This thesis described the further development of the controlled human hookworm model and several applications of this model. First, the hookworm egg excretion is modelled over time using Bayesian... Show moreThis thesis described the further development of the controlled human hookworm model and several applications of this model. First, the hookworm egg excretion is modelled over time using Bayesian statistics, resulting in the description of a plateau phase in egg output. Repeated infections a re then investigated as a means to improve the accuracy and statistical power of this output as an outcome measure. The hereby established model is then applied in an immunization study, which shows that it is possible to develop a protective response against short-term larval infection. The skin phase and IgG1 seem to play a role in the development of this protection. Furthermore, gut microbiome changes during controlled hookworm infection are described. Also, volunteers’ motivations and decision making process are investigated, resulting in the characterization of controlled human infection participants as ‘deliberate decision-makers’ and not ‘money-oriented risk-takers’. Following up on the findings in the study described, the importance of a multidisciplinary approach for the improvement of controlled human infection trials is argued in the discussion, with several recommendations made for further collaborative efforts in order to maximise social and scientific output of these studies. Show less
Earlier detection of pancreatic cancer is necessary to improve its poor prognosis. Currently, screening of the general population is not feasible due to the relatively low lifetime risk. However,... Show moreEarlier detection of pancreatic cancer is necessary to improve its poor prognosis. Currently, screening of the general population is not feasible due to the relatively low lifetime risk. However, up to one in ten cases occur in individuals with a strong family history of germline mutation carriers, known as high-risk individuals (HRIs). For these HRIs, pancreatic cancer surveillance in expert centers is recommended. The first part of this thesis focuses on evaluating the effectiveness of pancreatic cancer surveillance in carriers of a germline CD2KNA/p16 mutation who have a very high lifetime risk of developing pancreatic cancer. The second part focuses on various aspects to improve pancreatic cancer surveillance programs, including the study of biomarkers, risk stratification, and assessment of psychosocial aspects. Finally, attention is given to the identification of individuals at increased risk from the general population. Show less
Colorectal cancer (CRC) screening programs have been established worldwide to prevent the development of CRC and to detect it early. CRC screening can be targeted at average- or high-risk... Show moreColorectal cancer (CRC) screening programs have been established worldwide to prevent the development of CRC and to detect it early. CRC screening can be targeted at average- or high-risk individuals. For average-risk individuals, the Dutch fecal immunochemical testing (FIT)-based CRC screening program was introduced in 2014, inviting all individuals aged 55-75 biennially. In Part I of this thesis, outcomes of the CRC screening program in the Netherlands are analyzed (i.e., CRC incidence, mortality, stage distribution, treatment). To optimize the balance between benefits and harms of CRC screening, risk stratification based on fecal hemoglobin concentrations after negative FIT could be the way forward. Part II describes the study protocol of a randomized controlled trail on personalized CRC screening and evaluates the information needs of the target population for personalized CRC screening strategies. For high-risk individuals, intensified CRC screening and surveillance may be needed, given these individuals have higher risk of developing CRC during their lifetime. Testicular cancer survivors treated with platinum-based chemotherapy can be considered high-risk individuals, as they have an increased risk of developing second primary gastrointestinal malignancies. Part III of this thesis explores the carcinogenesis of CRC and the yield of colonoscopy in these individuals. Show less
This thesis has found a balance between individual data protection rights and the free flow of data. On the one hand, this balance serves to protect the individual and his data. On the other hand,... Show moreThis thesis has found a balance between individual data protection rights and the free flow of data. On the one hand, this balance serves to protect the individual and his data. On the other hand, health care and health research must take place using personal data.A balanced approach can be found in the following four ways. Firstly, a broad(-er) interpretation of the lawful basis of consent can facilitate secondary health research. Secondly, the use of other lawful bases can be a solution for the legitimation of secondary health research. Furthermore, a separate legal ground for secondary research can be a solution to resolve the issue of a lawful basis for health research.Thirdly, a balance can be found in the individual’s autonomy vis-à-vis the accountability of the health institution and the attention drawn to the free flow of data. The focus is shifted from the individual’s control over his data towards the health institution with other lawful bases than consent and a fair balance between data protection rights and the free flow of data.Fourthly, a risk-based approach to monitoring compliance contributes to balancing the rights and interests of individuals with data sharing for health care and research. Show less
