Long-term survival for univentricular heart patients with a Fontan circulation is nowadays excellent, with the majority of patients expecting to reach adulthood. Nevertheless, a general attrition... Show moreLong-term survival for univentricular heart patients with a Fontan circulation is nowadays excellent, with the majority of patients expecting to reach adulthood. Nevertheless, a general attrition rate remains present and the majority of Fontan patients will be faced with significant morbidity. However, no Fontan patient is the same and there is a need for better understanding which patients will do worse, ideally by (early) identification of adverse factors that can be optimized. In this thesis, the role of flow efficiency in the TCPC was thoroughly investigated leading to multiple new insights. A novel three-dimensional blood flow MR sequence (3D flow MRI) was developed and shown to be superior to conventional 2D and 4D flow MRI sequences which could potentially lead to a more widespread use. Adverse flow patterns associated with reduced flow efficiency were shown at multiple areas within the TCPC which were related to adverse energetics. Increased 4D flow MRI derived energetics in turn are associated with reduced exercise capacity and increased levels of liver fibrosis/venous congestion. A focus on conduit size adequacy demonstrated that the currently used 16-20mm extracardiac conduits become undersized for teenage and adolescent Fontan patients. Undersized conduits proved to be an important factor leading to reduced flow efficiency, especially during exercise conditions. Achievement of optimal blood flow in Fontan patients may ultimately lead to improved long-term outcome. Show less
Given the accelerating appearance of antimicrobial resistance, there is an urgent need for more fundamental research into novel antibiotic strategies. The work in this thesis helps to address this... Show moreGiven the accelerating appearance of antimicrobial resistance, there is an urgent need for more fundamental research into novel antibiotic strategies. The work in this thesis helps to address this global problem by developing new antibiotic compounds, inspired by the antibacterial mechanisms of the natural antibiotic bacitracin. By unravelling the unique mechanism of action that bacitracin employs, we discovered that the inclusion of a small hydrophobic group in key locations of the molecule results in a dramatic enhancement of antibacterial activity, in some cases more than 100 times more potent than bacitracin. Crucially we found that the most potent analogues are particularly active against antibiotic-resistant bacteria including those bearing clinically challenging resistance genes. In doing so we have developed potent next-generation variants of this classic antibiotic and have taken important steps in the fight against antimicrobial resistance. Show less
In de loop van de eerste vier decennia van de twintigste eeuw dringt de poëzie vanaf 1880 door in bloemlezingen voor de hoogste klassen van gymnasium en h.b.s. In deze studie worden de overwegingen... Show moreIn de loop van de eerste vier decennia van de twintigste eeuw dringt de poëzie vanaf 1880 door in bloemlezingen voor de hoogste klassen van gymnasium en h.b.s. In deze studie worden de overwegingen om poëzie te bloemlezen en de keuzes die daaruit voortkomen van een vijftal bloemlezers (allen leraren) beschreven. Elk van hen propageert een methodiek om poëzie in de literatuurles te verwerken, van een open, globale kennismaking tot een intensieve analyse van een gedicht. Soms wordt een gedicht van een context voorzien maar doorgaans wordt een gedicht als zelfstandige tekst aangeboden. Naast deze bloemlezers brengt voordrachtskunstenaar Paul Huf ter ondersteuning van het onderwijs op een veertiental grammofoonplaten zijn gesproken bloemlezing. Zijn voordracht kan als voorbeeld dienen. Verder inventariseert deze studie de inhoud van 85 schoolbloemlezingen uit de periode 1898–1941 met in totaal 6758 gedichten van 254 dichters. Uit deze inventarisatie blijkt naast de voorkeur voor dichters uit de eerste jaren vanaf 1880 de vrij snelle popularisatie van anderen in de loop van de jaren 1920, 1930. Bloemlezers volgen op literair-historische gronden keuzes van voorgangers, daarnaast tonen zij een brede persoonlijke keuze. Schoolbloemlezingen representeren de voortgang van de contemporaine poëzieproductie en representeren het belang dat docenten voor de literatuurles hechten aan poëzie. Show less
