In de afgelopen jaren zijn er tal van maatregelen genomen om de kwaliteit van de zorg voor patiënten met een slokdarm- of maagcarcinoom te verbeteren. De combinatie van volumestandaarden,... Show moreIn de afgelopen jaren zijn er tal van maatregelen genomen om de kwaliteit van de zorg voor patiënten met een slokdarm- of maagcarcinoom te verbeteren. De combinatie van volumestandaarden, evidence based richtlijnen en een meetinstrument waarmee processen en uitkomsten van de zorg kunnen worden geëvalueerd, heeft geleid tot aanzienlijke verbeteringen in de kwaliteit van zorg voor deze groep patiënten. Een dergelijk meetinstrument als de Dutch Upper GI Cancer Audit (DUCA) biedt bovendien mogelijkheden ten aanzien van multidimensionale en internationale kwaliteitsevaluatie. Show less
The thesis discusses sugar trade in the Persian Gulf in the eighteenth century. The existing historiography of the region still stresses eighteenth-century imperial and economic decline. But the... Show moreThe thesis discusses sugar trade in the Persian Gulf in the eighteenth century. The existing historiography of the region still stresses eighteenth-century imperial and economic decline. But the study argues a maintained vitality of the Gulf trade by illuminating remarkable changes in the relationship between trade and consumption in the context of the Persian Gulf and beyond, namely that of the Indian Ocean. Show less
We studied a novel triage approach to the organisation of routine assessments by Preventive Child Health care (PCH), including task-shifting among professionals. In the triage approach, access to... Show moreWe studied a novel triage approach to the organisation of routine assessments by Preventive Child Health care (PCH), including task-shifting among professionals. In the triage approach, access to PCH, and the detection of the health problems studied, were comparable with the usual approach. The efficient deployment of PCH professionals using triage and task-shifting reduced the costs and involvement of PCH physicians and nurses in routine assessments, particularly in the youngest age group (5 to 6 years). The associated release of workforce and budgets may create more opportunities for the delivery of care to children and their families with specific health-care needs. In our study, in the triage approach PCH physicians and nurses provided more demand-driven care at the request of parents and others such as school professionals. We have emphasised the importance of making the PCH programme more flexible to create time for PCH professionals to collaborate with professionals from the school system, and from the youth care and primary care systems, with the aim of improving joint commitment to early detection, and the delivery of more coordinated care. More research is needed into the outcomes of referral to extra care and into the cost benefits of the triage approach. Show less
Galaxies form and evolve through close interaction with their surroundings. As a result, the heavy elements ('metals') that are synthesized in stars, are found both inside and outside galaxies.... Show moreGalaxies form and evolve through close interaction with their surroundings. As a result, the heavy elements ('metals') that are synthesized in stars, are found both inside and outside galaxies. They trace the gas returned by stars, while providing information on the time-scales and physical conditions characterizing various stages of galaxy evolution through their elemental composition and ionization state. In this thesis, we explore what metals can tell us about galaxy formation. We complement theoretical work using the EAGLE simulations, where we focus on the galaxies as well as the surrounding medium, with an observational study of the low-redshift (z < 1) circumgalactic medium using the MUSE instrument on the VLT. Show less
- Het onderwerp van dit proefschrift is Dans- en Muziekgeneeskunde (Performing Arts Medicine). De nadruk ligt op "relevé": het op de tenen (niet op “spitzen”) staan bij dansers. 30% van de... Show more- Het onderwerp van dit proefschrift is Dans- en Muziekgeneeskunde (Performing Arts Medicine). De nadruk ligt op "relevé": het op de tenen (niet op “spitzen”) staan bij dansers. 30% van de dansers heeft symptomatische hyperpronatie (inrollen van de voeten), die goed reageert op behandeling met harde, orthopaedische steunzolen. In een literatuuronderzoek bleek operatieve behandeling van een pijnlijk en beperkt relevé door inklemming van een stukje bot aan de achterzijde van de enkel (“dansers-hiel”), vaak gecombineerd met een peesontsteking van de buigpees naar de grote teen (“dansers-tendinitis”), effectief en veilig bij dansers. Dit gold zowel voor de open operatie als behandeling via een kijkoperatie. De operatieve behandeling van dansers-hiel en dansers-tendinitis in het Medisch Centrum voor Dansers en Musici (MCDM) via de open techniek gaf in 91% van de gevallen een (veel) beter resultaat. Het direct postoperatieve herstel na een kijkoperatie bleek minder gunstig. De open techniek is dus de gouden standaard. Relevé bij dansers kan ook pijnlijk en beperkt zijn door een doorbloedingsstoornis van het kopje van het tweede middenvoetsbeentje, of een aangeboren, abnormale verbinding tussen twee voetwortelbeentjes, of een extra botje aan de binnenzijde van de voetboog. Alle drie zijn bij adequate behandeling geen reden om te stoppen met dansen. Show less