Dental calculus. This small, hard, inconspicuous substance that forms on the teeth of humans and animals contains a surprising amount of information about our lives. During its formation and growth... Show moreDental calculus. This small, hard, inconspicuous substance that forms on the teeth of humans and animals contains a surprising amount of information about our lives. During its formation and growth as a living biofilm, it accumulates a wide variety particles, especially bacteria and food debris.What makes this so interesting to archaeologists is that, when plaque hardens and forms dental calculus, these particles become trapped and well-protected against removal and degradation during hundreds to thousands of years, preserving a picture of past activities.The major problem—one of the major problems, for there are several—one of the many major problems is that this picture was never a complete picture of a lifetime of activities, and that picture fades over time. We know that these problems exist and that they limit our interpretations of past activities. What we need to do is approach these problems at a fundamental level. In my dissertation I introduce a protocol for growing artificial dental calculus. Working with a very controlled model allows me to explore the influence of a wide range of factors that may affect the uptake of particles into dental calculus, and better explain why and how our picture is incomplete. Show less
Tuberculosis (TB) is associated with 1.5 million deaths annually. There is a need exists to optimize both current as well as novel antibiotic combination treatment strategies to improve the... Show moreTuberculosis (TB) is associated with 1.5 million deaths annually. There is a need exists to optimize both current as well as novel antibiotic combination treatment strategies to improve the effectiveness and safety of treatments against TB. This PhD thesis has described how various quantitative pharmacology modeling approaches can contribute to the further development and optimization of both existing and novel therapies and treatment strategies against TB. Show less
This book focuses on the general right of suspension regulated in article 6:52 et seq. of the Dutch Civil Code. The author pays attention, among other things, to the requirements for the power to... Show moreThis book focuses on the general right of suspension regulated in article 6:52 et seq. of the Dutch Civil Code. The author pays attention, among other things, to the requirements for the power to suspend, including the coherence criterion (Dutch: samenhangcriterium), which is also the central requirement. The author explains that this criterion is not a measure of judgment or criterion to be judged by itself, but the existence of sufficient coherence between mutual obligations to justify suspension is rather a conclusion that follows the application of the coherence criterion. The author also discusses how the general right of suspension is exercised. Under circumstances, that exercise may be unacceptable. This involves weighing the interests involved in that exercise. Procedural aspects of the general right of suspension are also discussed, including the dictum. The author discusses that under circumstances an order for gradual performance fits a defense of suspension better than a rejection of the claim. The author makes this concrete using many examples mainly from case law. This book is therefore relevant for both law and legal practice. Show less
The fundamental research question in this dissertation is what the image of man - in the broadest sense of the word - entails within the classical and modern enlightenment points of view. This... Show moreThe fundamental research question in this dissertation is what the image of man - in the broadest sense of the word - entails within the classical and modern enlightenment points of view. This overarching question is considered with regard to the notions of man maintained by the ancients and moderns, with regard to their visions of society, and with regard to the worldview these theories entail. We also evaluate which of the two paradigms is the more convincing upon scrutiny. We have answered such questions by distilling the ideas of the classical philosopher Aristotle -and some ontological ideas from his teacher, Plato- on the one hand, and from the modern intellectual giant, Thomas Hobbes, on the other hand. This is premised on the belief that the essential features of the classical and modern idealtype are to be found within their thought and works.In order to answer our central question, we had to look into the values which underly each vision of man. After all, values are the ideas that motivate our actions as individuals and as a community. We found that the classical vision is guided by the value of Virtue/Duty, Hierarchy and the pursuit of Community in a world permeated with objective values, whilst the modern conception embraces Freedom, Equality and Individuality in a world that is set free of objective values. Show less
Lung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of... Show moreLung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of immunotherapy in 2015, this survival has increased significantly, with the first results showing a survival of even a few years. However, the response rate is relatively low, the treatment is expensive and the (low percentage of) side effects are severe. Therefore a biomarker is needed to predict which patients would benefit of immunotherapy.This thesis is about the search for a new biomarker. With the use of the RNA of platelets, proteins, tumor markers in blood and a an electronic nose for exhaled breath, we tried to find a non-invasive biomarker for the prediction of response on immunotherapy and for the (future) use in clinical practice, some of which are promising. Show less