After standard surgery for neck hernias, about 25% of patients report low satisfaction. This thesis applied inferential statistics to clinical data and Machine Learning to medical imaging, with the... Show moreAfter standard surgery for neck hernias, about 25% of patients report low satisfaction. This thesis applied inferential statistics to clinical data and Machine Learning to medical imaging, with the goal of finding out where differences in functional outcomes after surgery come from and how artificial intelligence can improve the diagnostic and prognostic process. The initial idea that differences in functional recovery were due to surgical technique was refuted by an RCT from this dissertation. The differences in functional recovery between three different surgical groups (removal of the intervertebral disc without artificial material, placement of intervertebral disc prosthesis, and fusion of vertebrae with a cage) were found to be minimal. It was striking that not surgical technique, but patients' mental health and preoperative, radiological imaging were found to be predictive of clinical recovery after surgery. Although the intervertebral disc prosthesis did not deliver on the promise of preserving mobility and thus could not prevent degeneration at adjacent levels, using Deep Learning based solely on the preoperative MRI of the neck, researchers were able to predict, among other things, which patients would require reoperation after surgery for that adjacent degeneration. The Deep Learning model did that significantly better than an experienced neuroradiologist and neurosurgeon. Such Deep Learning models eliminate the need for time-consuming questionnaires and are thus more cost-effective and less stressful for the patient, while they can be used to identify radiological features important for predicting the postoperative course. After validation with larger radiological datasets, these models can support clinical decision-making and help physicians develop personalized treatment strategies. Challenges within image analysis research for the spine lies in integrating different models into one automated process, preferably built into the electronic health record. Show less
An Active Galactic Nucleus (AGN) is a highly luminous region at the center of a galaxy, powered by the accretion into a supermassive black hole and emitting energy from radio waves to gamma rays,... Show moreAn Active Galactic Nucleus (AGN) is a highly luminous region at the center of a galaxy, powered by the accretion into a supermassive black hole and emitting energy from radio waves to gamma rays, often outshining the host galaxy. In the context of the AGN unification paradigm, the concept of the dusty “torus” plays a crucial role to discern between Type-1 and Type-2 AGNs depending on whether it obscures the AGN from the observer’s line of sight. NGC 1068, a well-studied AGN across the electromagnetic spectrum, is a nearby barred galaxy (d=14.4 Mpc) considered the prototypical Type-2. Using MATISSE at the VLTI, we have obtained direct evidence of the dusty torus enshrouding the AGN in NGC 1068. The multi-band capabilities of the instrument in the infrared wavelengths and the high spatial resolution that the interferometric technique can achieve have enabled us to study in detail the characteristics of the obscuring dust and its spatial distribution. We further analyse ALMA observations of the molecular gas with a comparable angular resolution. The revealed kinematics suggest an ongoing merger event, potentially contributing to the observed asymmetries in the torus and the water-maser disk, offering new insights into the dynamic processes in AGNs. Show less
People belonging to sexual minorities and people who do not conform to gender stereotypical roles still have a disadvantaged position in society. To promote inclusivity, it is important to... Show morePeople belonging to sexual minorities and people who do not conform to gender stereotypical roles still have a disadvantaged position in society. To promote inclusivity, it is important to understand how individuals are socialized into heteronormativity: everyday ways in which heterosexuality and traditional gender roles are positioned as normal and natural. In this dissertation, I examine the extent to which individuals (adolescents in particular) are socialized with heteronormativity by the national context in which they live, by Dutch schoolbooks and within Dutch families.Individuals appear to be socialized with heteronormativity in different ways: at the national level, progressive laws appear to be important, in school textbooks gender stereotypical patterns, underrepresentation of women and exclusion of sexual minorities, and within families the transmission of gender stereotypical and homophobic attitudes from parents to children. It appears that there is still a long way to go to achieve inclusion based on gender and sexual orientation. It seems important to continue to investigate both conscious and unconscious heteronormative messages and to address them in policy. More representation of counter-stereotypical role models and the normalization of public expressions and relationships of lesbian women and gay men seem necessary. Show less
