International Migration, Integration and Social Cohesion online publications
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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
TRIP13 and germline gene expression in cancer:Mechanisms of acquired radioresistance
No full textCancer is a major global health challenge, characterized by increasing incidence rates and significant therapeutic obstacles. Despite the diversity among cancer types, they share common characteristics, referred to as the hallmarks of cancer, which serve as critical drivers of tumor progression. These hallmarks have been effectively exploited as therapeutic targets, given their essential role in supporting cancer cell proliferation and survival. Recent research has identified a subset of germline-cancer (GC) genes—normally restricted to germline cells but aberrantly expressed in tumors—that regulate key processes such as meiosis, gene regulation, and DNA repair, with their activation linked to poor prognosis. In this thesis, we demonstrate that high GC gene expression in lung cancer cell lines is associated with enhanced DNA double-strand break (DSB) repair, increased proliferation, and radioresistance. Among these genes, TRIP13 was identified as a key driver of this phenotype. Functional studies showed that TRIP13 inhibition or knockout reduces clonogenic survival, sensitizes cells to ionizing radiation, and downregulates DNA repair proteins. Repeated radiation exposure induced TRIP13 expression, conferring acquired radioresistance and correlating with poor prognosis in lung cancer patients. Moreover, we show that melatonin (MT), acting via the MTNR1B receptor, downregulates TRIP13 and its downstream DNA repair proteins. TRIP13 inhibition also diminished EGFR expression and phosphorylation, indicating additional oncogenic functions beyond DNA repair. Collectively, these findings uncover a novel mechanism of therapeutic resistance driven by aberrant germline gene activation and highlight TRIP13 as a promising therapeutic target to enhance the efficacy and specificity of lung cancer treatment.</p
Perspective matters in recovery:From fragmented to collaborative care in complex psychosis
No full textPeople with a hard to manage psychosis and complex co-occurring challenges (“complex psychosis”) and their families often go through long and difficult care trajectories in mental healthcare, including admission to long-term inpatient mental health rehabilitation services. Arguably, they face a complicated (personal) recovery process. People with a complex psychosis, families and professionals often hold diverging views on the problem, and what should happen, which complicates their collaboration for recovery. Unfortunately, research on complex psychosis is scarce, due to the very complexity of problems and potential unwillingness and/or inability to consent to research. This thesis explored perspectives that potentially help to improve care for people with a complex psychosis and their families. Part I discusses prerequisites to do research in this hard-to-access group. Part II focuses on preventing cumbersome trajectories, including the role of familial cognitive vulnerability, long-term outcome prediction and hypotheses on ways to care delivery to people with complex psychosis. Part III focuses on the needs people with a complex psychosis, their family and mental health professionals have to effectively collaborate for recovery, based on their personal perspectives. In conclusion, participatory research, early identification of vulnerabilities of those with complex psychosis, and collaborative care that tolerates diverging perspectives, with continuity of those involved, should go together, to prevent fragmentation and foster growth in people with a complex psychosis, their family and professionals
Evaluating surgical patient experiences and clinical outcomes
No full textThis thesis explores the significance of patient-centred care in modern surgical practice, focusing on both general and cardiac surgery. Patient-centred care prioritises the patient’s beliefs, values, and experiences, aiming to improve not only traditional clinical outcomes—such as mortality, complications, and technical performance—but also patient-reported outcomes (PROs) like pain, health-related quality of life (HRQoL), and emotional well-being. The introduction highlights that while clinical metrics are well established, PROs remain underutilised, especially in cardiac surgery, despite their importance in capturing the long-term challenges patients face after surgery.The thesis is divided into two main parts. The first part examines chronic post-surgical pain management, particularly the use of neuromodulation techniques such as spinal cord and dorsal root ganglion stimulation. These studies assess both clinical and patient-reported outcomes, demonstrating the value of integrating PROs to evaluate the effectiveness and sustainability of pain management strategies.The second part focuses on cardiac surgery, with special attention to perioperative coagulation management in patients with infective endocarditis (IE) and the use of PROs in patients undergoing thoracic aortic surgery. Surveys and registry analyses reveal significant variation in clinical practice and underscore the need for standardised protocols and better preoperative management. Studies on aortic surgery patients show that survivors face persistent physical, mental, and social challenges, reinforcing the necessity of including PROs in surgical evaluation.Overall, the thesis advocates for a shift towards more personalised, patient-centred surgical care, aligning clinical success with patient-defined goals and long-term quality of life
