics and dynamics vary with different selection pressures and maps the evolutionary path that enzymes may take. The underlying structural mechanisms are established to provide a rationale for the observed effects. Show less
The far-reaching invasion of Ukraine by the Russian Federation on 24 February 2022 poses the greatest threat to international peace and security in Europe since the end of World War II. The... Show moreThe far-reaching invasion of Ukraine by the Russian Federation on 24 February 2022 poses the greatest threat to international peace and security in Europe since the end of World War II. The unjustified attack also impacts the relations between Russia and other Arctic nations, i.e. Norway, Sweden, Finland, Iceland, Denmark, Canada, and the United States of America, all of which are members of the European Union or the North Atlantic Treaty Organization, or both. This thesis analyses the existing legal framework in the Arctic with a special focus on the region's governance and its indigenous people. It will be argued that the Arctic Council as a forum for the Arctic cooperation will continue to play a role in the future, but that international cooperation for governance in the Arctic will be very different as compared to the last three decades. The thesis offers an extensive analysis of the Arctic's legal framework, and of the need for a comprehensive and efficient Arctic Governance Regime based on International Law and the main principles and purposes of the United Nations Charter. Show less
With ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is... Show moreWith ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is increasingly recognised as a key modifiable cause. This thesis aims to investigate biological pathways between risk factors of cardiometabolic disease and cognitive function, in a population of older adults at increased risk of cardiovascular disease (CVD). We hypothesise that changes in physiological functioning caused by (sub)clinical CVD are possible mediators within the pathway leading to cognitive dysfunction. In the first part of this thesis, we studied electrocardiogram-based intervals and serum cardiac biomarkers (such as troponin) in relation to cognitive function. In the second part of this thesis, we studied the interplay of body mass index and serum leptin, loss of body weight and body weight variability, as well as metabolomics-based health scores in relation to cognitive function. We found that various cardiometabolic risk factors are associated with worse cognitive function. The results of this thesis strongly suggest that subclinical changes in cardiometabolic health may exist before cognitive dysfunction becomes apparent. Treating these cardiometabolic risk factors may be of benefit to future cognitive health. Show less
The formation of stars and planets happens over multiple scales, which can interact. In particular, planet formation happens in the dense, complex environment of star forming regions. This thesis... Show moreThe formation of stars and planets happens over multiple scales, which can interact. In particular, planet formation happens in the dense, complex environment of star forming regions. This thesis primarily explores the effects of high stellar density and presence of nearby massive stars (or a low density and absence of massive stars) on the evolution of protoplanetary disks, and their consequences for planet formation. Additionally, the dynamics of stellar feedback-driven shells is explored, and a novel operator splitting algorithm is introduced that allows for flexible coupling of a large number of physical models. Show less
Debates on biotechnological developments, such as genetic modification, stem cell research, and human-animal hybridity, show that we actually do not know how to deal with the unknown dimensions of... Show moreDebates on biotechnological developments, such as genetic modification, stem cell research, and human-animal hybridity, show that we actually do not know how to deal with the unknown dimensions of biological life. Yet, boundary shifting biotechnological activities leave us no choice but to pursue a way to acknowledge these obscure domains. In this dissertation, I present concepts about how bioart allows for the development of an ethical attitude toward life. A discussion of critiques from Science and Technology Studies on the frameworks "principlism" and "empirical bioethics" show how bioethical practices of self-regulation and quantification fall short in thinking about life. The concept of "the excess of meaning of biological life” presents the idea that life is emergent, fluid, temporal, and consequential, and cannot be controlled or known, which is developed by discussing Georges Bataille's excess theory and Karen Barad's "agential realism” among other theories. Analyses of four bioartworks specify what form of knowledge art can generate about life, for which insights from art philosophy, new media studies, and risk theory are applied. I conclude that it is possible to take "absolute (ir)responsibility" for the excess of meaning of biological life in the personal “resonating” experience of a morally ambiguous artwork. Show less