Prematurely born neonates require, amongst others, pharmaceutical therapy. Dosing guidelines for these therapies are often based on data from term born neonates or older infants, while these are... Show morePrematurely born neonates require, amongst others, pharmaceutical therapy. Dosing guidelines for these therapies are often based on data from term born neonates or older infants, while these are not necessarily similar to prematurely born neonates. When suboptimal dosing guidelines are applied the neonates are at risk for under- or overdosing. In this thesis the pharmacokinetics and pharmacodynamics of a variety of drugs frequently used in preterm neonates were characterized, ultimately to optimize treatment. Specifically, caffeine, ibuprofen and fluconazole were studied which are drugs to treat apnea of prematurity, to close a patent ductus arteriosus and to treat or prevent infections with Candida in newborns, respectively. These drugs were introduced and used in clinical practice without sufficient knowledge, especially on appropriate dosing for this subpopulation. For caffeine and ibuprofen we found that the clearance rapidly increases with postnatal age, while for fluconazole clearance is better reflected by body weight and serum creatinine. For these drugs dosing guidelines were proposed based on identified covariates for their pharmacokinetics. Ibuprofen therapy was further investigated by examining the course of spontaneous closure of the ductus arteriosus, and evaluating the effects of ibuprofen exposure and patient characteristics simultaneously. Show less
Hydrocarbonylation of alkenes with carboxylic acids in synthesis of carboxylic acid anhydrides is relatively less explored. We herein present a study and optimization of a palladium-catalyzed... Show moreHydrocarbonylation of alkenes with carboxylic acids in synthesis of carboxylic acid anhydrides is relatively less explored. We herein present a study and optimization of a palladium-catalyzed hydrocarbonylation reaction of alkenes using carboxylic acids as the nucleophile, by which acid anhydrides can be obtained in moderate to excellent yields under mild conditions. Further, we have developed a method to synthesize symmetric acid anhydrides by in situ generation of carboxylic acids from the alkene itself, thereby eliminating the need of the corresponding pre synthesized Cn+1 carboxylic acid. The obtained anhydrides from the catalysis can be converted to (primary) amides, thioesters, esters or ketones via simple one-pot derivatization reactions. Following the establishment of the concept, we applied it in the synthesis of cyclic anhydrides from biobased sources such as pentenoic acid. A study on the regioselectivity demonstrated the different catalytic conditions that assisted in the formation of five-, six- or seven- membered cyclic anhydrides from pentenoic acid; with a major interest towards the formation of the seven-membered ring - a potential intermediate in the synthesis of caprolactam for nylon-6 production. Show less
From the second half of the third century BCE onwards, Rome was inundated with ‘non-local’ objects. The great Roman conquests of the period, like the sack of Syracuse in 211 BCE, brought objects... Show moreFrom the second half of the third century BCE onwards, Rome was inundated with ‘non-local’ objects. The great Roman conquests of the period, like the sack of Syracuse in 211 BCE, brought objects from all the conquered regions to the city of Rome. Among these objects was a vast number of ‘non-local’ statues that moved from the Greek world to Rome. In the city, they were put on display in public locations and became an integrated part of the Roman cultural environment and daily life. Such statues changed Rome on multiple levels – and this was also perceived as such by the Romans themselves.This dissertation investigates the introduction and impact of Greek statues in Republican Rome through an archaeological perspective. It attempts to study the appropriation of such ‘non-local’ statues, and the shock of the new that society experienced, from an object perspective, by analysing the biographies of some specifically selected individual statues. As such, this research explores how Greek statues became integrated into the city of Rome and how their appropriation was connected to change and innovation in Roman society. Show less
