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
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
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
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
A dense region of a gaseous and dusty cloud collapses to form a protostar surrounded by a disk and an envelope. This thesis uses both observations and models to study physical and chemical... Show moreA dense region of a gaseous and dusty cloud collapses to form a protostar surrounded by a disk and an envelope. This thesis uses both observations and models to study physical and chemical conditions of these protostellar systems which are likely where planets start to form. From the observational side, ALMA is used to quantify abundance ratios of complex organic molecules (COMs) in the gas around young protostars. These ratios are found to be remarkably constant for various nitrogen-bearing COMs which points to formation of these molecules under similar conditions, likely in ices of the prestellar phase. Moreover, observations of JWST are used to tentatively detect molecules such as methyl cyanide and ethyl cyanide in interstellar ices for the first time. In addition, high angular resolution ALMA observations of a protostellar system are analyzed to report the first detection of a disk wind candidate in methanol and hydrogen cyanide. From the modeling side, radiative transfer models are used to investigate how physical conditions such as source structure can change the molecular emission and molecular abundances. These models show that disk and optically thick dust can decrease the emission from COMs and change the correlations among their column densities. Show less
Current sexual health care has not yet succeeded to guide men and their partners sufficiently when it comes to dealing with the consequences of prostate cancer (PCa) diagnosis and treatment. The... Show moreCurrent sexual health care has not yet succeeded to guide men and their partners sufficiently when it comes to dealing with the consequences of prostate cancer (PCa) diagnosis and treatment. The majority of men need a standardized consultation with a specialized healthcare provider (HCP) to discuss sexual health issues preferably within three months after treatment. Although current written information provision coming from urology departments discusses sexual health more often than radiotherapy departments; sexual dysfunction (SD) is still not routinely addressed. Focus during consultations is mostly on men while most of the partners also experience difficulties when dealing with sexual side effects. Regarding HCPs, urology residents experience lack of knowledge and competence to treat SD after PCa treatment and an unmet need exists for additional education and training. A symposium on sexual health care in PCa led to an increase of awareness to discuss SD more often during consultations. In case HCPs feel lack of knowledge, competence, time or tools to discuss sexual health after PCa treatment, referral to a specialized HCP should occur; according to the needs and preferences of men and their partners. However, management of outpatient clinics and availability of referral options are still in need of melioration. Show less
Thermodynamics is one of the founding scientific pillars that has helped us better understand heat engines, biology, ecosystems, and even black holes. While it fundamentally describes large systems... Show moreThermodynamics is one of the founding scientific pillars that has helped us better understand heat engines, biology, ecosystems, and even black holes. While it fundamentally describes large systems by examining the bulk behavior of their constituents, it is anchored in the statistical equivalence of equilibrium configurations of a formally infinite number of microscopic constituents. A question of its validity arises when one scales down to small quantum systems. Here, we have derived dynamic non-equilibrium relations that surprisingly resemble the classical thermodynamics laws, with a mix of quantum features that encode the dynamics of quantum information. Understanding the relation between the out-of-equilibrium dynamics of finite-size quantum systems and their initial thermodynamic state might have been a purely academic exercise fifteen years ago. But now, thanks to ultra-cold atomic quantum simulators and progress in quantum computers, the thermodynamics of finite-size quantum systems has practical implications too. The findings of this thesis contribute to understanding quantum many-body systems, particularly in the context of entanglement, non-equilibrium dynamics, thermalization, and charge transport. Show less
The blood circulations of monochorionic twins are connected through vascular anastomoses on the shared placenta. In about 10% of the monochorionic twin pregnancies, a disbalance occurs in blood... Show moreThe blood circulations of monochorionic twins are connected through vascular anastomoses on the shared placenta. In about 10% of the monochorionic twin pregnancies, a disbalance occurs in blood flow from the placenta to the children: one child, the recipient, receives more blood than the other child, the donor. This situation is called twin-twin transfusion syndrome (TTTS) and is often lethal for both twins. Fetoscopic laser therapy is the preferred and only causal treatment for TTTS and since the introduction in the 90’s, has improved survival rates from 65 to 90%. However, fetoscopic laser therapy is not always successful and residual anastomoses can persist, which can cause recurrence of TTTS or TAPS. In addition, fetoscopic laser therapy can induce pregnancy complications. In this thesis rates and risk factors for complications as intertwin membrane rupture, placental abruption and post-procedural amniotic band syndrome are investigated. We studied short-term and long-term outcomes and evaluated neurodevelopmental impairment at age 2 and 5 years. Show less