Space data provide timely and reliable information that enables a wide variety of civil and commercial applications. Thanks to their volume, velocity, variety, and veracity, space big data create... Show moreSpace data provide timely and reliable information that enables a wide variety of civil and commercial applications. Thanks to their volume, velocity, variety, and veracity, space big data create the potential for additional benefits from space data.The benefits of space big data depend on the ways in which data are collected, accessed, used, and disseminated, therefore the laws and data policies that affect them should be studied. This thesis answers the question ‘How could space big data be regulated to address existing legal challenges and enhance their benefits?’. In particular, it identifies the laws and data policies that are relevant to the collection, access, use, and dissemination of space big data, among the legal frameworks that govern activities involving space or data. It also assesses the impact of the relevant laws and data policies, in terms of the limitations they impose on data collection, access, use, and dissemination. From the analysis of the relevant laws and data policies and their impact, the thesis draws the areas where their application encounters difficulties and describes the respective legal challenges. Based on these findings, recommendations are provided for overcoming the legal challenges and enhancing the collection, access, use, and dissemination of data, and by extension, their benefits. Show less
In this dissertation, Dutch secondary school teachers’ attitudes, knowledge, noticing skills and reasoned practices regarding culturally responsive teaching in a multicultural classroom context,... Show moreIn this dissertation, Dutch secondary school teachers’ attitudes, knowledge, noticing skills and reasoned practices regarding culturally responsive teaching in a multicultural classroom context, were examined. These components of culturally responsive teaching were addressed in three explorative, qualitative studies. In the first study, expert teachers’ reasoned practices were examined by in depth interviews. In the second and third study, spherical video-based virtual reality (SV-VR) clips of a multicultural classroom were used to provide teachers an immersive, authentic and comparable experience. The second study focussed on student teachers’ and expert teachers’ noticing through a cultural lens. In the third study, the SV-VR clips were used for deeper reflections in focus groups through which expert teachers’ culturally responsive attitudes, knowledge, noticing skills and reasoned practices were examined. The main results of this dissertation show that expert teachers teaching at Dutch multicultural schools indicate that working on a good interpersonal relationship with students is crucial. Moreover, the importance of adopting a genuinely curious attitude regarding students’ Funds of Knowledge/ Identity is often referred to. Such knowledge is also seen as necessary to notice relevant classroom events. Recommendations are made for teacher education regarding preparing teachers to teach multicultural classes. Show less
Time-series forecasting through modelling sequences of temporally dependent observations has many industrial and scientific applications. While machine learning models have been widely used to... Show moreTime-series forecasting through modelling sequences of temporally dependent observations has many industrial and scientific applications. While machine learning models have been widely used to create time-series forecasting models, creating efficient and performant time-series forecasting models is a complex task for domain users. Automated Machine Learning (AutoML) is a growing field that aims to make the process of creating machine-learning models accessible for non-machine learning experts. This is achieved by optimising machine learning pipelines automatically. Time-series machine-learning pipelines include various specialised pre-processing steps that are not currently supported by existing AutoML systems. This dissertation investigates how AutoML can be extended to time-series data analysis problems such as time-series forecasting. Several challenges arise when developing specialised AutoML systems for time-series forecasting. For instance, advanced machine-learning pipelines that can extract time-series features and select well-suited machine-learning models need to be developed. Also, extra hyperparameters such as the window size, which shows how many historical data points are helpful, need to be optimised by the AutoML system. This dissertation addresses these issues. We provide a comprehensive overview of the AutoML research field, including hyperparameter optimisation techniques, neural architecture search, and existing AutoML systems. Next, we investigate the use of AutoML for short-term forecasting, single-step ahead time-series forecasting, and multi-step time-series forecasting with time-series features. Show less
This thesis contains several investigations into the contribution of complement proteins, especially C1q, in several human diseases. Additionally, human autoantibodies against C1q (anti-C1q) are... Show moreThis thesis contains several investigations into the contribution of complement proteins, especially C1q, in several human diseases. Additionally, human autoantibodies against C1q (anti-C1q) are studied, cloned and characterized in order to further the understanding of their role in autoimmune disease. Show less
In this dissertation, I draw on twelve months of ethnographic fieldwork with Egyptians in Amsterdam to study how the nationalization of our imagination and social-legal and material infrastructures... Show moreIn this dissertation, I draw on twelve months of ethnographic fieldwork with Egyptians in Amsterdam to study how the nationalization of our imagination and social-legal and material infrastructures mediates social life. I describe how, just like the group of people categorized as Egyptian in Amsterdam is diverse, the Dutch state is too, consisting of a a range of images, laws, organizations, and people that embody them. I argue that this Dutch state multiple structures almost all aspects of life, but ultimately cannot define who we are, or what we do. Show less