This research delves into the unique cultural approach of the Tenggerese people, an Indigenous community in East Java, Indonesia, regarding elderly care. It focuses on their traditional practices... Show moreThis research delves into the unique cultural approach of the Tenggerese people, an Indigenous community in East Java, Indonesia, regarding elderly care. It focuses on their traditional practices of bakti (‘filial piety’) and sayan (‘mutual aid’), deeply ingrained in the community's lifestyle and values. These indigenous institutions have been pivotal in shaping and maintaining the care of the elderly within the community for generations.The study explores Tenggerese people's perspective on combining traditional, transitional, and modern elderly care systems. It seeks to understand the role traditional institutions play in the sustainable development and integration of elderly care. This involves examining how these various systems can coexist and complement each other to provide comprehensive, efficient, and satisfactory care tailored to the elderly's specific needs and preferences.Furthermore, the research emphasises the importance of managing integrated care at the service delivery level, including case management, to ensure that the elderly receive the support and care they need. This involves a holistic approach that integrates family care with community-based care and modern elderly care, aiming for a seamless and effective care system that enhances access, quality, user satisfaction, and efficiency. The study provides insight into the complexities and potential of integrating traditional practices with transitional and modern care systems for elderly, contributing to sustainable development goals in the community. This research focuses on indigenous knowledge systems with the ethno-economics and ethno-management approach Show less
This in-depth study explores how women navigate corporate careers and take decisions in pursuit of a meaningful work and personal life. It analyzes the lived experiences of female employees working... Show moreThis in-depth study explores how women navigate corporate careers and take decisions in pursuit of a meaningful work and personal life. It analyzes the lived experiences of female employees working at major firms in Japan and South Korea to reveal how women's agency interacts with a changing environment inside and outside the workplace. It applies the comprehensive Gender Organization System's framework and interpretive approach with life story interview method to identify constellations of factors that influence women's work-family behaviors and attitudes over time. The careful analysis of individual interviews with 24 Korean and 39 Japanese women underscores that we must first understand the specific contexts individuals deal with in localized settings and explore women's personal interpretations of broad concepts to advance the increasingly broad theories in the gender and work literature. The findings suggest that dynamics and conditions at the work group level, and particularly the role of immediate supervisors, are of higher significance than the general organizational or socio-institutional context. Show less
The primary aim of this thesis is to investigate vascular and structural neuroimaging findings in migraine to ultimately identify possible causes for the well-known increased risk of structural... Show moreThe primary aim of this thesis is to investigate vascular and structural neuroimaging findings in migraine to ultimately identify possible causes for the well-known increased risk of structural brain lesions. To this purpose, we used advanced MRI techniques in migraine patients, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) patients and controls to evaluate vascular function. Moreover, we evaluated structural brain changes in repetitive hemiplegic migraine attacks. Secondary aim of this thesis is to describe the neuroimaging findings in a large Dutch cohort of RVCL-S patients of different ages. Show less
As most patients still experience either primary or secondary resistance against immunotherapy, we aimed to identify what dictates immunotherapy response and searched for novel targets with the aim... Show moreAs most patients still experience either primary or secondary resistance against immunotherapy, we aimed to identify what dictates immunotherapy response and searched for novel targets with the aim to ultimately improve therapy outcome. In Part I two immunosuppressive immune cells (Treg & CD163hi macrophages) and their mechanism of action were introduced and we showed that immunotherapy resistance could be relieved by specific targeting of these cells. In Part II we then revealed that unleashing the anti-tumor potential of inflammatory myeloid cells (iNOS+ neutrophils & macrophages) in the TME can contribute to totaltumor eradication. While the immunotherapeutic treatment strategies used in these studies (ICB, vaccination, bsAb) are all T-cell based, throughout this thesis we demonstrate that the response (or resistance) is dependent on several other cells in the TME, in which the myeloid-T cell interactions take the center stage. Show less
This work describes the use of click-to-release chemistry to get spatiotemporal control over immunocytokine activity. Until now, immunocytokines (cytokines coupled to a tumor-targeting-moiety)... Show moreThis work describes the use of click-to-release chemistry to get spatiotemporal control over immunocytokine activity. Until now, immunocytokines (cytokines coupled to a tumor-targeting-moiety) remained active throughout the body, being able to bind their respective receptors, causing mild to severe side-effects in cancer patients. Attempts have been made to improve the specific action of these immunocytokines, but these solutions remained very cytokine-specific and toxicity was not reduced significantly. Click-to-release chemistry allows us to inactivate a cytokine by blocking its free amines, present in lysines. This prevents the cytokine, IL-1β and TNF-α in particular, from binding its receptor. Removal of the blocking agent using a tetrazine restores the native amine and for IL-1β also its activity. By coupling the blocked cytokine to a targeting moiety allows for transport to the target, the tumor(-environment) upon which the unblocking or decaging can take place. This blocking-unblocking or caging-decaging was assessed using various cell-based assay. This technique can provide new opportunities in the immunocytokine field, as it is not cytokine-specific, and thereby opportunities in cancer therapy development. Show less
