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From the battlefield to the courtroom (and back):The interplay between international humanitarian law and international criminal law
No full textInternational humanitarian law (IHL) was created to work preventatively, on the battlefield; for its part, international criminal law (ICL) has been drafted for use in retrospect, in a courtroom-setting. This thesis considers the interplay between these two branches of public international law. While the clarification and development of IHL by international criminal courts and tribunals was very welcome, the manner in which it has been applied during international trials was not always correct and may also be critiqued. In addition, the application of IHL in retrospect, as part of the prosecution and adjudication of alleged war crimes or other international crimes, such as crimes against humanity, is challenging. The scope of application of IHL, for example, has been assessed through a criminal law ‘lens’, leading to a significant broadening of its scope. The resultant expansive application of IHL by international criminal courts and tribunals may have a negative impact on the protection of persons under IHL or other bodies of law. Similarly, rulings on questions related to the conduct of hostilities may impact the legal framework governing military operations in times of armed conflict, and thus affect members of the military or on indeed other persons working with IHL during conflicts. The present book critically analyses the case law of war crimes trials before the International Criminal Tribunals for the former Yugoslavia and Rwanda, the Special Court for Sierra Leone, and the International Criminal Court (ICC) and finds that more attention must be paid to ensure that IHL is correctly applied. For the ICC, statutory changes are required to avoid war crime provisions being applied incorrectly, intentionally or not, and the law distorted to prevent impunity; otherwise, such distortions may result in a version of IHL that can no longer be applied preventatively on the battlefield. Of equal note is that those reading international criminal and humanitarian law judgments must be mindful of the scope and limitations of such rulings
Potassium and its effect on natriuresis and cardiovascular outcomes in health and kidney disease
No full textIn this thesis, we explored the complex relationship between potassium intake, natriuresis, blood pressure (BP), and cardiovascular disease (CVD) outcomes in health and chronic kidney disease (CKD). In the first chapter, we studied dietary potassium intake in the general population and found that higher intake was associated with lower systolic BP and reduced CVD risk—particularly in women. Notably, in women, the association between potassium intake and systolic BP was modified by sodium intake. In the following chapters we examined the acute effects of a single oral potassium load on potassium and sodium balance. In healthy individuals, both changes in acid–base balance and aldosterone levels contributed to potassium uptake and excretion. Moreover, in healthy individuals, natriuresis increased in response to a single oral load of potassium, while in patients with CKD G3b–4 potassium-induced natriuresis was absent. Next, we evaluated the effects of 14-d supplementation of potassium chloride in patients with CKD G3b–4. We showed that potassium supplementation increased plasma potassium, but had no significant effect on BP or eGFR. Also, in proteinuric CKD patients, the proteinuria, but not BP-lowering response to losartan during a habitual high-sodium diet was hampered during high potassium intake. However, differences disappeared after sodium status change by low-sodium diet. Finally, we reviewed potassium management in haemodialysis patients, emphasizing the need for individualized strategies. Altogether, this thesis highlights that the beneficial effects of potassium may highly depend on patient characteristics including sex, sodium intake, kidney function and use of single renin-angiotensin-system (RAS) blockers
Impact of diversity on cardiovascular health:Insights from the HELIUS study
No full textThis thesis explores cardiovascular ageing and its determinants, focusing on differences by sex and ethnicity. We used data from the HELIUS cohort study, a large, multi-ethnic, population-based study in Amsterdam. Part I introduces a conceptual framework for cardiovascular ageing, defined as the progressive deterioration of the cardiac and vascular systems. Key biomarkers, such as pulse wave velocity (PWV), carotid intima-media thickness (IMT), and NT-proBNP, were identified, with an emphasis on the need for ethnic-specific cut-off values. We also examined ethnic differences in carotid plaque presence and IMT, revealing significant disparities. Additionally, longitudinal data showed increasing ethnic differences BMI levels over time, particularly among younger individuals. Part II focuses on hypertension as a key determinant of cardiovascular ageing. Longitudinal analyses revealed widening disparities in systolic blood pressure levels among Ghanaian, Moroccan, and Turkish groups compared to the Dutch. We also explored sex differences in hypertension phenotypes. Compared to men, women had a higher risk of developing sustained hypertension, particularly those with isolated diastolic hypertension, highlighting the need for closer blood pressure monitoring in young women. Part III examines the impact of cardiovascular risk factors on cerebrovascular health. MRI data showed that higher BMI and diabetes were associated with lower brain volumes, while hypertension and a history of cardiovascular disease correlated with white matter hyperintensities. Associations between cardiovascular risk factors and cerebral blood flow were weaker. Finally, carotid plaque components, such as lipid cores, calcifications, and intraplaque hemorrhage, were associated with distinct cardiovascular risk factors