Several studies during the past decade have shown that patients with venous thrombosis have an increased risk of subsequent arterial thrombosis, thus suggesting a link between the two diseases. The... Show moreSeveral studies during the past decade have shown that patients with venous thrombosis have an increased risk of subsequent arterial thrombosis, thus suggesting a link between the two diseases. The aim of this thesis was to investigate the associations of traditional cardiometabolic risk factors with risk of a first and recurrent venous thrombosis. We showed that levels of major lipids, i.e. total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, were not associated with a first venous thrombosis. In contrast, low levels of apolipoproteins B and A1 were associated with an increased risk of a first event. Regarding recurrence, tests for lipid levels, glucose levels and hematologic variables did not identify patients at an increased risk of recurrent venous thrombosis, and these tests should not be done for this indication nor influence decisions on duration of anticoagulant treatment. In this thesis, we further searched for associations between lipids and hemostatic factors, and found that levels of vitamin K-dependent factors (VKDFs), including factor IX, were associated with triglyceride levels. We hypothesized that this association could be explained by common mechanisms, regulating levels of both VKDFs and triglycerides. Show less
Over the past years it has been discovered that the population of extra-solar planets is large and diverse. This fact feeds expectations for finding habitable Earth-like planets and potentially... Show moreOver the past years it has been discovered that the population of extra-solar planets is large and diverse. This fact feeds expectations for finding habitable Earth-like planets and potentially extra-terrestrial life. However without a reliable characterization, the fundamental nature of these planets would remain unknown after their initial discovery. This thesis focuses on the development of new spectroscopic observation and analysis methods to characterize planets after their discovery. The techniques presented in this thesis can be used in the future to detect the signs of life and habitability on Earth-like exoplanets that are expected to be discovered over the coming years. Show less
This dissertation contains two theoretical chapters and three empirical chapters describing how everyday actions are acquired and executed in both humans and robots. An emphasis is placed on... Show moreThis dissertation contains two theoretical chapters and three empirical chapters describing how everyday actions are acquired and executed in both humans and robots. An emphasis is placed on sequential actions and its modes of execution. Show less
According to the amyloid cascade hypothesis, accumulation of beta-amyloid (Aβ) peptides initiates the pathological cascade in Alzheimer's disease (AD). Early in the disease process, before clinical... Show moreAccording to the amyloid cascade hypothesis, accumulation of beta-amyloid (Aβ) peptides initiates the pathological cascade in Alzheimer's disease (AD). Early in the disease process, before clinical symptoms, an increase in Aβ concentrations leads to formation of toxic Aβ oligomers. These oligomers drive the neurodegeneration in AD brain. An important therapeutic strategy is to lower Aβ concentration in the CNS. Theoretically, this can prevent all subsequent pathological processes. Aβ is the final product of sequential proteolytic cleavages of the precursor protein APP. The drug effects on the individual pathways of APP processing are hard to predict, because these are regulated by a complex biochemical network. In this research, a 'systems pharmacology' approach was applied, integrating available knowledge of biology and pharmacology of system reactions into mathematical models. The APP-system-pharmacology-model provides important information about the APP processing pathways: (i) Aβ production inhibition leads to a relatively greater decrease in Aβ oligomers compared to monomers (ii) dissociation of oligomers contributes to the drug effect; (iii) Aβ42 is the major Aβ variant that contributes to the oligomer pool; (iv) inhibition of the enzyme GS stimulates alternative processing of APP by feedback. The APP-system-pharmacology-model can be of value in development of therapeutic interventions for AD. Show less
Vertrekkend vanuit een communicatief perspectief en concentrerend op mediatiseringsprocessen, formuleert deze dissertatie een alternatief voor het probleem van equivociteit binnen de studie naar... Show moreVertrekkend vanuit een communicatief perspectief en concentrerend op mediatiseringsprocessen, formuleert deze dissertatie een alternatief voor het probleem van equivociteit binnen de studie naar populaire muziek. Verschillende culturele en theoretische perspectieven zijn ingezet om de diverse vormen en betekenissen van populaire muziek te evalueren, bijvoorbeeld het type van muziek dat via complexe netwerken van betekenis in verschillende ambits door de geglobaliseerde wereld snelt. Authenticiteit en commodificatie zijn geïdentificeerd als de belangrijkste concepten voor de duiding van populaire repertoires -en van het begrip ‘'populair’ in relatie tot 'kunst' en 'folk'. Deze identificatie openbaart een patroon van betekenis-gevende praktijken, welke ik de ‘strategie van afwijzing’ heb genoemd. Deze strategie maakt het voor de cultuur-theoreticus mogelijk om inzicht te krijgen in de manier waarop het genre van populaire muziek is gedefinieerd, haar productie, verspreiding en consumptie. De essentie van het populaire lied wordt doorgaans negatief gedefinieerd, dat wil zeggen, door aan te geven wat het niet is: noch kunst noch folk. Opmerkelijk is dat negatieve definities van populaire muziek getuigen van latente spanningen tussen muziek producenten en consumenten, specifiek met betrekking tot de eclectische krachten gesignaleerd door het postmoderne denken en de waardeoordelen toegekend aan haar verschillende verschijningen. Show less