Fungal infections pose a significant threat to individuals with compromised immune systems and despite advancements in diagnosis and treatment, they continue to jeopardize patient’s health.... Show moreFungal infections pose a significant threat to individuals with compromised immune systems and despite advancements in diagnosis and treatment, they continue to jeopardize patient’s health. Maximizing the effectiveness of existing antifungal drugs is imperative. Among these, fluconazole and posaconazole are commonly prescribed to treat severe and life-threatening fungal infections. In this thesis, among others, we aimed to understand better how well different posaconazole formulations are absorbed. Through computational modeling and simulation, we learned that posaconazole is best taken with food to reduce the risk of inadequate drug absorption and subsequent therapeutic failure. This applies not only to the suspension but also to the tablet, which results in higher and more predictable absorption even though it does not achieve concentrations similar to those upon intravenous administration. Fluconazole was studied in individuals with obesity. Our findings indicate that heavier adult males may require a higher dose to achieve the desired exposure. Consequently, we proposed dosing recommendations for treating obese patients. In summary, this research, a result of the long-term collaboration between Leiden University and Radboudumc, enhanced our knowledge of factors that reduce exposure to antifungal drugs, allowing us to guide how to individualize and optimize antifungal treatment in individual patients. Show less
Vestibular schwannomas (VS), also named acoustic neurinoma, are benign tumors that originate from the Schwann cells of one of the four vestibular nerves (two at each side). These nerves are part of... Show moreVestibular schwannomas (VS), also named acoustic neurinoma, are benign tumors that originate from the Schwann cells of one of the four vestibular nerves (two at each side). These nerves are part of the eighth cranial nerve, the vestibulocochlear nerve, also known as the statoacoustic nerve. The vestibular nerves are located in the cerebellopontine angle, the space between brainstem, cerebellum and temporal bone. VS are the most common neoplasm located in the cerebellopontine angle and account for 8% of all intracranial tumors (1). The majority (95%) of VS are sporadic and occur unilateral. VS may exhibit a remarkable variable growth pattern: some tumors show a clear progression while others remain dormant and on occasion undergo shrinkage (2). The clinical symptoms most frequently seen are progressive (unilateral) hearing loss, vertigo, and tinnitus. Options for Treatment are observation (wait and scan), radiotherapy, or microsurgery. The choice of treatment depends on tumor size, severity and progression of the clinical symptoms, age of the patient, and patient preference.This thesis describes some of the clinical aspects of VS which are relevant for treatment. These concern the epidemiology, diagnostic challenges, clinical predictors affecting selection, and surgical technique and outcome. Show less
In this dissertation various aspects of the Roman economy and of Roman society related to food are reconstructed based on an interdisciplinary approach. The study focuses on the city of Rome in the... Show moreIn this dissertation various aspects of the Roman economy and of Roman society related to food are reconstructed based on an interdisciplinary approach. The study focuses on the city of Rome in the period between the 2nd century BCE and the beginning of the 4th century CE. First of all, the food culture and eating habits of the Romans are reconstructed. Subsequently, the food supply chain is investigated, and the role of the state and that of the free market in obtaining food are clarified. A comparative historical solution is proposed to reconstruct the food baskets of various income groups in Roman society, together with the costs of such baskets. Eventually, the value of the food annually consumed in Rome is calculated. Many historians interested in the ancient economy believe that most of Rome’s population struggled for survival on a monotonous and nutritionally inadequate diet. This thesis shows that such view is inconsistent with the available sources. The eating patterns of the inhabitants of ancient Rome were rather diversified, and food choices were mainly linked to income. In addition, broadly accepted figures regarding the size of the Roman economy are underestimated. Show less
Cancers accounts for approximately one-in-six deaths worldwide. Despite the advances in treatment options over the past couple decades surgery remains the cornerstone for almost all solid tumors.... Show moreCancers accounts for approximately one-in-six deaths worldwide. Despite the advances in treatment options over the past couple decades surgery remains the cornerstone for almost all solid tumors. Radical excision is crucial for curative treatment, however, intraoperative tumor identification is hampered by (1) fibrosis, inflammation and necrosis due to neoadjuvant therapy, and (2) an altered surgical field due to the adoption of laparoscopic and robotic procedures. In response, fluorescence guided surgery (FGS) has been introduced to the operating theater. FGS utilizes near-infrared light to visualize, an often intravenously administered, tumor-targeting tracer in real-time. In this thesis, uPAR was studied as target for FGS and uPAR-targeting FGS tracers were developed and compared in various cancer models. Show less