Accountability is a cornerstone of democratic governance. But with the emergence of increasingly complex multi-level and multi-stakeholder governance structures, and an increasing amount of... Show moreAccountability is a cornerstone of democratic governance. But with the emergence of increasingly complex multi-level and multi-stakeholder governance structures, and an increasing amount of delegation of public powers and tasks to both public and private non-majoritarian bodies, safeguarding public accountability has however become an increasingly complicated endeavour. This is not the least to be seen in the EU, where discussions about the EU's democratic deficit often centre around questions of accountability, with the accountability of non-majoritarian and (semi-)independent EU agencies being of particular concern. This dissertation focuses on how institutional EU account-holders execute their account-holding roles, in particular vis-à-vis EU agencies. Findings indicate that EU account-holders, within the constraints of their specific account-holding roles, are visibility-seeking organisations looking to take centre stage. This has important democratic accountability implications: Does the visibility-seeking behaviour of account-holders lead to low(er)-visibility agencies and issues escaping democratic scrutiny, or does it push account-holders towards going above and beyond their formal account-holding obligations. Show less
Virus-specific T cells play a key role in the control of viral-reactivations in healthy individuals and this cellular immunity is impaired in patients receiving allogeneic stem cell transplantation... Show moreVirus-specific T cells play a key role in the control of viral-reactivations in healthy individuals and this cellular immunity is impaired in patients receiving allogeneic stem cell transplantation. In the period around the transplantation, donor-derived T cells are either depleted or suppressed to reduce the risk of graft versus host disease (GVHD). However, in the absence of donor-derived T cells, latent viruses such as CMV, EBV and AdV can reactivate and remain uncontrolled and at the same time the curative graft versus leukemia (GVL) effect is abrogated. Therefore, the major challenge in the field of alloSCT is to find a balance between the GVL effect, protection against viruses and GVHD. The research described in this thesis focusses on the options to control for viral reactivations using adoptive transfer of virus-specific T cells or TCRs and the risks associated with this. Show less
The Dutch healthcare system is facing multiple challenges which have put a strain on the healthcare system in terms of finances and workforce shortages. eHealth offers innovative and promising ways... Show moreThe Dutch healthcare system is facing multiple challenges which have put a strain on the healthcare system in terms of finances and workforce shortages. eHealth offers innovative and promising ways of providing healthcare, including remote and digital care. However, despite the potential of eHealth to transform healthcare and improve patient outcomes, its wide-spread adoption and implementation have been limited. One major obstacle is limited usage, often due to the insufficient engagement of end-users, including patients, in the early design phase. The dissertation underscores the importance of participatory design to actively involve users. Another challenge is the short-term usage of eHealth applications, often a result of inadequate user engagement. The integration of "Persuasive games," incorporating game elements to promote behavioural change, is suggested to enhance engagement and encourage sustained use. The digital divide presents a third challenge, affecting specific user groups like those with limited (e)health literacy. Bridging this gap necessitates not only access to digital technologies but also promoting ehealth literacy and involving users in eHealth development. Moreover, a lack of evidence on the effectiveness of eHealth interventions impedes widespread acceptance. Traditional research designs, like randomized clinical studies, often overlook the complexity of intervention contexts. The dissertation seeks to address these challenges through practical research projects, emphasizing participatory design, evaluating effectiveness in real-world settings, translating and assessing the eHealth Literacy questionnaire, and creating tools for effective knowledge transfer. Advocating for early end-user engagement and a critical review of existing research paradigms, the dissertation offers valuable insights for overcoming challenges and advancing eHealth for improved patient and healthcare outcomes. Show less