Without a proper treatment, critical congenital heart defects (CCHD) lead to death in the first month of life. Timely diagnosis is pivotal for reducing morbidity and mortality. Pulse oximetry is... Show moreWithout a proper treatment, critical congenital heart defects (CCHD) lead to death in the first month of life. Timely diagnosis is pivotal for reducing morbidity and mortality. Pulse oximetry is used in many countries to screen newborns for CCHD. However, this screening has not been implemented in the Netherlands, because of the unique perinatal care system, with a high home birth rate and early discharge after hospital deliveries. This thesis describes research performed to assess the feasibility, accuracy, acceptability and costs of neonatal screening for CCHD with pulse oximetry in the Dutch perinatal care system. To do this, the protocol that is used in the United States and Scandinavia was adapted to fit the working scheme of community midwives. Show less
Diabetic nephropathy is a major cause of end-stage renal disease worldwide. In this thesis we investigated several aspects of diabetic nephropathy, including histological lesions scored... Show moreDiabetic nephropathy is a major cause of end-stage renal disease worldwide. In this thesis we investigated several aspects of diabetic nephropathy, including histological lesions scored according to the pathologic classification of diabetic nephropathy, inflammatory markers, the CNDP1 gene and the carnosine metabolism. Several studies of this thesis used histological and clinical data obtained from an autopsy cohort of patients with diabetes. The renal tissue of this autopsy cohort provided us with the opportunity to investigate more than 100 glomeruli per case and gave us the opportunity to challenge several hypotheses in a unique setup. Show less
The main aim of this thesis was to unravel the signaling and regulatory networks that drive tumor cell migration during breast cancer metastasis. Understanding how tumor cells migrate, how this... Show moreThe main aim of this thesis was to unravel the signaling and regulatory networks that drive tumor cell migration during breast cancer metastasis. Understanding how tumor cells migrate, how this process is differentially regulated, and how this highly heterogeneous and plastic behavior is coordinated during metastatic dissemination, will ultimately provide novel insights in therapeutic opportunities. The work presented in this thesis includes different microscopy techniques and analytical tools to study migratory behavior (Chapters 2, 3, 4, and 5), reveals an important role for adhesion GPCRs in cell adhesion and migration (Chapter 3), provides a compendium of genes that drive tumor cell migration in breast cancer (Chapter 4), and investigates the intricate connection between adhesion dynamics, cell migration and contractility (Chapter 5). Collectively, this work provides novel insights in the molecular determinants of tumor cell migration and will help us better understand the signaling landscape that drives the formation of breast cancer metastases. Show less
In this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was... Show moreIn this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was to determine which predictors and associated factors contributed to the development of certain non-motor symptoms in Parkinson’s disease (PD). Strengths of our cohort study include the length of the follow-up period, broad clinical characterization, limited loss-to-follow-up and the large cohort size. The following non-motor symptoms have been addressed in this thesis: psychosis (hallucinations), dementia, excessive daytime sleepiness (EDS), insomnia, depression and anxiety. We found that while certain non-motor symptoms are inherent components of PD that increase in severity as the disease progresses, others symptoms such as excessive daytime sleepiness are inarguably caused by antiparkinsonian medication. For the future, we hope to see more longitudinal data on the disease progression in PD from large cohorts. Knowledge from longitudinal studies does not only contribute to more insight in the underlying pathobiology of PD, but it could also help the caregiver to monitor patients with particular risk factors more closely and adjust treatment if necessary. Show less
