This thesis explores the 4 pillars of Primary Healthcare (PC), the innovations that have been implemented to improve them, and the role digital technologies may have had as part of these... Show moreThis thesis explores the 4 pillars of Primary Healthcare (PC), the innovations that have been implemented to improve them, and the role digital technologies may have had as part of these innovations, with a focus on their impact in the management of chronic conditions. This thesis seeks to identify the optimal way to incorporate digital technologies in PC and how they could improve the PC consultation, in particular, and the PC field in general. It is composed of three parts: the first revises the concept of PC and explores interventions to improve it; the second part, delves into the role digital technologies have had in improving PC and looks at how apps may impact the treatment of chronic conditions. And the third, explores the digital competencies required for PC professionals to use these technologies. 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 research presented in this thesis explores the chemotherapeutic potential of metal-based compounds as chemotherapy agents, with an initial focus on the synthesis and DNA interaction studies of... Show moreThe research presented in this thesis explores the chemotherapeutic potential of metal-based compounds as chemotherapy agents, with an initial focus on the synthesis and DNA interaction studies of platinum and palladium compounds utilizing the [Pt(bapbpy)]2+ scaffold. The study identifies intercalation as the primary mechanism of action for these complexes. Furthermore, it provides a detailed structure-activity relationship analysis, highlighting the critical role of the complex's protonation state in influencing its biological activity and efficacy. Subsequently, the study delves into photoactivated chemotherapy (PACT) using ruthenium (II) complexes, where light activation of ruthenium complexes enables targeted drug delivery to tumor cells, thereby reducing adverse effects. This research emphasizes the development of ruthenium-based compounds that can photorelease a DNA repair inhibitor, specifically targeting the RAD51 protein, essential for Homologous Recombination (HR). By disrupting the DNA repair mechanisms in cancer cells, this approach seeks to enhance the cytotoxicity of the therapy and address drug resistance. Show less
The development of class cleavages in Chile in the 20th century has been notable for its similarity to European cases, which gave rise to important socialist left-wing parties. However, the Chilean... Show moreThe development of class cleavages in Chile in the 20th century has been notable for its similarity to European cases, which gave rise to important socialist left-wing parties. However, the Chilean left was characterised by its revolutionary socialist project channelled through the legal and democratic means of the time, known as the Chilean road to socialism. This thesis seeks to explain the formation of this project through a historical analysis of the development of socialism as a political expression of the class cleavage in Chile between 1891 and 1938. To this end, the study focuses on the ideological dimension of cleavages, with emphasis on three specific aspects of ideological groups: their strategic configurations, their organisational forms, and their political adaptability. The thesis reconstructs the ideological trajectory of the various socialist currents of the period, whose strategies and organizations encompassed a wide range of both institutional and extra-institutional projects. Through this analysis, it identifies the ideological patterns that facilitated or hindered certain socialist groupings from successfully channelling their respective political projects and eventually integrating themselves into the Chilean party system. 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
Quantum computing is an emerging technology, which holds the potential to simulate complex quantum systems beyond the reach of classical numerical methods.Despite recent formidable advancements in... Show moreQuantum computing is an emerging technology, which holds the potential to simulate complex quantum systems beyond the reach of classical numerical methods.Despite recent formidable advancements in quantum hardware, constructing a quantum computer capable of performing useful calculations remains challenging.In the absence of a reliable quantum computer, the study of potential applications relies on mathematical methods, ingenious approximations, and heuristics derived from the fields of application. This thesis focuses on developing new quantum algorithms, targeting some of the key challenges in the simulation of complex quantum systems.The techniques introduced in this thesis span from quantum state preparation to mitigation of hardware and algorithmic noise, from efficient expectation value measurement to noise-resilient applications in quantum chemistry. A common thread connecting all these algorithms is the introduction of a single auxiliary qubit – a fundamental unit of quantum information – which has an active and distinctive role in the task at hand. 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