Central serous chorioretinopathy (CSC) is a multifactorial disease of the retina and the choroid in the human eye. The disease is characterized by a serous detachment of the neurosensory retina in... Show moreCentral serous chorioretinopathy (CSC) is a multifactorial disease of the retina and the choroid in the human eye. The disease is characterized by a serous detachment of the neurosensory retina in the central macula, which causes visual complaints including blurred vision, a central relative scotoma, metamorphopsia, and alterations in color and contrast vision. Multimodal imaging techniques have revealed that abnormally thickened, leaking choroidal blood vessels cause an excessive fluid outflow into the interstitial space, which presumably causes the characteristic thickened choroid. This thesis addresses the clinical spectrum of CSC including the acute CSC, the chronic CSC and the severe chronic CSC. Here we suggest a strict but practical classification of CSC phenotypes based on findings on multimodal imaging techniques. We also report on the outcome of treatment, especially photodynamic therapy (PDT), in all phenotypes of CSC and provide recommendation regarding disease management and therapy. Furthermore, in this thesis we assess the roll of genetic variations among different phenotypes of CSC for a better understanding of the pathogenesis of the disease. Despite the genetic associations found in CSC phenotypes, we conclude that the so far known genetic variations do not explain the different clinical disease presentation of CSC phenotypes. Show less
Ten years ago, the Single Supervisory Mechanism (SSM) was created, centralizing European banking supervision. In the SSM, the European Central Bank (ECB) cooperates closely with the National... Show moreTen years ago, the Single Supervisory Mechanism (SSM) was created, centralizing European banking supervision. In the SSM, the European Central Bank (ECB) cooperates closely with the National Competent Authorities (NCAs). The unprecedented degree of integration between NCAs and the ECB leads to supervision often being a joint exercise. SSM composite procedures are a specific type of such a joint exercise.Composite procedures culminate in a final ECB or NCA decision, yet are based on input from both. This integrated decision-making forms a paradox with the European system of judicial protection, which to an important extent remains to be organised dualistically. In short, national courts still review only national acts while the EU Courts, in principle, review only EU acts.This paradox raises concerns regarding effective judicial protection. This dissertation aims to investigate whether the EU principle of effective judicial protection is currently safeguarded within the SSM, particularly where it concerns composite procedures. It examines both the action for annulment and the action for damages, addressing the interplay between the EU and Dutch national legal framework. It is concluded that effective judicial protection is not always achieved. The dissertation therefore proposes several recommendations aimed at enhancing effective judicial protection within SSM composite procedures. Show less
Uveal melanoma (UM) is a rare ocular tumor. Up to 50% of the patients develop distant metastases predominantly targeting the liver. The median survival after diagnosis of patients with hepatic... Show moreUveal melanoma (UM) is a rare ocular tumor. Up to 50% of the patients develop distant metastases predominantly targeting the liver. The median survival after diagnosis of patients with hepatic metastases is approximately 4-6 months and hardly increased in the past decades due to lack of novel effective therapeutic options. Within the scope of this thesis we investigated the signaling landscape of metastatic UM and searched for novel avenues of therapy. In Chapter 2 we demonstrate that combinations of the multitarget drug Trabectedin with either the CK2/Clk double-inhibitor Silmitasertib or with the c-MET/TAM receptor inhibitors show synergistic growth inhibitory effects and induce apoptosis of UM cells in vitro. Chapter 3 describes the application of a CRISPR-Cas9 synthetic lethality screen for identification of molecular targets whose inhibition synergistically enhances the effect of the mTOR inhibitor everolimus in UM cells. In Chapter 4 we show that the combination of genetic depletion YAP1/TAZ together with Mcl-1 inhibition resulted in a synergistic inhibitory effect on the viability of UM cell lines. In Chapter 5 we analyzed the phospho-proteome of two UM metastatic cell lines and a primary tumor cell line from the same individual, and studied the role of MARK3 in YAP1/TAZ signaling. Show less