Lending colour to the black box:Insights into the course and burden of primary sclerosing cholangitis
No full textPrimary sclerosing cholangitis (PSC) is a rare cholestatic liver disease marked by multifocal bile duct strictures and is strongly associated with inflammatory bowel disease (IBD). The disease runs an unpredictable course with increased risk of developing colorectal and hepatobiliary cancers, frequently culminating in liver transplantation. While its cause remains unclear, no proven medical therapy exists to halt disease progression.Part I assessed the disease burden of PSC. Although individually rare, cholestatic liver diseases pose a significant epidemiological and economical burden. Dutch registry data revealed that patients lose an average of 11.8 healthy life-years in the first 30 years post-diagnosis, spend 12 hospital days annually, incur average yearly medical costs of €12,169, and experience a 25% work productivity loss. Health-related quality of life is reduced, particularly by IBD symptoms, pruritus, and advanced liver disease, but improves post-transplant.Part II explored the gut–liver axis. Proctocolectomy with permanent ileostomy was linked to a 60% reduced risk of transplantation or PSC-related death, while colectomy with remnant colon or pouch did not show survival benefit. IBD presence or endoscopic activity showed no direct impact on transplant-free survival, presumably due to persistent microscopic gut inflammation.Part III evaluated biliary tract interventions. Cholecystectomy showed no significant survival effect and should therefore not be avoided in PSC. Ursodeoxycholic acid (UDCA) use did not improve long-term outcomes, though a possible chemoprotective effect against hepatobiliary malignancy was noted, warranting further study
Direct oral anticoagulants for atrial fibrillation:On comparing apples and oranges
No full textAtrial fibrillation is the most common sustained cardiac arrhythmia. It increases the risk of thromboembolism, which oral anticoagulants reduce effectively. For decades, vitamin K antagonists were the only class of oral anticoagulants available, but their narrow therapeutic window and need for close monitoring limited their use. Direct oral anticoagulants (DOACs) offered safer, more convenient alternatives, backed by robust phase III trials. This thesis examines key concerns that arose after their approval and widespread use in clinical practice.Part I reviews nonadherence and treatment patterns. Tracing the history of anticoagulant trials, we see how DOACs became the preferred agents. Large cohort studies reveal a clinician preference for factor Xa inhibitors, show that switching and serious nonadherence are relatively uncommon, and identify candidate predictors for both outcomes.Part II focuses on higher-risk patients and off-label dosing. We found sex differences in how clinicians assess frailty using clinical judgment alone. Patients with atrial fibrillation and atherosclerotic disease in routine practice show better cardiovascular health and fewer events than those in original trials — likely due to patient selection, improved care, or tailored treatment. We critique flawed off-label dosing studies and recommend integrating clinical judgment into DOAC dosing decisions for higher-risk individuals. Finally, we show that higher event rates seen with apixaban in daily practice mainly reflect patients’ underlying risk, not off-label dosing.Part III is on drug-level monitoring. We updated DOAC on-therapy ranges to aid interpretation of measured levels, and we found that a single apixaban measurement may help personalize dose selection.<br/
Let misophonia be heard:Advancing recognition, diagnostics and treatment of misophonia in youth
No full textMisophonia is a recently identified disorder of decreased tolerance to specific sounds or associated stimuli (so-called “triggers”). Triggers primarily include human-made sounds such as eating or breathing. Confrontation with triggers elicits intense emotional, behavioral and physiological responses that are difficult to control. Misophonia typically develops during childhood and has considerable consequences for the daily lives of children and families. Often, children can no longer eat, sleep or travel by car together with their family, and they experience problems at school and with friends. There is a great need for adequate diagnostics and evidence-based treatment. The main aim of this thesis is to improve care for children, adolescents and families suffering from misophonia. We present the first controlled study worldwide investigating misophonia in 95 children and adolescents (aged 8-18). We: 1) assessed clinical characteristics, psychiatric comorbidity and quality of life; 2) designed and validated two child-specific questionnaires for screening and severity assessment of misophonia in children and adolescents; 3) performed a randomized controlled trial (RCT) investigating combined cognitive behavioral and psychomotor group therapy (CBT+PMT); 4) performed a cost-of-illness study investigating the financial burden of misophonia on families and society. This thesis underlines the importance of classifying misophonia as a discrete disorder. By providing two validated questionnaires and the first evidence-based treatment, this thesis paves the way for improved recognition, diagnostics and treatment of misophonia in youth
Threatened preterm birth and beyond:Clinical management and child follow-up
No full textDespite advances in obstetric care, the optimal management of threatened preterm birth remains to be determined. This thesis contributes to improving the management of threatened preterm birth by evaluating the role of tocolytics and investigating the optimal timing of birth in late preterm prelabour rupture of membranes, considering both short- and long-term child outcomes. Furthermore, this thesis discusses different approaches to long-term follow-up research of children prenatally exposed to obstetric interventions, an area that still receives limited focus. Future studies must further refine the risk assessment of threatened preterm birth, and the evaluation of long-term child outcomes should be standardised in preterm birth studies. Ultimately, by aligning treatment strategies with individual risk profiles, we can improve outcomes not only at birth, but throughout childhood and beyond