Learning from small data sets in machine learning is a crucial challenge, especially when dealing with data imbalances and anomaly detection. This thesis delves into the challenges and... Show moreLearning from small data sets in machine learning is a crucial challenge, especially when dealing with data imbalances and anomaly detection. This thesis delves into the challenges and methodologies of learning from small datasets in machine learning, with a particular focus on addressing data imbalances and anomaly detec- tion. It thoroughly explores various strategies for effective small dataset learning in ML, examining both existing approaches and introducing novel techniques. The research pivots around two key questions: firstly, it investigates current methods employed for learning from small datasets in machine learning, and secondly, it assesses the efficacy of batch normalization in enhancing model performance and utilizing salient image segmentation as an augmentation policy in self-supervised learning.The thesis comprehensively reviews techniques for managing small datasets, in- cluding data selection and preprocessing, ensemble methods, transfer learning, regularization techniques, and synthetic data generation. A critical examination of batch normalization reveals its significant role in improving training time and testing errors for minority classes in highly imbalanced datasets. The study also demonstrates that utilizing salient image segmentation as an augmentation policy in self-supervised learning substantially improves representation learning. This improvement is particularly evident in the context of downstream tasks such as image segmentation, highlighting the effectiveness of this technique in enhancing model performance.In summary, this study contributes to the field of machine learning by exploring strategies for learning from small datasets. It offers a detailed analysis of batch normalization, highlighting its potential in improving performance for minority classes in imbalanced datasets. Additionally, the study introduces salient image segmentation as an augmentation policy in self-supervised learning, showing its effectiveness in tasks like image segmentation. These findings provide a solid foundation for further research in small sample learning and present practical insights for machine learning practitioners working with limited data. 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
Cholesterol-lowering medications aim to prevent cardiovascular events, caused by arteriosclerosis. Older adults (75 years and older) have a high cardiovascular risk based on age alone, and it is... Show moreCholesterol-lowering medications aim to prevent cardiovascular events, caused by arteriosclerosis. Older adults (75 years and older) have a high cardiovascular risk based on age alone, and it is estimated that 1 in 3 older adults use cholesterol-lowering medication. The vast majority (96% in the Netherlands) use a statin.The appropriateness of cholesterol-lowering medication for older adults is under debate. While there is strong evidence for the benefits of statins in relatively healthy older adults with a history of cardiovascular disease, for other groups the evidence is less convincing. Also, statins are associated with hindering side effects. In this thesis, various aspects of the appropriateness of cholesterol-lowering medication for older adults were studied, using different research designs. Five recurrent themes were of the utmost importance in the assessment of the appropriateness of cholesterol-lowering medication in older adults; 1) the individual context of a patient, 2) life expectancy, 3) hindering side effects, 4) cardiovascular history, and 5) the complexity of health problems. Based in these five themes, five key questions were distilled that can be used in a systematic evaluation of the appropriateness of cholesterol- lowering treatment for an individual patient. Show less
The research in this dissertation aims to optimise blood donation processes in the framework of the Dutch national blood bank Sanquin. The primary health risk for blood donors is iron deficiency,... Show moreThe research in this dissertation aims to optimise blood donation processes in the framework of the Dutch national blood bank Sanquin. The primary health risk for blood donors is iron deficiency, which is evaluated based on donors' hemoglobin and ferritin levels. If either of these levels are inadequate, donors are deferred from donation. Deferral due to low hemoglobin levels occurs on-site, meaning that donors have already traveled to the blood bank and then have to return home without donating, which is demotivating for the donor and inefficient for the blood bank. A large part of this dissertation therefore has the objective to develop a prediction model for donors' hemoglobin levels, based on historical measurements and donor characteristics.The prediction model that was developed reduces the deferral rate by approximately 60\% (from 3\% to 1\% for women, and from 1\% to 0.4\% for men), showing the potential of using data to enhance blood bank policy efficiency. Additionally, the model predictions were made explainable, providing the blood bank with insights into why specific predictions are made. These insights increase our understanding of the relationships