International Migration, Integration and Social Cohesion online publications
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    Cardiovascular care in a multiethnic community:Detection, delays, and gender differences

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    Ischemische 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

    Incremental cartilage damage of the ankle:Steps towards an evidence-based personalized approach

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    The present thesis highlights the etiology, incidence, phenotypes as well as management of (osteo)chondral injuries to the ankle throughout a wide and inter- and multidisciplinary scope. The overreaching goal of the thesis was to work towards an evidence-based personalized approach for the treatment of incremental cartilage damage of the ankle with a specific focus on the treatment of large, secondary osteochondral lesions of the talus, hence aiming to prevent the further progression in the above-mentioned cascade from osteochondral lesion to end-stage osteo-arthritis

    Preterm birth prevention:Cervical length assessment and long-term follow-up

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    Als een kind voor 37 weken zwangerschapsduur geboren wordt, kan dit nadelige gevolgen hebben op de korte én lange termijn. Het voorkomen van een vroeggeboorte is daarom belangrijk. Dit proefschrift richt zich op (1) hoe kan de voorspelling van een spontane vroeggeboorte verbeterd worden met behulp van een meting van de cervix (baarmoedermond) en (2) wat zijn de lange termijn gevolgen van interventies die worden ingezet om een vroeggeboorte te voorkomen?Op basis van dit proefschrift concludeerden wij dat er aanzienlijke verschillen bestaan, zowel tussen als binnen landen voor de methode van meten van de cervixlengte. Een gestandaardiseerde meting van de cervixlengte zal de identificatie van vrouwen met een verhoogd risico op een vroeggeboorte verbeteren. Tevens toonden wij aan dat de afname van de cervixlengte over de tijd potentieel bijdragend is aan de voorspelling van een vroeggeboorte. Er moet overwogen worden om de afkapwaarde voor een korte cervix per populatie aan te passen.Veel gebruikte interventies in de zwangerschap zijn progesteron en laag gedoseerde aspirine. Wij concludeerden dat het gebruik van deze middelen veilig lijkt voor het kind op de lange termijn. Dit ondersteunt een bredere indicatiestelling ter preventie van een vroeggeboorte. Vervolgonderzoek moet uitwijzen of meer vrouwen baat hebben bij deze eventuele interventies

    Novel fluorophores for advancing super-resolution and correlative microscopy

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    Optical and electronmicroscopy are fundamental imaging techniques in life and material sciences.However, conventional optical microscopy is constrained by the diffractionlimit (~200 nm), preventing visualization of fine subcellular structures.Single-molecule localization microscopy (SMLM) overcomes this limitation byexploiting photoswitchable fluorophores to achieve nanometre-scale resolution.Further expanding SMLM applications and enabling super-resolution correlativelight and electron microscopy (SR-CLEM) require intrinsically blinking andchemically stable fluorophores.This thesis reportsthe development of two classes of such fluorophores—nanographenes and rylenes—anddemonstrates their utility in advanced imaging. Hydrophilic and functionalizednanographenes were synthesized and exhibit environment-independent blinkingunder diverse conditions, enabling SMLM imaging of amyloid fibrils in air,lysosomal dynamics in live cells, and nascent peptide translation in neurons.These studies revealed heterogeneous local translation along axonal branches.To extend SMLM intothe near-infrared (NIR) region, intrinsically blinking rylene derivatives weredeveloped, offering reduced phototoxicity for live-cell SMLM imaging. Theirexceptional chemical stability allowed successful application in SR-CLEM,retaining robust blinking behavior after osmium tetroxide fixation and Epon resinembedding. Both single- and dual-color SR-CLEM were achieved, and theOsO₄-induced quenching mechanism, involving energy/electron transfer and aninner filter effect, was elucidated, providing valuable guidance for the futuredesign of SR-CLEM-compatible fluorophores.Overall, this researchestablishes nanographenes and rylenes as robust, intrinsically blinkingfluorophores for SMLM and SR-CLEM. The mechanistic insights and moleculardesigns presented here advance the development of fluorophores and expand thefrontiers of super-resolution microscopy in the life sciences.</p

    The molecular orchestra of early placenta development:Key determinants of maternal-fetal health

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    This 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

    KRAB-ZNFs: controllers of transposable element activity and safeguards of genome integrity

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    Transposable elements (TEs) are mobile DNA sequences that can move within genomes, shaping genomic diversity and evolution. However, their movement can cause DNA breaks and structural rearrangements, leading to genomic instability. As a defense mechanism, KRAB zinc finger proteins (KRAB-ZNFs) evolved as key repressors of TEs, binding specific TE sequences to silence them through epigenetic mechanisms. This dynamic interplay between TEs and KRAB-ZNFs has fueled an evolutionary arms race, promoting rapid diversification of both elements. Consequently, TE and KRAB-ZNF interactions have profoundly influenced genome architecture, regulatory networks, and species-specific traits across vertebrates. This thesis explores the versatility of KRAB-ZNF functions in the human genome, suggesting roles that extend beyond their established involvement in TE transposition repression. While previous research has primarily focused on KRAB-ZNFs as regulators of gene expression as an alternative model, this work broadens the scope to investigate additional roles, including the KRAB-ZNF mediated control of TEs involved in stem cell pluripotency and protecting our genome from excessive meiotic recombination. The findings presented here aim to inform and inspire further research into KRAB-ZNFs’ diverse contributions to gene expression network innovation, genome stability and human genome evolution

