What physics controls the properties of quantum matter, such as how electrons flow inside high-temperature superconductors? This question has captivated the physics community and industry for... Show moreWhat physics controls the properties of quantum matter, such as how electrons flow inside high-temperature superconductors? This question has captivated the physics community and industry for decades, in part due to the great technological potential such materials have, but also because they have resisted all traditional methods of understanding. It calls for a complete change in paradigm. An unexpected venue for progress was found in the study of gravity. By studying special gravitational solutions such as black holes and stars made of electrons, it turns out to be possible to shed some light on the physics and transport properties of quantum matter. This analysis relies on the use of high-performance computations to obtain these gravitational solutions, but the payoff is access to uncharted areas of physics. So far, such methods have successfully brought some insight into the flow of energy in such systems, but the flow of electric charge or the quantum information patterns remain shrouded in mystery. The findings of this thesis address key parts of these questions, particularly in the context of black holes as models of exotic quantum metals. Show less
More than 5,000 exoplanets have been found over the past couple of decades. These exoplanets show a tremendous diversity, ranging from scorching hot Jupiters, common super-Earths, to widely... Show moreMore than 5,000 exoplanets have been found over the past couple of decades. These exoplanets show a tremendous diversity, ranging from scorching hot Jupiters, common super-Earths, to widely separated super-Jupiters on the planet/brown dwarf boundary. We have now moved into the era of exoplanet atmospheric characterisation. Two crucial techniques for characterizing these exoplanets from the ground are high-contrast imaging and high-resolution spectroscopy. In the first part of the thesis, existing facilities are used to characterize the atmospheres of two of the most accessible types of planets: An ultra-hot Jupiter (WASP-76b) and a young supter-Jupiter (beta Pictoris b). The second part of the thesis develops instrumental concepts that are required to push exoplanet characterization towards smaller and closer-in planets. It shows how we can choose between spectral resolution, bandwidth, and field-of-view in developing an instrument for exoplanet detection, and how one can design an nearly optimal wavefront sensor for adaptive optics. Finally, it is demonstrated how machine learning techniques can help us improve the performance of these adaptive optics systems such that we can reach deeper contrasts for exoplanet imaging and characterization. Show less
In this thesis, topics relating to the optimization of high-throughput pipelines used for imaging are discussed. In particular, different levels of implementation, i.e., conceptual, software, and... Show moreIn this thesis, topics relating to the optimization of high-throughput pipelines used for imaging are discussed. In particular, different levels of implementation, i.e., conceptual, software, and hardware, are discussed and the thesis outlines how advances on each level need to be made to make gains in computationally demanding imaging applications. Chapter 2 concerns the implementation of real-time segmentation of X-ray computed tomography (CT). Chapter 3 concerns the end-to-end optimization of various CT workflows by using auto-differentiation frameworks. Chapter 4 concerns a novel pruning method for neural network to significantly increase the speed of convolutional neural networks (CNNs). Chapter 5 comprises a benchmark study of optimization algorithms for tuning GPU kernels, and introduces a novel graph-based approach to quantify search space difficulty. Chapter 6 introduces a novel model to improve the energy efficiency of GPUs. Show less
The aim of this thesis was to gain a better understanding of the deleterious effects of Neonatal Brachial Plexus Palsy (NBPP) on central development by analyzing sensory and motor function.The... Show moreThe aim of this thesis was to gain a better understanding of the deleterious effects of Neonatal Brachial Plexus Palsy (NBPP) on central development by analyzing sensory and motor function.The explanation for problems with hand function was not clear in children who had an upper NBPP where only the C5 and C6 spinal nerves are affected, which predominantly innervate the shoulder and elbow flexion. The main findings of this thesis: Children with an upper NBPP have a diminished sensibility of the thumb and index finger which correlates with diminished dexterity. The ability to localize stimuli to the thumb, index, third and fourth fingers is disturbed in children with an upper NBPP. Most children with an upper NBPP are not aware of the diminished sensibility in their affected hand. Also Grip force of the hand is reduced in children with an upper NBPP lesion. NBPP is a peripheral nervous lesion, which affects the development of the central nervous system as well. The age at which children with NBPP can walk independently is delayed, which does not depend on the severity of the lesion. Treatment of children with a NBPP had to focus on the total development of the child. Show less