Diagnostic tests are performed for various reasons. Testing has both positive and negative effects on patient outcome. The main effects are indirect, mediated through treatment decisions and their... Show moreDiagnostic tests are performed for various reasons. Testing has both positive and negative effects on patient outcome. The main effects are indirect, mediated through treatment decisions and their impact on patient outcome. To base test decisions on expected net benefit, it is important to estimate or measure those effects in a structured manner. Positive and negative effects vary over the different stakeholders in test decisions: the healthcare provider, patient and society. While testing in a situation with low pre-test probability for a certain condition can be highly valued by patients, the associated costs of testing, with limited effect on patient outcome, diverts resources from societal areas with higher benefit. In this thesis we quantified the benefit of testing across different aspects of value of diagnostic information using a pediatric example, and provided argumentation and guidance for structured evaluation of existing screening programs. We explored practice variation in pediatric testing and interviewed pediatricians to elucidate their considerations in test decisions. The general discussion provides guidance on how to increase the efficiency and thus quality of testing through both system-level interventions and interventions directed at individual providers and patients. We argue that limiting testing in diagnostic situations with a (very) low pre-test probability is equally important as a structured evaluation of test consequences for efficient use of public resources. Show less
The present dissertation investigated adolescents’ overall stress and perceived stressors, the effectiveness of a universal psychoeducational program about stress, the Stress Lessons, and... Show moreThe present dissertation investigated adolescents’ overall stress and perceived stressors, the effectiveness of a universal psychoeducational program about stress, the Stress Lessons, and adolescents’ self-referral to a targeted school-based intervention. Another aim was to examine whether adolescents from different demographic groupings vary in their experience of stressors and the effect of psychoeducation. A large and heterogeneous sample was recruited from schools with variation in educational tracks and self-perceived ethnic backgrounds. The sample consisted of 1613 predominantly young adolescents with an average age of 13 years old. Most adolescents have to maneuver through a world of stressors, mostly related to the school environment, their health, and future uncertainty, while adolescents experience less stress from social pressure and financial pressure. Furthermore, our results indicate that the Stress Lessons were effective regarding improving adolescents’ knowledge about stress, but not in terms of stress levels. Finally, we found that adolescents who reported higher levels of test anxiety were generally more likely to show interest in an intervention targeting reduction of performance anxiety after the Stress Lessons. However, we did not find that adolescents with lower levels of social skills were more interested in an intervention targeting improvement of social skills. Show less
The thesis reconstructs Carl Schmitt's 1956 monography on 'Hamlet'. By scanning and unearthing books, essays, think-pieces, articles, personal diaries and private correspondence, this investigation... Show moreThe thesis reconstructs Carl Schmitt's 1956 monography on 'Hamlet'. By scanning and unearthing books, essays, think-pieces, articles, personal diaries and private correspondence, this investigation fully addresses the unwritten philosophy of history -partially developed- in Schmitt's late thought. The question of tragedy, theater, art and myth are also discussed. Show less
Although anti-cancer treatments have significantly advanced over the past decades, obstacles to accomplishing successful treatment still exist. The occurrence of treatment resistance is one of the... Show moreAlthough anti-cancer treatments have significantly advanced over the past decades, obstacles to accomplishing successful treatment still exist. The occurrence of treatment resistance is one of the major factors that limit the long-lasting efficacy of anti-cancer treatment. Additionally, substantial variability in pharmacokinetics (PK) / pharmacodynamics (PD) of anti-cancer drugs also challenges successful oncology treatment. Therefore, gaining knowledge of and ultimately better suppressing evolutionary resistance development during treatment, and applying personalized treatment are desired to improve anti-cancer treatment. In this thesis, we have applied quantitative modeling approaches to address these needs, aiming for improved treatment for oncology patients. Our work demonstrated that with the quantitative models, the evolutionary progression of tumors could be characterized and predicted, accounting for interactions among heterogeneous tumor cells and supported by mutant gene variants detected in circulating tumor DNA (ctDNA). In addition, we developed population PK /PD models which enabled quantitative description of the PK and PD of anti-cancer drugs and corresponding variabilities in real-world patients. The developed models have been further applied to support the identification of optimal treatment strategies and guide individualized treatment for oncology patients. Show less