    Interventions for pancreatic diseases:Improving treatment while considering costs

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    This thesis explores the clinical and economic aspects of pancreatic diseases, focusing on pancreatic resections, interventional strategies for acute pancreatitis, and advancements in minimally invasive surgical techniques for chronic pancreatitis. Through systematic reviews, cost analyses, and randomized controlled trial protocols, key challenges and opportunities in optimizing pancreatic disease management are identified. The findings highlight the significant financial burden of pancreatic resections, underscoring the need for standardized reporting of complications and costs. Additionally, the potential benefits of robot-assisted surgery are evaluated, which may improve patient outcomes and reduce hospital stays, while considering its cost. In acute pancreatitis, a step-up, delayed approach for infected necrotizing pancreatitis, in line with current guidelines is recommended. The ongoing PICUS-2 and PANACOTTA trials will further expand on treatment strategies for idiopathic acute pancreatitis and chronic pancreatitis, respectively. Future research should focus on refining surgical techniques, enhancing perioperative care, and evaluating long-term (patient-reported) outcomes. Integrating cost-effective, patient-centered strategies will be crucial for advancing pancreatic surgery and improving both clinical and economic outcomes. This thesis provides insights that could shape future clinical practices and healthcare policies in pancreatic disease management

    <i>Wenyi</i> and its discontents:A study of creative practices and politics in Hong Kong

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    “Time will pass while our voice will last,” I titled the conclusion of this project with this line of lyrics, which I wrote in 2022. This line points to a key question of this project: How and when is wenyi politically engaged in the protests in Hong Kong? With the accelerating integration into China, and a definite return to Beijing looming in the year 2047 (Sino-British Declaration 1984), the future is increasingly unspeakable. Whilst it is often claimed that the future belongs to the young, a group of young literary practitioners, wenyi, have been involved in and struggling with, if not failing, their engagement with the anti- Extradition Law Amendment Bill movement in Hong Kong. This project asks when and how the creative practices of this group of wenyi practitioners– ranging from flash mobs to art, and from music to poetry – and politics intersect during the Anti-ELAB protests.The Hong Kong protests provide a unique prism through which to study the entanglement between creative practices, wenyi culture, and politics. Among the eruption of large protests worldwide, Hong Kong was a reference of Chilean and Catalonia protests. This project explores the relations between creativity, youth, and politics in Hong Kong by zooming in on wenyi practitioners – local young creative practitioners involved in different phases of the protests, from the beginning to the period of abeyance

    Systemic treatment in breast cancer:Towards a golden ratio

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    Breast cancer affects over 2 million patients worldwide annually. Systemic treatment options for breast cancer are ample, and vary from endocrine treatment to chemotherapy and targeted therapies. Systemic therapies hold great promise for patients, but also come with a risk of toxicity for patients (in terms of side effects) as well as societies (in terms of resource use). This thesis describes several studies aimed at optimizing different types of systemic treatment for patients with breast cancer. The main findings include: - The use of aromatase inhibitors in early breast cancer is not associated with early markers for cardiovascular disease (carotid intima media thickness, advanced glycation end products and dyslipidemia) - Patients with limited metastatic burden, so-called oligometastatic disease, have a favorable prognosis compared to patients with more widespread disease- Intensified alkylating chemotherapy does not improve clinical outcome compared to standard chemotherapy regimens in patients with oligometastatic breast cancer, whose tumor harbors homologous recombination deficiency - Using CDK4/6 inhibitors in first- versus second-line does not provide clinical benefit (in terms of progression-free nor overall survival) and is associated with an increase in toxicity for patients and higher drug expenditures for societies- Efficiency clinical trials are essential for affordable and sustainable health car

    Optimizing the treatment for anorectal disease:Surgical and patient-reported outcomes

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    This thesis focuses on optimizing treatment strategies for two prevalent benign anorectal conditions: hemorrhoidal disease and cryptoglandular perianal fistulas. It emphasizes the importance of integrating surgical outcomes with patient-reported experiences to improve clinical decision-making and personalized care.Part I evaluates the management of hemorrhoidal disease. The HOLLAND trial compared rubber band ligation (RBL) with hemorrhoidectomy for grade III hemorrhoids, revealing that hemorrhoidectomy provided superior long-term symptom relief, improved quality of life, and lower recurrence, though it was associated with higher morbidity and costs. A cost-effectiveness analysis highlighted that its value depends on willingness-to-pay thresholds. Additionally, the thesis critically assessed the Goligher classification, revealing its limitations and advocating for symptom-based alternatives that better reflect disease burden.Part II explores the prevention and treatment of cryptoglandular perianal fistulas. The ATLAS trial investigates the role of postoperative antibiotics in preventing fistula formation following surgical drainage of a perianal abscess. Novel use of 3D high-resolution anorectal manometry (3D-HRAM) was explored, though its clinical utility in predicting continence outcomes after fistula surgery remains inconclusive. Long-term follow-up studies of sphincter-sparing techniques (LIFT and advancement flap) demonstrated high recurrence and continence deterioration, underscoring the need for careful patient selection and informed counseling. A pilot study of the Semiflex catheter showed potential for integration in multimodal strategies, though feasibility targets were not fully met.Altogether, this thesis advocates for patient-centered, evidence-based approaches in anorectal disease management, highlighting the need for standardized outcome measures and pragmatic trial designs to guide future research and clinical practice

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