Advancing hyperthermia treatment through treatment planning and small animal research
No full textHyperthermia, the heating of tumours to 40–43 °C for one hour, is an established sensitiser to radiotherapy and chemotherapy, effective in several cancers such as melanoma, sarcoma, bladder, recurrent breast, cervix, and rectum. New applications include pancreatic cancer and combinations with immunotherapy. Wider adoption, especially for deep-seated tumours, requires consistent clinical protocols, yet current progress is hindered by variability across institutes and insufficient translational models.This thesis addresses hyperthermia treatment consistency through two main aims: improving the accuracy of hyperthermia treatment planning (HTP) for deep-seated tumours, and enabling clinically representative small-animal studies. In Chapter 2, uncertainty in tissue properties and perfusion was systematically evaluated using a Polynomial Chaos Expansion (PCE) methodology. Results showed that electrical conductivity and perfusion strongly affect predicted temperatures, with variations of up to 9 °C in pancreatic cases. In Chapter 3, robust stochastic optimisation strategies were developed to mitigate these uncertainties, reducing hotspots while maintaining effective tumour heating, thus improving treatment reliability and reducing operator adjustments.Chapters 4, 5, and 6 focus on translational research with the ALBA micro8, a novel miniature phased-array system for mice. Simulations and phantom experiments demonstrated its ability to achieve precise and robust heating of deep-seated tumours under realistic conditions, with high spatial accuracy and tolerance to physiological variations. Dedicated bioheat models for mice further enhanced preclinical HTP accuracy. This system provides a reliable platform for studying hyperthermia’s biological and immunological effects in tumour models.Overall, the research strengthens the foundation for standardised, reproducible hyperthermia delivery, facilitating multi-centre trials and broader clinical implementation. Standardisation and improved consistency will support wider adoption and reimbursement, ultimately advancing oncological care
From crisis to cure:Allogeneic stem cell transplantation for adults with sickle cell disease
Get PDFSickle cell disease (SCD) is a group of inherited hemoglobinopathies, associated with chronic hemolytic anemia, recurrent vaso-occlusive pain episodes, and progressive organ damage. To date, allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative treatment for patients with SCD. Historically, HSCT was used in children with severe SCD and an available matched sibling donor, applying myeloablative conditioning regimens. More recently, non-myeloablative conditioning and haploidentical HSCT protocols have been developed, rendering HSCT a feasible treatment option for many more patients, including adult patients with SCD. In the Netherlands, the first non-myeloablative transplantation program for adult patients with SCD was implemented in 2018 at the Amsterdam UMC. The studies presented in part I of this thesis aim to improve the outcomes after non-myeloablative HSCT in adult patients with SCD, with a focus on reducing graft failure rate while balancing the toxicity of the conditioning regimen and the risk of GvHD. In part II of this thesis, three studies are presented which sought to enhance our understanding of the impact of allogeneic HSCT on the patients’ immune system. Last, part III of this thesis focusses on evaluating the effects of HSCT on SCD-related organ (dys)function and health-related quality of life.</p
Molecular conversations with soluble adenylyl cyclase:A journey of serendipity
Get PDFAdenylyl cyclases are enzymes that produce cAMP. In contrast to the more well-known transmembrane adenylyl cyclases, soluble adenylyl cyclase (sAC) is found in the cytoplasm and in intracellular organelles. sAC is also not regulated by G-proteins or activated by forskolin; instead, it is regulated by intracellular bicarbonate, calcium, and ATP concentrations. Recent studies have demonstrated the role of sAC-specific cAMP in various tissue-specific and cell autonomous contexts. Despite these unique known properties and functions, not much is known about how cellular sAC protein levels are regulated or maintained. In this thesis, using the H69 cholangiocyte cell line as our model, we set out to investigate how sAC is regulated at the post-translational level and is involved in cholangiocyte-specific functions and physiology, such as cellular apoptosis and ciliogenesis. The observations presented in this thesis imply that sAC could potentially be therapeutically targeted to restore or maintain cholangiocyte physiology in diseases such as primary biliary cholangitis or polycystic liver disease
Cardiovascular care in a multiethnic community:Detection, delays, and gender differences