This dissertation has approached marriage and divorce among Muslims in ‘peripheral’ areas in Indonesia from various angles, employing legal analysis as well as historical and ethnographic research.... Show moreThis dissertation has approached marriage and divorce among Muslims in ‘peripheral’ areas in Indonesia from various angles, employing legal analysis as well as historical and ethnographic research. The study seeks to understand the intricate relationship between the interpretation of Muslim family law as promulgated by the state, and the different forms of empirical laws or norms operating within Indonesia’s multicultural Muslim society. Focussing on Mukomuko in Bengkulu province, on the west coast of Sumatra, this study discusses marriage and divorce practices in three different but connected sites or contexts: i.e. everyday practices at societal level; relevant cases available in the first instance Islamic courts; and landmark decisions and developments within the Islamic Chamber of the Indonesian Supreme Court, at the national level. Mukomuko is a case in point, in which the state’s patriarchally-inclined Islamic law conflicts with matrilineal Muslim community traditions. On the basis of ten months of fieldwork I conducted in this region and during several subsequent shorter visits from 2017 to 2019, this study reveals that even though marriage and divorce practices in Mukomuko are increasingly influenced by the state’s patriarchally inclined Islamic law, matrilineally-inclined Islamic law and its institutional actors have shown remarkable resilience. Show less
Pancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently... Show morePancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently onlypatients with localized pancreatic tumors can undergo surgery, which is the cornerstone in thetreatment of pancreatic cancer, whether or not preceded by neoadjuvant (chemo/radio)therapy. To establish the diagnosis, imaging techniques are used, tumor tissue must be obtained, and certain tumor markers can be determined in the blood. During surgery, the tumor must be removed in its entirety to prevent early recurrence. This thesis describes the potential role of tumor markers, which can be determined in the blood, and several experimental optical imaging techniques applied to pancreatic cancer. Show less
This book contains two main messages. First, an attempt is made to explain the diverse beneficial findings on cognition and mental health in the literature of meditation practices by the factor of... Show moreThis book contains two main messages. First, an attempt is made to explain the diverse beneficial findings on cognition and mental health in the literature of meditation practices by the factor of breathing. In the respiratory vagal nerve stimulation model of contemplative practices (rVNS) specific respiratory patterns lead to changes in autonomic nervous system functioning that in turn produce changes in the central nervous system, which can be observed in a healthier cognitive and emotional balance. Second, there are two empirical chapters that show null-results on cognition with meditative movement (Tai Chi Chuan) and breathing interventions. The possible reasons for these lack of results are extensively discussed in this dissertation and put into a wider perspective within the scientific field. Show less
This PhD thesis addresses southern African archaeology, emphasizing the importance of considering geoarchaeological context when using archaeological remains to support hypotheses. It focuses on... Show moreThis PhD thesis addresses southern African archaeology, emphasizing the importance of considering geoarchaeological context when using archaeological remains to support hypotheses. It focuses on Umhlatuzana and Umbeli Belli rockshelters, conducting a comprehensive stratigraphic analysis for a deep understanding of their depositional history and archaeological context.Umhlatuzana's stratigraphic sequence reveals primary, unaltered depositional micro-layering throughout, challenging assumptions of sediment movement. Bioturbation features are present but do not significantly impact lithic assemblages.Umbeli Belli rockshelter shows intense percolating water activity, causing poor preservation of organic remains. Different geogenic processes and pulsed occupations form varying artifact densities and sterile zones, but overall, the archaeological context remains secure with minimal bioturbation.This research highlights the need for taphonomic studies to understand the visibility, invisibility, or absence of specific proxies in the archaeological record. In-depth geoarchaeological analysis contributes to assessing archaeological record completeness and revealing remnants affected by post-depositional processes.In conclusion, this study underscores the importance of geoarchaeological research in elucidating site formation processes and archaeological visibility, especially in challenging preservation conditions, like Umhlatuzana and Umbeli Belli rockshelters, providing valuable insights into southern African archaeology. Show less