The mid-sixteenth century was a time of rapidly intensifying interest in the study of living nature. Networks of experts described a rapidly growing number of species, complementing descriptions... Show moreThe mid-sixteenth century was a time of rapidly intensifying interest in the study of living nature. Networks of experts described a rapidly growing number of species, complementing descriptions with ad vivum depictions. Since the increase in the number of known species soon called for an organisation of this information, to keep this accessible and navigable, naturalists experimented with classifications and the presentation of information in text and image. This dissertation explores questions about the management of knowledge and information specifically in the context of natural history, looking at a subfield of zoology, the study of fishes and other aquatic animals, as an example, taking as a point of departure the works published by the naturalist Conrad Gessner (1516-1565). Gessner aimed to incorporate into his works an overview of the state of knowledge. As a result his work presents an ideal case study from which to approach questions such as: What happens when a field of knowledge experiences a sudden influx of information? How is information made accessible, how do researchers keep the overview of an increasing quantity of information? How is rudimentary and incomplete information processed and presented, how does it affect established interpretations and methods of working? Show less
International trade has played a major role in defining the modern global economy. Trade, however, entangles the environmental pressures of economic sectors, giving the illusion of environmental... Show moreInternational trade has played a major role in defining the modern global economy. Trade, however, entangles the environmental pressures of economic sectors, giving the illusion of environmental improvements, while the opposite may be occurring. This dissertation explores the role of international trade on the environmental impacts of two sectors: the food system and the plastic waste system. For each system, this work finds that international trade leads to unwelcomed tradeoffs. Within the food system, in the form of consumption patterns that have been able to shift towards more land intensive diets. Adopting more autarkic food policies may help shift food consumption back towards diets that are more in line with planetary boundaries while also improving the efficiency of currently underdeveloped food supply chains. Within the plastic waste system, international trade has been detrimental by increasing plastic waste leaking to the aquatic environment, particularly from high-income countries. Recycling policies within these countries have amplified the quantities of plastic waste being exported to reach recycling metrics, ultimately highlighting the need for improved metrics to evaluate the environmental tradeoffs of plastic waste disposal. Show less
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
Dit onderzoek richt zich op steunverlenende overheden die in het kader van het EU-staatssteunrecht algemene belangenafwegingen verrichten. In de verbodsfase van staatssteun moeten overheden... Show moreDit onderzoek richt zich op steunverlenende overheden die in het kader van het EU-staatssteunrecht algemene belangenafwegingen verrichten. In de verbodsfase van staatssteun moeten overheden beoordelen of een steunmaatregel (zoals een subsidie) als staatssteun kwalificeert. De weging van het algemene belang van staatssteun (bijvoorbeeld milieubescherming of cultuur) is gereserveerd voor de verenigbaarheidsfase. Bij de staatssteunhandhaving betrekt de Unie in toenemende mate nationale actoren (overheden en rechters) bij de beoordeling van deze algemene belangen, zowel in de verbodsfase als in de verenigbaarheidsfase. Dit proefschrift onderzoekt de algemene belangenafwegingen die ongelijke behandeling van ondernemingen rechtvaardigen, diensten van algemeen economisch belang uitzonderen en expliciet erkende sportbelangen een voorkeursbehandeling geven. Aansluitend wordt de beleidsruimte ter toetsing van groepsvrijstellingen aan verenigbaarheidscriteria door nationale actoren geanalyseerd. Daartoe worden een aantal knelpunten geïdentificeerd. Allereerst leiden de belangenafwegingen tot een vervaging van het onderscheid tussen de verbodstoepassing en de verenigbaarheidstoepassing. Zij raken daarmee aan de bevoegdheidsverdeling tussen nationale actoren en de Europese Commissie. Voorts mist het rechtmatigheidskader voor ex ante belangenafwegingen rechts zekerheid en ontbeert de ex post rechtmatigheidscontrole hierop een doeltreffende rechtsbeschermingsfunctie. Ter versterking van een gedecentraliseerde handhaving en een doeltreffende rechtsbescherming biedt dit onderzoek aanbevelingen op grond waarvan de Commissie verdere (afgebakende) bevoegdheden aan nationale actoren kan toestaan. Show less