Get PDFIschemische hart- en vaatziekten (IHVZ) vormen een belangrijke doodsoorzaak in Nederland, met aanzienlijke verschillen in ziektelast tussen vrouwen en mannen, en verschillende etnische groepen. Vroege opsporing en tijdige zorg zijn cruciaal om de gezondheidsuitkomsten te verbeteren. Daarom richt dit proefschrift zich op het optimaliseren van preventieve en curatieve zorg voor diverse populaties, met specifieke aandacht voor vrouwen en verschillende etnische groepen.In deel 1 onderzochten we hoe preventieve zorg verbeterd kan worden via betere risicoscreening. Psychosociale factoren, specifiek opleidingsniveau en arbeidsstatus, kunnen gebruikt worden als aanvullende selectiecriteria voor cardiovasculaire risicoscreening, vooral bij vrouwen en sommige etnische groepen. Deel 2 richtte zich op vertraging in curatieve zorg. Kwalitatief onderzoek liet zien dat in het bijzonder klachtherkenning, maar ook verschillende andere factoren, bijdragen aan vertraging in het zoeken van zorg. In ons kwantitatieve onderzoek zagen we verschillende patronen in (mogelijke) vertraging in de zorg tussen vrouwen en mannen, en tussen verschillende etnische groepen. In deel 3 beschreven we de ontwikkeling, implementatie, en evaluatie van een gender- en cultuursensitieve toolkit om klachtherkenning en zorgzoekgedrag voor (potentieel) cardiale klachten te verbeteren. De eerste evaluaties waren positief: we zagen een hoge tevredenheid, en lichte toename in kennis over klachten en risicofactoren op de korte termijn. Verdere studie naar (kosten)effectiviteit is nodig.Het proefschrift concludeert dat er geen universele aanpak is voor vroege herkenning en tijdige zorg voor IHVZ in een diverse populatie. Maatwerk, inclusief voorlichting en screening, is essentieel. Daarnaast illustreert dit onderzoek het belang van inclusief en participatief onderzoek
Young citizens and their parents, peers, and teachers in a changing world:Social contexts of citizenship competences in adolesence
No full textCitizenship knowledge, attitudes, and skills enable adolescents to understand and participate in a pluriform and democratic society. Adolescents today grow up in a complex and uncertain world, facing serious challenges. In different social settings, adolescents share opinions, exchange ideas, practice principles of democracy, and experience what it means to be part of a community. This dissertation aimed to enhance understanding of the associations between adolescents’ citizenship competences and contextual factors. The central research question was: “To what extent are adolescents’ experiences with their parents, peers, and teachers, as well as their concerns about the world’s future, associated with their citizenship competences?”. A quantitative, large-scale, and representative dataset among adolescents in the Netherlands (13-14 years old) was used. The data included a civic knowledge test, a questionnaire on civic attitudes, engagement and skills, and a questionnaire about European issues. By including additional questions about parents and peers, a unique dataset was created that provided deeper insight into adolescents’ citizenship competences in relation to various important social contexts. Three main conclusions are drawn: 1) Adolescents’ citizenship competences are associated with their (interrelated) experiences with their parents, peers, and teachers; 2) Even in times of societal and educational changes, adolescents’ experiences within schools remain important for their citizenship competences; and 3) Civic engagement in adolescence manifests in various ways and is intertwined with individual perspectives on macrosocial issues. Taken together, this dissertation underscores the importance of acknowledging adolescents’ social contexts and their own macrosocial concerns to understand and support their citizenship competences
The molecular orchestra of early placenta development:Key determinants of maternal-fetal health
Get PDFThis dissertation investigates the molecular mechanisms underlying healthy and pathological early human placenta development. The placenta is essential for fetal growth and survival, mediating nutrient and gas exchange, hormone production, and immune protection. Disruptions in its formation can lead to complications such as preeclampsia and fetal growth restriction. These complications originate early in pregnancy, during the period when in healthy conditions trophoblast cells differentiate and establish the maternal–fetal interface. Using human trophoblast stem cells, trophoblast organoids, and first-trimester placental and decidual tissue, this work explores both fetal and maternal factors regulating trophoblast differentiation and invasion. The findings reveal that reduced fetal activity of the transcriptional coactivator EP300 impairs the formation of both syncytiotrophoblasts and extravillous trophoblasts, identifying EP300 as a key regulator of trophoblast lineage development. In addition, maternal excess of the pro-inflammatory cytokines IFN-α and TNF-α inhibit trophoblast invasion without affecting differentiation, offering insight into how maternal autoimmune conditions may predispose to placental dysfunction. Together, these results emphasize the need for balanced molecular signaling between fetal and maternal components to support normal placentation. Additional studies showed no adverse effects of the maternal immune response to COVID-19 mRNA vaccination on trophoblast development, reinforcing vaccine safety in pregnancy. Furthermore, analyses of alternative RNA splicing during trophoblast differentiation, and optimized methods for deriving patient-specific trophoblast stem cells, provide new hypotheses and tools for investigating regulatory pathways and disease mechanisms. Overall, this thesis highlights the intricate coordination required for placental development and its critical role in ensuring healthy pregnancy outcomes