This thesis attempts firstly to reconstruct the urban system or systems of the Roman Near east in the second and early third centuries C.E., consisting of the provinces of Syria Coele, Syria... Show moreThis thesis attempts firstly to reconstruct the urban system or systems of the Roman Near east in the second and early third centuries C.E., consisting of the provinces of Syria Coele, Syria Phoenice, Syria Palaestina, Osrhoene, Mesopotamia and Arabia. Secondly it analyses the different regional patterns within these systems. The first two chapters of the thesis describe the urban systems in the north and south of the Roman Near East respectively. The third chapter analyses to what degree the distribution of cities, and their sizes, relate to the agricultural productivity of the urban territories. The fourth chapter takes a detailed look at the largest city of the region, Antioch. The research shows that geographic factors and historical developments certainly played a role in the long term and defined the shape of urban networks in the region, but with ample room for human agency. Although we clearly see population growth compared to earlier periods, Roman cities in the Near East were nonetheless not particularly big, and most could be sustained with agricultural production from their direct hinterlands. From that perspective there is no reason to assume that integration into the Roman empire also brought stronger economic integration. Show less
The main research question of this thesis was: Can nitrogen cycling on dairy farms on peat soil in the Dutch Green Heart area be improved by adapting management to the nitrogen supply from soil and... Show moreThe main research question of this thesis was: Can nitrogen cycling on dairy farms on peat soil in the Dutch Green Heart area be improved by adapting management to the nitrogen supply from soil and by using other grassland species and crops without affecting milk production? There is increasing pressure to reduce nitrogen losses from dairy farming on peat soil. Ambitious policy targets regarding N loss have been put in place by the Dutch government. This thesis comprised four studies, which focused on 1) estimating the nitrogen supply from soil, 2) the possibility of lowering nitrogen levels of perennial ryegrass through population selection, 3) on the effect of plantain on the soil nitrogen cycle and 4) on growing cattail as alternative roughage on rewetted peat soil. The results of the research were used to estimate the effects of nitrogen fertilisation adapted to the nitrogen supply from soil and of the cultivation of low-nitrogen perennial ryegrass, plantain and cattail on nitrogen losses of an average dairy farm. The estimated nitrogen loss reductions were, even when combined, not sufficient to achieve policy targets on farm level. The options may however be combined with other options which were not investigated in this thesis. Show less
Differentiation has evolved into a systematic feature of European integration. Still, EU member states have been eager to maintain unity and not let differentiated integration (DI) be reflected in... Show moreDifferentiation has evolved into a systematic feature of European integration. Still, EU member states have been eager to maintain unity and not let differentiated integration (DI) be reflected in institutions and processes of EU governance. The sovereign debt crisis was a turning point, triggering an unprecedented reinforcement of euro area specific institutions and policies. So far, few contributions have studied the institutional implications of DI in the EU. This dissertation examines whether and, if so, how and with what implications DI has been institutionalised in EMU governance. It analyses the organisational inclusiveness of crisis management structures, the evolution of the Eurogroup and Eurogroup Working Group, procedural norms and elite ideas. The findings suggest that the distinction between euro area insiders and outsiders has become embedded in how member state representatives perceive political reality, determine mutual role expectations and organise governance processes. While this institutionalisation of DI in EMU was facilitated by particular circumstances of the sovereign debt crisis, its implications are evident in EMU governance and reform processes until today. The dissertation makes theoretical and empirical contributions to account for DI in institutional and political developments in EMU and, thus, aims to enrich institutionalist debates in EU studies. Show less
Freshwater biodiversity has been threatened by eutrophication due to excessive nutrients in the environment. Releasing the freshwater species from such pressures requires efforts from industry and... Show moreFreshwater biodiversity has been threatened by eutrophication due to excessive nutrients in the environment. Releasing the freshwater species from such pressures requires efforts from industry and manufacturers to avoid emissions to vulnerable and high-risk regions. The first step is to know which nutrient influences where and the effects thereof on species loss. These impacts can be assessed by methods of life cycle impact assessment (LCIA). This thesis contributes to such knowledge by improving the LCIA method, for instance, by developing more regionalized and comprehensive indicators as well as adding the consideration of both phosphorus (P) and nitrogen (N) and which of these two nutrients is limiting. Show less