In this on-line dissertation, jazz saxophonist Dick de Graaf investigates a variety of compositional and improvisational models and techniques in contemporary jazz and Western art music, and... Show moreIn this on-line dissertation, jazz saxophonist Dick de Graaf investigates a variety of compositional and improvisational models and techniques in contemporary jazz and Western art music, and discusses possible applications of these materials in current jazz practices. The study includes examinations of educational publications by five selected jazz artists (Dave Liebman, Jerry Bergonzi, George Garzone, Walt Weiskopf, and John O’Gallagher), and the analysis of compositional techniques by two composers of the 20th century: Peter Schat's Tone Clock and Olivier Messiaen's modes of limited transposition. In addition, these theories and techniques are illustrated by selected examples (transcriptions and audio excerpts) and by examples of applications by various musicians, including the author. All examples are thoroughly analyzed and evaluated in order to determine their potential use in contemporary jazz practices. The research results provide comprehensive insights into compositional and improvisational processes in jazz, and offer materials that can be useful for the personal artistic development of jazz practitioners, including musicians, composers, and educators. Show less
This thesis reports on studies that have investigated the role of several factors on the risk of arterial thrombosis. The thesis is organised in two sections. The first section (Chapters 2-5)... Show moreThis thesis reports on studies that have investigated the role of several factors on the risk of arterial thrombosis. The thesis is organised in two sections. The first section (Chapters 2-5) deals with risk factors for the first arterial thrombotic event whereas the second section (Chapters 6 and 7) concerns risk factors for recurrence. The investigations touch several aspects of epidemiology, and make use of several observational study designs, encompassing case control, cohort and meta-analysis. Several statistical models were also applied ranging from logistic regression models, Cox proportional hazards time to event regression models as well as non-parametric statistics. Because of the heterogeneous nature, each investigation had specific problems in study design, data collection and analyses. A common line, however, is the haemostatic balance and its markers. Taken together, the findings of this thesis lead to the conclusion that there are differences in the aetiology of the two main forms of arterial thrombosis. Indeed, they support the hypothesis that hypercoagulability plays a greater role in the pathogenesis of ischaemic stroke than in that of myocardial infarction. Show less
We conclude that eHealth-supported self-management integrated into usual care can help patients with Chronic Obstructive Pulmonary Disease and Oral Anticoagulation Therapy to manage their... Show moreWe conclude that eHealth-supported self-management integrated into usual care can help patients with Chronic Obstructive Pulmonary Disease and Oral Anticoagulation Therapy to manage their disease. We assume that blended care with total integration of eHealth and usual care will provide better quality of care in the long term. Professional training of healthcare professionals on the care program including self-management supported by eHealth and personal assistance for the patients to guide them through the platform are essential elements to stimulate the use of eHealth. With appropriate training through e-learning or group training, self-management seems safe and reliable for a selected proportion of motivated patients. Even though eHealth-supported self-management was not superior to usual care regarding health status, the studies produced no negative effects, suggesting that eHealth is a safe option for delivery of self-management support and high-quality disease management. The usage of eHealth platforms is better under conditions of perfect integration into usual care and with personal assistance and the coaching of patients. The usage is highest for patients with platforms that add high practical value in daily life. Show less
Clinical development of drugs for central nervous system (CNS) disorders has been particularly challenging and still suffers from high attrition rates. This high attrition is mainly due to lack of... Show moreClinical development of drugs for central nervous system (CNS) disorders has been particularly challenging and still suffers from high attrition rates. This high attrition is mainly due to lack of efficacy during clinical development. To improve the prediction of CNS drug effects, knowledge of the drug concentration at the CNS target-site is indispensable. Unfortunately, measuring drug concentrations in the human CNS has major practical and ethical constraints. Therefore, alternative approaches to predict the drug pharmacokinetics (PK) at the target-site(s) in the human CNS should be searched for.In this research, a comprehensive CNS physiologically based PK (PBPK) model for prediction of drug concentration-time profiles in multiple CNS compartments was developed for both rats and humans. The CNS PBPK model only requires knowledge of physicochemical properties of the drugs, with the influence of the net active transporters on the drug exchange across the BBB and the BCSFB that can be obtained from in silico predictions, literature information and in vitro studies (if needed). Because of this, the developed CNS PBPK model is a powerful tool to predict drug PK in the CNS in the early stage of the drug development. Show less