between donor characteristics and hemoglobin levels. If this prediction model would be implemented in practice, the explanations could also be shared with the donor to help them understand why they are (not) invited to donate, which could also contribute to donor satisfaction and retention.In a collaborative effort with blood banks in Australia, Belgium, Finland and South Africa, the same prediction model was applied on data from each blood bank. Despite differences in blood bank policies and donor demographics, the models found similar associations with the predictor variables in all countries. Differences in performance could mostly be attributed to differences in deferral rates, with blood banks with higher deferral rates obtaining higher model accuracy.Beyond hemoglobin prediction models, additional research questions are explored. One study aims to identify determinants of ferritin levels in donors through repeated measurements, and linking these to environmental variables. Another study involves modeling the pharmacokinetics of antibodies in COVID-19 recovered donors, and finding relationships between patient characteristics, symptoms, and antibody levels over time.In summary, the research in this dissertation shows the potential within the wealth of data collected by blood banks. The proposed data-driven donation strategies not only decrease deferral rates but also increase donor retention and understanding. This comprehensive approach allows Sanquin to provide more personalised feedback to donors regarding their iron status, ultimately optimising the blood donation process and contributing to the overall efficacy of blood banking systems. Show less
Clostridioides difficile is well-known for its potential to cause healthcare-associated diarrhea in patients with previous antibiotic use. However, C. difficile can also be found as an asymptomatic... Show moreClostridioides difficile is well-known for its potential to cause healthcare-associated diarrhea in patients with previous antibiotic use. However, C. difficile can also be found as an asymptomatic colonizer of the gut. This thesis focuses on C. difficile colonization with the aim to better understand this condition and its role in epidemioloy of C. difficile infections. Investigations included microbiota analyses and transmission analyses. Show less
This dissertation takes as its point of departure the many problems that Dutch secondary-school classics students have in using their dictionary while translating authentic texts. The main goal is... Show moreThis dissertation takes as its point of departure the many problems that Dutch secondary-school classics students have in using their dictionary while translating authentic texts. The main goal is to complete the first phases of an educational design study in order to lay the groundwork for a curriculum for dictionary use in classics education. By taking the approach of situated cognition, we learned that translating authentic classical texts is inherently complex, because of the ever-changing lingual ‘situations’ that the students need to deal with. A ‘one size fits all’ procedure to manage these ‘problems’ is not a sensible approach. Observing expert learners, we found that their look-up process can be described as a feedback loop, continually monitoring their progress and critically testing their hypotheses. They decided efficiently when to employ the affordances available in a dictionary (and when not to). We argue that Cognitive Apprenticeship (CA) is an effective didactic method to teach this kind of complex situated problem solving. Following CA, the practical outcome of the project consists of the Look-up Curriculum and five design principles for dictionary instruction. These were constructed in collaboration with a teacher design team, that also designed example exercises for the everyday teaching practice. Show less
This thesis focusses on the temperature structure in protoplanetary disks. The relation between structures seen in the dust and gas-phase molecules is investigated. This is crucial to understand... Show moreThis thesis focusses on the temperature structure in protoplanetary disks. The relation between structures seen in the dust and gas-phase molecules is investigated. This is crucial to understand the chemical composition of the planet forming material as well as to quantify the amount of gas present in the disk, a crucial parameter to determine if planets are likely present in the disk. One of the important regions in the disk is the water snowline, the midplane location where water freezes-out onto the dust grains. In this thesis, chemical modelling is used to infer the snowline location in a hot disk. This result is confirmed in the next chapter by 2D imaging of the water snow surface, the 2D equivalent of the water snowline. Additionally, the temperature structure across transition disk cavities is investigated to determine the mass of the planets that may be carving that cavity. Finally, the relation between the structures traced in the gas by different molecules and the dust is investigated to show that the chemical composition at the location of the dust rings and dust trap in the HD 100546 and OPH-IRS 48 disks, respectively, are different than in the other disk regions. Show less