The studies described in this thesis investigate the effects of different pharmacotherapieson antinociception and ventilatory control. Additionally, inherent variabilities in patient phenotypes... Show moreThe studies described in this thesis investigate the effects of different pharmacotherapieson antinociception and ventilatory control. Additionally, inherent variabilities in patient phenotypes within the population were assessed to gain a deeper understanding of the individual effects of analgesics and the ventilatory effects of disease, particularly type 2 diabetes mellitus (T2DM). Show less
Proteinuria is an independent risk factor for the progression of kidney injury, cardiovascular morbidity, and overall mortality. In this thesis, the pathways leading to proteinuria are explored by... Show moreProteinuria is an independent risk factor for the progression of kidney injury, cardiovascular morbidity, and overall mortality. In this thesis, the pathways leading to proteinuria are explored by revisiting elements previously considered essential, investigating known pathways, and identifying new players in the field of proteinuria. First, a zebrafish embryo model for developing new therapeutic options for the rare but devastating disease of nephropathic cystinosis is presented. The studies presented in thesis also investigate loss of heparan sulphate glycosaminoglycans in a zebrafish embryo model and in multiple osteochondroma patients. These studies show that loss of heparan sulphate glycosaminoglycans does not always lead to proteinuria. Next, dynamin is described as a promising potential therapeutic target for treating proteinuria. The final study introduces transmembrane protein 14A as an essential factor in maintaining glomerular filtration barrier function. Overall, these studies contribute to elucidating the pathways to proteinuria in the hope to keep advancing the field towards targeted treatment of proteinuria for the benefit of our patients. Show less
The aim of the thesis was to contribute to a better understanding of the influence of differences in implant design and surgical techniques on the migration of total knee arthroplasties (TKAs) and,... Show moreThe aim of the thesis was to contribute to a better understanding of the influence of differences in implant design and surgical techniques on the migration of total knee arthroplasties (TKAs) and, more broadly, the effect of using Radiostereometric Analysis (RSA) and other markers to detect early loosening. In this thesis, we compared various types of TKAs in different randomized controlled trials. Additionally, we investigated whether the positioning of TKAs relative to the patient's specific leg axis (e.g., neutral, varus, or valgus alignment) affects the stability of the prosthesis. We also analyzed, by combining registry data with data from a meta-analysis, whether TKAs evaluated with migration analysis (radiostereometric analysis; RSA) yield better results than TKAs that have not been previously examined with RSA. Finally, we conducted a systematic review to explore whether there are markers that can indicate loosening/failure of a prosthesis. 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
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
Cerebral Amyloid Angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly, and affects millions of people worldwide. CAA is caused by the deposition of the... Show moreCerebral Amyloid Angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly, and affects millions of people worldwide. CAA is caused by the deposition of the protein Amyloid-β in the walls of the cerebral and leptomeningeal vessels, which leads to vessel fragility and eventually rupture. CAA has a variable disease course and can present with a spectrum of symptoms. There is currently no cure for CAA, and certain diagnosis during life remains challenging.This thesis has used data from patients with hereditary and non-hereditary (sporadic) CAA to investigate novel clinical and radiological (MRI) markers of CAA, and has used them to formulate a pathophysiologic framework for the temporal ordering of disease processes in CAA. Our results provide new insights in the disease cascade, can aid in diagnosing the disease and have important implications for future clinical trial design, aiding in the identification and timing of candidates for disease-modifying treatments and the choice for the appropriate biomarkers to monitor treatment effect. CAA is a disease with a complex disease cascade and a large variety in disease course, both clinically and radiologically. However, it is just this variety that gives hope for the future: if we find what drives variability in CAA we might find ways for disease modification, prevention and treatment, and identification of in vivo biomarkers with specificity for CAA are a vital part of this search. 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
