International Migration, Integration and Social Cohesion online publications
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Exploring neural models for human cytomegalovirus infection studies
Get PDFThis thesis explores the use of clinical CMV isolates in the validation of antiviral effects against CMV infection of human CNS models in the context of cCMV disease. Next, it elucidates the use of advanced human neuronal models in CMV research. Lastly, it proposes the application of these neuronal models in the testing of novel antiviral drugs.This thesis systematically describes the culture of neural organoids (NOs) in their use for neurodevelopmental research. Different human NO models are discussed together with their characteristics and applications. This thesis focusses then on human NOs as models for virus research and provides insights into the currently most applied NO models in virus research studies as well as their outcomes. Next, it explores techniques to increase virus yields cell lines, optimise virus concentrations and cryopreserve virus titres of clinical CMV isolates. Furter, this thesis elucidates on differences in antiviral efficacy of blocking CMV infection in a regionalised NO model. Letermovir, ganciclovir and maribavir are assessed in different concentrations in 2D and 3D neural models, using a clinical CMV isolate and a mCherry-tagged BAC strain. Next, the inhibition efficacy of halofuginone hydrobromide on different viruses, including CMV, in different human organotypic models is discussed. Finally, the advantages and challenges of using clinical isolates in CMV research are discussed, together with NOs as models of the developing human brain. The current antiviral therapies and alternative strategies to treat and/or prevent CMV infection in vulnerable populations are also discussed
Amplification of a chromosomal beta-lactamase gene during amoxicillin resistance development in <i>E. coli</i>
No full textBacteria can acquire high levels of resistance after long-term exposure to sublethal concentrations of antimicrobials. Beta-lactams are the most used antimicrobials. The overexpression of the chromosomal beta-lactamase gene ampC, through gene amplification, is a crucial factor in beta-lactam resistance development in E. coli. This study focusses on this process of amplification and the factors influencing it. Development of resistance starts with mutations in the ampC promoter. The ampC amplification occurs about halfway during amoxicillin resistance evolution. When ampC is removed, no amplification is observed. When ampC is translocated, a DNA fragment around it at the new location is amplified. Replacing ampC by a tetracycline resistance gene and exposure to tetracycline yields amplification of a similar fragment. Of the genomic changes between the onset of ampC amplification and the end of the evolutionary process, mostly those located in sigma factor RpoD correlated with ampC amplification. These mutations, introduced as point mutations at the 445 and 570 amino acids of RpoD, enhance beta-lactam resistance. By removing some of the hitchhiking genes within the amplicons and the hotspot regions defining amplification boundaries, the sugE and epmA genes located neighbouring ampC were found to contribute to amoxicillin resistance development.</p
Decoding B cell responses to SARS-COV-2:Insights from immune dynamics and monoclonal antibodies
No full textSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), first identified in late 2019, rapidly escalated into a global health crisis, ultimately culminating in the COVID-19 pandemic. This unprecedented event profoundly impacted nearly every aspect of our society, from public healthcare systems to global economies.This thesis investigates the human humoral immune response to SARS-CoV-2, with a focus on the dynamic interaction between B cells (and the antibodies they produce) and this novel virus. We detail how this interplay has not only shaped individual immune protection but also driven the virus’ evolution through selective pressures, contributing to the emergence of novel variants with distinct antigenicity and immunogenicity profiles. Furthermore, we discuss how advances in the understanding of humoral immunity have accelerated the development of effective vaccines and antibody-based therapeutics, playing an essential role in the global response to the pandemic. Lastly, this work reflects on the key lessons learned from COVID-19 and considers how these insights can inform future strategies for improved preparedness and rapid response in the face of emerging zoonotic viral outbreaks
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
Haagsche quaesties:Een studie naar de ontwikkeling van de culturele infrastructuur in Den Haag 1890-1920
Get PDFDe directe aanleiding tot dit onderzoek vormde de vondst van een groot aantal ontwerptekeningen die deel uitmaken van de ‘schouwburgquaestie’. Dit vraagstuk ontstond in 1890, ingegeven door het achterstallig onderhoud van het schouwburggebouw. De discussie over de juiste locatie groeide uit tot een over het belang van de schouwburg in de snel veranderende stad en zou de Haagse gemoederen drie decennia bezig houden. Deze studie laat zien dat dit vraagstuk niet op zich zelf stond. Naast de schouwburgquaestie en een eveneens langdurige museumquaestie kende Den Haag nog een museumkwestie (met een k) en een orkestkwestie. Juist in de hofstad waren deze vraagstukken, meer dan elders, nauw verweven met de grootstedelijke problematiek van die tijd. Het belang van deze studie ligt in de integrale benadering. In het hofstedelijk sociale verkeer was zien en gezien worden, dus deelname aan het plaatselijk vertier en het culturele leven, van eminent belang, evenals beeldvorming. Vandaar de sterke