The decision for immediate breast reconstruction after mastectomy is a preference-sensitive decision. For preference-sensitive decisions, shared decision making is propagated, but not yet properly... Show moreThe decision for immediate breast reconstruction after mastectomy is a preference-sensitive decision. For preference-sensitive decisions, shared decision making is propagated, but not yet properly implemented. Furthermore, prior studies identified unmet decision support needs in women considering breast reconstruction. With this thesis we aimed to optimally support women in making an informed decision about breast reconstruction. For this purpose, we developed an online patient decision aid (pDA) for breast cancer patients considering immediate breast reconstruction after mastectomy. This thesis describes the development and evaluation of this pDA. In our multicenter randomized controlled trial including 250 participants, we found that women who used the pDA felt better prepared for decision making, than women who received usual care. Other outcomes did not differ between both groups. Show less
The parabolic Anderson model (PAM), which is the Cauchy problem for the heat equation with random potential. The PAM is a mathematical model that describes how mass (i.e. matter or energy) flows in... Show moreThe parabolic Anderson model (PAM), which is the Cauchy problem for the heat equation with random potential. The PAM is a mathematical model that describes how mass (i.e. matter or energy) flows in a medium in the presence of a field of sources and sinks.The PAM has been extensively studied on regular lattices and is well understood there. However, the lattice is not always a suitable model and we look for extensions to random graphs. Very little is known for general graphs and the literature is extremely sparse. The present thesis is a contribution to this developing area. Because sparse random graphs can often be approximated by trees, the natural first step is to consider the PAM on a tree. In particular, this thesis is devoted to studying the PAM on random trees. Show less
The research presented in this thesis concerns one of the most important questions in software engineering of our time: how can we make sure that software is free from memory safety bugs? Memory... Show moreThe research presented in this thesis concerns one of the most important questions in software engineering of our time: how can we make sure that software is free from memory safety bugs? Memory safety bugs are the major cause of common vulnerabilities and exposures, and their presence threatens the stability and security of our digital world. This question is so important that it has escalated to the highest level. In a recent White House press release (February 26, 2024), the National Cyber Director of the United States of America calls on the academic community to help solve this hard problem: “addressing [this challenge] is imperative to ensuring we can secure our digital ecosystem long-term and protect the security of our Nation.” The accompanying technical report advises on the use of memory safe programming languages, and prominently mentions formal methods as one way to achieve the highly desired freedom from bugs, including memory safety bugs.In this thesis, formal methods are studied that are used to analyze software for its correctness, where correctness means that software satisfies its specification and incorrectness means the presence of a bug. The focus is on separation logic, a formal method designed as a scalable technique in ensuring freedom from memory safety bugs. Nowadays, separation logic is a well-established field of research: it has been widely studied academically in the past twenty years, and is successfully applied on an industry-wide scale to ensure memory safety. For example, separation logic is the technique used to prove, with mathematical certainty, that memory safe programming languages (such as Rust and Go) indeed live up to the promise that “they offer a way to eliminate, not just mitigate, entire bug classes.”In two parts, this thesis presents important scientific contributions that fill a gap in the academic literature. The first part contains the missing completeness theorem for separation logic, that is on par with the fundamental result by Goedel for first-order logic. Completeness is important for any formal method as it shows that the formal method can be adequately used for demonstrating every validity. The second part finally introduces dynamic separation logic that gives an alternative way to analyze memory safety problems, such that now it is possible to prove elementary specifications without needing extra logical techniques. This is important because it ensures ‘backwards compatibility’ with automated reasoning techniques that are optimized for first-order logic. Show less
The use of opioid is increasing in the Netherlands, which is reflected in an increase in complications associated with the use, such as hospital admission and death due to opioid poisoning. In... Show moreThe use of opioid is increasing in the Netherlands, which is reflected in an increase in complications associated with the use, such as hospital admission and death due to opioid poisoning. In addition to these direct hazards of opioid use, patients also face the risk of unplanned ICU admission and all-cause mortality. Dependent on socio-demographic characteristics and co-morbidities the risk of theseoutcomes may vary, but is unique to the general population of the Netherlands when compared to other countries. Show less
