International Migration, Integration and Social Cohesion online publications
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Bleeding matters:Perspectives on the clinical phenotype and management of hemophilia
Get PDFHemophilia A and B are X-linked inherited coagulation disorders that are caused by a deficiency in coagulation factor VIII or IX, respectively. As a consequence, persons with hemophilia have an increased bleeding tendency. The most characteristic symptoms of hemophilia include bleeds into the joints and muscles, which may result in disabling and irreversible joint damage. A rare but potentially devastating complication in hemophilia is the occurrence of intracranial hemorrhage. While the clinical picture is extensively studied in severe hemophilia, information on the bleeding phenotype and optimal management in non-severe hemophilia remains limited. This thesis contributes knowledge on the clinical phenotype, treatment and management of hemophilia, with a specific focus on non-severe hemophilia. These findings may guide expectations and education for persons with non-severe hemophilia, as well as for persons with severe hemophilia treated on novel products in whom the phenotype is converted into that of mild hemophilia. Priorities in research and care that are identified in this thesis include the high incidence of intracranial hemorrhage, the presence of joint changes in non-severe hemophilia and a potential suboptimal use of desmopressin treatment
An untold tale of tolerance:Conditioning dendritic cells to restore immune balance using tolerogenic nanocarriers
Get PDFChronic inflammatory disorders, including various autoimmune diseases and allergies, put a significant burden on our societies. As these conditions stem from a breach in immune tolerance, immune modulation could provide novel avenues for disease prevention or cure. Dendritic cells (DCs) are specialized immune cells that can effectively induce the development of regulatory T cells (Tregs), critical adaptive immune cells for dampening inflammation. Both active metabolites of vitamin D3 (VD3) and retinoic acid (RA) can induce tolerogenic DCs, subsequently fostering a Treg response in vitro. Nanocarriers, such as liposomes or plant-based bioparticles, can be used to combine VD3 or RA with autoantigens or allergens and target these factors simultaneously to DCs in tissue to achieve disease-specific tolerance in vivo. In this thesis, we embarked upon developing a nanocarrier-based vaccine product for future in vivo modulation of DCs. We established negatively charged liposomes as most suitable for administering adjuvants to DCs. We found that various subsets of DCs treated with VD3 or RA, in soluble or liposome-loaded form, induced the development of CD4+ but also CD8+ Tregs in vitro. Furthermore, we established an activating yet hypo-allergenic effect of peanut allergen-loaded bioparticles on DCs. Finally, we present a randomized controlled phase I clinical trial examining the peripheral immune effect of subcutaneous VD3 administration in birch pollen allergic patients. Thus, this thesis encompasses the first steps toward a putative DC-targeted vaccine treating chronic inflammation
Influenza and common cold viruses in critically ill adults
Get PDFThere is an increasing appreciation of common cold respiratory viruses as causal agents of critical illness in adults. However, challenges remain regarding disease burden estimates, interpretation of molecular test results, deployment of clinical diagnostics, and clinical management of viral respiratory tract infections (RTIs). This thesis aims to advance insights into the role of influenza and common cold viruses in critically ill adults, and guide diagnostics, treatment and infection control measures. Firstly, we found that viral RTIs are frequently detected in critically ill adults admitted to the intensive care unit (ICU). Secondly, we addressed the clinical interpretation of detecting a respiratory virus in critically ill patients, as detection does not automatically imply a causative role in the presenting illness. The presented prospective cohort with case-control design allows for estimates of these coincidental infections. The findings point to a substantial burden of common cold virus-associated severe disease in adults, although confounding remains challenging. Next, the practice of clinical diagnostics was addressed. Our findings indicate that many viral RTIs, including influenza, are missed in the adult ICU setting, and including a sample from the lower respiratory tract greatly increases diagnostic yield. Lastly, shedding dynamics were studied. In the majority of patients viral RNA remained detectable throughout invasive mechanical ventilation. Also, viral RNA shedding was significantly longer in samples from the lower respiratory tract, and associated with a fatal outcome. Potential implications for infection control measures and decisions on the duration of influenza treatment are discussed
Scaffolding small groups’ mathematics learning
Get PDFThis dissertation addresses how teachers can guide student collaboration in mathematics. Group discussions in mathematics contribute to student learning. However, when groups get stuck, some kind of content help is needed to get the discussion back on track. Teachers tend to find supporting these small groups difficult. Consequently, this dissertation aimed to develop and test a tool designed to help teachers provide scaffolding on the level of the group, i.e., adapt their support according to group needs. The main research question was the following: What is the effect of small-group scaffolding on the quality of mathematical discussions, and does it raise the mathematical knowledge level of students in seventh-grade early algebra classes? The first study focused on designing early algebra lessons to evoke mathematical discussions. Subsequently, a small-group scaffolding tool (SGS-Tool) was developed in the second study. In particular, this SGS-Tool assists teachers in deciding whether to give content support (when a group gets stuck) or process support, i.e., stimulating the group to continue the discussion among themselves. The effectiveness of this tool was tested in a quasi-experimental design. The results showed that the use of the SGS-Tool improved the teachers’ group scaffolding. Finally, another quasi-experimental study evaluated the effect of small-group scaffolding at the group level. The results revealed that small-group scaffolding not only improved the quality of mathematical discussions but also enhanced students’ mathematical knowledge. This dissertation demonstrates that the SGS-Tool is a powerful tool that can help teachers effectively scaffold student groups at the group level
The tail that wags the dog:The effects of secured credit on access to debt financing and financial stability