Timing of light:Circadian and metabolic effects
No full textIn mammals, the circadian timing system consists of a light- sensitive central brain clock located in the hypothalamic suprachiasmatic nucleus (SCN) and various peripheral clocks. Disruption of this circadian system is associated with adverse health problems including adiposity and diabetes mellitus. This thesis aims to study the timing of light, and the circadian and metabolic effects on rats and humans. Chapter 2 investigates the adaptation speed of behavioral and metabolic parameters in a rat model of jet lag and shift work, and the effects of time-restricted food intake as a potential strategy to mitigate the negative effects of such phase-inversions in rats. Chapter 3 investigates possible changes in the liver and muscle insulin signaling pathway, the adaptation speed of the molecular clock in liver, muscle and white adipose tissue (WAT) and the daily body temperature rhythm in the same rat model. Moreover we investigate the effect of high fat diet, either ad libitum or restricted to the dark period, on the adaptation speed after a 12h phase shift of the light/dark cycle in rats. Chapter 4 investigates the blood oxygenation level dependent light responsiveness of the SCN-area in three groups of obese people: 1) normal insulin sensitivity, 2) insulin resistance and 3) type 2 diabetes. Further, we investigate the resting-state functional connectivity from the SCN-area to pre-specified regions of interest in brain as a marker of resting-state SCN-area activity. Chapter 5 investigates the effect of morning bright light exposure on the human WAT transcriptome.<br/
Personalising treatment and targets in IBD
No full textInflammatoire darmziekten (IBD) zijn chronische ontstekingsziekten van de darm. De precieze oorzaak is onbekend. Klachten die vaak voorkomen zijn buikpijn, diarree, bloed bij de ontlasting en een plotselinge, onhoudbare aandrang voor ontlasting. IBD kan niet worden genezen. De behandeling is erop gericht de ontsteking te onderdrukken, maar dat lukt niet altijd. In dit proefschrift hebben we onderzocht of meer persoonlijke aanpak van zowel de behandeling als de behandeldoelen kan zorgen voor betere uitkomsten voor patiënten.In het eerste deel keken we naar het personaliseren van de behandeling. Uit eerder onderzoek bleek dat patiënten met een ernstige aanval van colitis ulcerosa mogelijk een hogere dosering van het medicijn infliximab nodig hebben, maar dat de optimale dosis verschilt per persoon. Wij hebben daarom in deze patiënten onderzocht of een persoonlijke dosis infliximab (afgestemd op de concentratie infliximab in het bloed) beter werkt dan de standaarddosis. We vonden dat een persoonlijke dosering mogelijk beter werkt en net zo veilig is als de standaarddosering. De persoonlijke dosis heeft daarom waarschijnlijk een beter risico/baten profiel.In het tweede deel richtten we ons op behandeldoelen. Voor veel patiënten is kwaliteit van leven een van de belangrijkste doelen. Bestaande vragenlijsten om dit te meten zijn echter vooral gemaakt door artsen, die kwaliteit van leven anders beoordelen dan patiënten zelf. Ook zijn de vragenlijsten vooral ontwikkeld in westerse landen en leggen ze nadruk op wat patiënten niet meer kunnen. Wij hebben daarom samen met patiënten wereldwijd een nieuwe vragenlijst ontwikkeld. Deze meet in hoeverre mensen met IBD een normaal leven kunnen leiden. De vragenlijst is getest in vier talen (Nederlands, Engels, Spaans en Hindi) en bleek goed en betrouwbaar te werken.Door behandeling en behandeldoelen te personaliseren, hopen we dat patiënten met IBD in de toekomst vaker een normaal leven kunnen leiden
Serotonin and dopamine:An updated investigation of neurochemical signals surrounding appetitive and aversive stimuli
No full textMany people believe that dopamine and serotonin are key players in experiencing reward and happiness, but this understanding oversimplifies the complex roles these neuromodulators play in influencing behavior. Our current understanding of dopamine and serotonin signaling remains incomplete, limiting the development of effective treatments for neuropsychiatric disorders such as obsessive-compulsive disorder (OCD), addiction, depression, and Parkinson’s disease. In this thesis, we employed high-precision techniques with high specificity, sensitivity, and temporal resolution to better characterize dopamine and serotonin signaling. By utilizing fast-scan cyclic voltammetry (FSCV) to measure real-time serotonin and dopamine release and optogenetics to selectively activate serotonergic neurons, we investigated how these neuromodulators respond to appetitive and aversive stimuli on behaviorally-relevant timescales. We found dopamine release is differentially regulated across striatal subregions and that, within the ventromedial striatum (VMS), value-based changes in dopamine signaling in response to rewards occur rapidly and incorporate both model-based and model-free reinforcement learning mechanisms. Additionally, we found that VMS dopamine tracks aversive stimulus duration and prediction but not value or prediction error. Lastly, we observed that serotonin mildly promotes voluntary actions and ongoing movement but does not influence instinctive or compulsive behaviors. Together, our findings provide new insights into how dopamine and serotonin influence behavior in response to appetitive and aversive stimuli. These insights offer promising avenues for improving therapeutic strategies for neuropsychiatric disorders