bemoeienis van de verschillende stedelijke maatschappelijke en opkomende politieke krachten met deze culturele vraagstukken.De uitwerking van het onderzoek is vervat in vier min of meer chronologische casussen: de ontwikkelingen in de jaren 1890-1898, de verwikkelingen rond respectievelijk het Residentie-Orkest, het Haagse theater en de Koninklijke Schouwburg en het Gemeentemuseum. Dit onderzoek toont onverwachte hiaten in het Haagse collectief geheugen – met name de interventies van koningin-regentes Emma bleken cruciaal voor de genoemde ontwikkelingen – en plaatst tegelijkertijd enige kanttekeningen bij de recente geschiedschrijving van de stad. In de eerste twee decennia van de twintigste eeuw vonden de Haagse culturele instellingen een eigen plek in de stad, programmering en publiek. In dezelfde periode werd de basis gelegd voor een gemeentelijk cultuurbeleid dat tot op de dag van vandaag herkenbaar is
Rebels, renegades, and Robin Hoods:The social-hierarchical dynamics surrounding norm violators
Get PDFWhen studying the social-hierarchical dynamics surrounding norm violators it is important to consider both perceptions of power as well as people’s willingness to actually grant power to a norm violator. People often submit to others who appear powerful, therefore norm violators may inspire submission through their powerful appearance. However, perceptions of power do not necessarily translate into the voluntary granting of power. Instead, observers may put the norm violator back in place, as we observed in Chapter 2 when sanctions removed the apparent power that the norm violator initially seemed to have. Therefore, when studying the social-hierarchical dynamics surrounding norm violators, it is important to also consider people’s willingness to grant power to norm violators. The findings of Chapters 3 and 4 suggest that people who bluntly break norms are not granted power (e.g., in the form of obtaining a leadership position). However, norm benders and parochial norm abiders may be readily granted power if there is a cause for their disregard for the norm – be it in the form of situational demands (competition calls for a dominant leader) or in the form of situational constraints (it is not possible to abide by group norms without violating community norms)
Patient-specific distal radioulnar joint arthroplasty:Towards a novel implant design using four-dimensional computed tomography
Get PDFThe distal radioulnar joint (DRUJ) is vital for multiple activities of daily life. A malunited distal radius fracture or hereditary disease can lead to osteoarthritis. In this instance the last treatment where a functional joint remains is arthroplasty. During a surgical procedure the joint is replaced by an implant. Unfortunately, the most prevalent implant is suspected to change the forearm’s motion pattern. Moreover, it suffers from a high complication rate and often needs revision surgery.In this thesis, a new approach to DRUJ arthroplasty is described where the motion pattern of the patient is defined such that it can be used to develop a patient-specific implant. To investigate the motion of the forearm, four-dimensional computed tomography (4D-CT) was used. The methodological error of 4D-CT was first validated. Subsequently, kinematic parameters like the forearm rotation axis, radius translation along the ulna and radius rotation about its own longitudinal axis were quantified. To be able to design a patient-specific implant, a reference must be present. An obvious choice would be the contralateral forearm. A review was conducted to analyze similarity regarding geometry and function. This review was supplemented by a study comparing intraindividual kinematics in healthy forearms. Both studies revealed high bilateral symmetry. Next, a patient study was conducted to determine the kinematic changes in patients with the most prevalent implant. It was found that the implant was incapable of restoring the healthy forearm’s motion pattern. Finally, the kinematic differences were reviewed with respect to complications that occurred during patient follow-up
ICU efficiency:Methods and applications in the general and COVID-19 ICU population
Get PDFHealthcare organizations continuously face challenges in providing optimal patient care while effectively and efficiently utilizing their resources. While doing so, they also continuously work on improving the quality of patient care. In this thesis, we focus on, effectiveness, in terms of (long-term) outcomes, and on efficiency in the context of intensive care. Efficiency in healthcare often focuses on the costs or cost-effectiveness of medical treatments. Although it is considered valuable, measuring and interpreting efficiency in terms of cost-effectiveness in an ICU setting can be difficult. We consider ICU efficiency in terms of ICU length of stay as a proxy for resource use under the condition that care is effective. With the knowledge of which organizational factors affect healthcare costs, care can be made more efficient. In this thesis, we focus on evaluating care provided in the ICU by measuring ICU efficiency and using conventional and machine learning methods to determine the effect of organizational factors on ICU efficiency. In the first part of this thesis, we measure efficiency in Dutch and Brazilian ICUs and explore different approaches to determine which ICU characteristics affect ICU efficiency. The duration of the PhD program partly overlapped with the COVID-19 pandemic, which had a significant impact on ICU care. In the second part of this thesis, we focus on long-term mortality as a measure of effectiveness for Dutch COVID-19 patients admitted to the ICU. In addition, we also focus on the effect of transfers on mortality as a measure of timeliness and efficiency