Get PDFIn this dissertation, I focus on the legal reforms in insolvency law and banking regulations, introduced under the Capital Markets Union Action Plan and the Banking Union initiatives, respectively. I delve in particular into the EU Directive on Preventive Restructuring Frameworks, and the Capital Requirements Regulation. The key question explored in this dissertation is: How do changes to the position of secured creditors, following from legal reforms in insolvency law and banking regulations, affect corporates’ access to debt financing and financial stability?The analyses in this dissertation suggests that the changes to the position of secured creditors, following from legal reforms in insolvency law and banking regulations not only fail to facilitate creating a diverse funding climate and also fail to increase financial stability, but also generate negative unintended consequences for corporates’ access to debt financing and financial stability. A thorough analysis of banks’ position as secured creditors, their governance and the implications of their position for other creditors is essential to strike a balance between managing risk, enabling growth and providing a stable access to finance. Against this background, I provide a number of recommendations that can be taken into consideration in legislative deliberations in the context of the Preventive Restructuring Directive and the Capital Requirements Regulation to foster a vibrant funding climate and to increase financial stability
Anorectal malformations:A complex disease in need of a multidisciplinary approach
Get PDFIn children born with an anorectal malformation (ARM), the anus is wrongly placed outside the external sphincter complex. Different types of ARM exist, and in patients with ARM different associated anomalies can occur. Additional anomalies are described, among others, as part of the VACTERL-association (Vertebral, Anorectal, Cardiac, Trachea-Esophageal, Renal and Limb anomalies), but also anomalies of the spinal cord or gynecological anomalies are described. In the first part of this thesis, the types of ARM are introduced and it is described what additional anomalies might be associated with any type of ARM. In addition, the value of screening for the different types of anomalies is demonstrated throughout this part. The studies performed in Chapter 1-5 were retrospective cohort studies. In the second part, a complex type of ARM; rectal atresia (RA) is discussed in Chapter 6-8. Finally, Chapter 9-10 form the third part of this thesis describing problems later in life in patients with ARM in primary school or after transitioning to adulthood
Antiviral CRISPR-Cas strategies:Intended and unintended effects
Get PDFCombination antiretroviral therapy (cART) can effectively inhibit replication of the human immunodeficiency virus (HIV) and prevent progression to AIDS. However none of the currently available drugs inactivate the HIV DNA that is integrated on one of the chromosomes of all infected cells. As a consequence, current cART does not lead to a cure of the virus infection and HIV-infected individuals need lifelong suppressive therapy to prevent AIDS. Novel strategies are being developed that aim at the inactivation of the integrated HIV DNA in infected cells, including the use of DNA cleaving CRISPR-Cas systems. In this thesis, I describe how we investigated the possibilities and risks of such antiviral therapy by analyzing the intended and unintended CRISPR-Cas effects. We demonstrate that CRISPR-Cas treatment of HIV-infected cells can permanently inactivate the viral DNA by causing small insertions and deletions (indels) at the target sites, or by causing excision or inversion of the DNA fragment between two target sites. However, we demonstrate that such treatment also causes much larger deletions, which can include flanking cellular DNA sequences. Using a novel quantitative assay we demonstrate that CRISPR-Cas treatment of cells causes large deletions at a surprisingly high frequency, with on average one large deletion for every two indels. As large chromosomal deletions may trigger oncogenic transformation and turn the cell into a cancer cell, this high frequency poses a serious safety risk for clinical application of the CRISPR-Cas systems. Therefore, it is crucial to closely monitor for such unintended effects when applying CRISPR-Cas systems in humans, not only in antiviral approaches but also in other gene therapy applications
The complement system in COVID-19
Get PDFIn this thesis, complement activation in COVID-19 was described and the effect of targeting complement factor C5a with the monoclonal antibody vilobelimab in severely and critically ill COVID-19 patients. The aim was to determine the effect of vilobelimab on mortality and safety in critically ill COVID-19 patients, to assess its effects on biomarkers of inflammation and coagulation in severely and critically ill COVID-19 patients, and to analyse its pharmacokinetics. In this thesis, it was shown that vilobelimab improved survival in critically ill, mechanically ventilated COVID-19 patients. Vilobelimab was found to efficiently inhibit C5a in severely and critically ill COVID-19 patients, without evidence of immunogenicity in critically ill COVID-19 patients. Finally, vilobelimab was shown to decrease the inflammatory response by lowering concentrations of CXCL8 over time. Further research should investigate whether different subphenotypes in COVID-19 respond differently to vilobelimab treatment and focus on the role of C5a and C5a inhibition in other viral infections that lead to ARDS
Supramolecular strategies for the templated synthesis of confined nanoparticles and their application in catalysis
Get PDFNanoparticles (NPs) and Nanoclusters (NCs, NPs with a diameter of <2 nm) have become invaluable assets in various scientific disciplines. The dimensions, surface environment and composition of nanoparticles are essential to their distinctive properties and catalytic features. Hence, developing methods to gain precise synthetic control over these features is of considerable interest. Motivated by the challenges involved in NP and NC synthesis and inspired by supramolecular metal catalyst pre-organisation strategies developed in our group, we were curious if we could employ self-assembled [M12L24] nanospheres as templates for controlled nanocluster and nanoparticle synthesis. The goal of the research in this thesis was to explore and develop new synthetic methods for the precise preparation of (mixed) metal nanoparticles and nanoclusters through supramolecular pre-organisation. We herein describe a new synthetic strategy involving the pre-organisation and subsequent hydrogenation of organometallic complexes within [M12L24] nanospheres, leading to the templated formation of encapsulated nanoclusters or nanoparticles that reside in a unique microenvironment