International Migration, Integration and Social Cohesion online publications
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The role of indoleamine 2,3-dioxygenase IDO in infectious diseases:COVID-19 and tuberculosis
Get PDFThe studies comprised in this thesis focus on the role of indoleamine 2,3-dioxygenase (IDO) enzymes, both IDO1 and IDO2, in the pathophysiology of infectious diseases, particularly on COVID-19, long COVID, and tuberculosis. For these studies, immunohistochemistry, cell culture approaches, and ex vivo cell culture methods were employed to elucidate the expression, activity and effects of IDO1 and IDO2 in various tissues and cells.The results show that, besides the presence of IDO1, the aryl hydrocarbon receptor (AHR)-IDO2-kynurenine pathway is active in severe/fatal COVID-19, likely contributing to cell death and cellular metabolic stress. This pathway is also induced in long COVID, where it is associated with aberrant cellular metabolism and mitochondrial activity. Inhibition of IDO2 expression and activity using an AHR antagonist attenuated cell death and cellular stress, suggesting a potential therapeutic target for long COVID.In tuberculous meningitis, granulomatous IDO1 expression was seen, but IDO2 expression was found to be beyond in granulomas, particularly in the cerebellum, medulla oblongata, and inferior olivary nucleus. IDO1 activity was shown to reduce the sensitivity of Mycobacterium tuberculosis (M. tuberculosis) to antibiotics by depleting tryptophan in vitro. This may be an important clue for shortening the duration of antibiotic treatment. However, IDO1 activity also promoted the fusion of lysosomes to M. tuberculosis-containing phagosomes. So, inhibition of IDO activity can be both beneficial and harmful to the host.The thesis highlights the complex roles of IDO1 and IDO2 in infectious diseases, including their potential as therapeutic targets. The findings suggest that modulation of IDO activity may be beneficial in treating long COVID and tuberculosis, but the dual effects of IDO1 in tuberculosis should be taken along with interventions. Overall, this research contributes to a better understanding of the pathophysiological mechanisms underlying (post-) infectious diseases and may lead to the development of novel therapeutic strategies
Advances in CT perfusion imaging and selection in acute ischemic stroke
Get PDFCT perfusion (CTP), while holding promise for guiding treatment decisions in patients with acute ischemic stroke, presents with challenges and uncertainties in its diagnostic application. The thesis investigates the diagnostic accuracy, patient selection, and cost-effectiveness of CTP in managing acute ischemic stroke. Part I evaluates the accuracy of various CTP software packages in estimating ischemic core volumes. We found significant variability in core volume estimates across different vendors, with moderate volumetric agreement but low spatial accuracy compared to MRI. These findings suggest that while CTP provides valuable insights, its results must be interpreted cautiously due to inconsistencies. Part II examines the role of imaging in patient selection for endovascular treatment (EVT). We found that both larger CTP ischemic core volume and older age are associated with worse functional outcomes post-EVT. However, neither ischemic core volume nor age can reliably predict treatment effect. Moreover, we tested an automated algorithm for detecting large vessel occlusions, noting its high accuracy and speed. The study emphasizes that this algorithm should complement rather than replace clinical expertise. Part III assesses the cost-effectiveness of using CTP for EVT selection, particularly within the first six hours of stroke onset. The findings indicate that excluding patients based on CTP-derived parameters does not lead to cost savings and may worsen outcomes, questioning the economic viability of CTP-based selection under current practices. CTP can enhance the diagnostic process for acute ischemic stroke, but its results must be interpreted with care. Continued research into its clinical application will help refine its use
Healthcare access in Indonesia:Patient values and ethical challenges
Get PDFA decade ago, Indonesia introduced its national health insurance to improve healthcare access through protection from financial risks. However, challenges persist, particularly related to the need for more attention to the importance of patient values and ethical issues. To explore this topic, we conducted a systematic review, in-depth interviews, a quantitative analysis of national datasets, a conceptual analysis, and a case study. Patients' values are rarely studied in low and middle-income countries; we synthesize that patients' values can be categorized into values that are related to the patient, expectations from the provider, provider-patient interaction, and the primary health care system. Patients could benefit from the implementation of personal continuity of care. The physical layout and environment of primary healthcare facilities affect patient privacy and quality of care. The standard practice of closing consultation room doors. Then, we analysed the traditional Javanese value of 'nrima', which means acceptance, and its implications for the patient-doctor relationship. We found that inequalities in the healthcare supply side posed a challenge to the use of national health insurance. There are drawbacks of hierarchy to the quality of care. Improvements that focus on the supply side are insufficient, and finally, it is important to pay more attention to daily ethics and values in medical practice
Bioinspired nanomedicine for the targeting and treatment of atherosclerosis
Get PDFAs the primary underlying cause of heart attacks and strokes, atherosclerosis places a significant burden on society. Studies over the last decades identified chronic maladaptive inflammation of the vessel wall as a key factor in the disease’s development and progression. Large-scale clinical trials revealed that inhibiting the inflammation that is driving the disease can improve outcomes. However, these trials also highlighted the complications associated with long-term suppression of physiological immune surveillance, which increases the risk of fatal infections and cancer. There is, therefore, an urgent need for therapeutics that can effectively suppress atherosclerosis-driving inflammation, while maintaining the physiological functioning of the immune system. This thesis explores the application of bioinspired nanomedicine to meet this need. We apply two nanomedicine platforms, hyaluronan nanoparticles and HDL nanobiologics, whose designs were inspired by naturally occurring nanomaterials and biological building blocks. This bioinspired approach offers additional benefits by enhancing biocompatibility and exploiting the natural interactions of the materials with their target cells. We explore the mechanisms by which the nanoparticles reach their target cells in the plaque and uncover the crucial role that the endothelium plays in this process. We demonstrate that hyaluronan nanoparticles can be utilized to image vessel wall inflammation, and anti-inflammatory compounds can be incorporated in HDL nanobiologics for treating atherosclerosis. Collectively, the studies in this thesis offer new opportunities for atherosclerosis treatment and identify key mediators of plaque targeting and inflammation
Parallel worlds:Assessing the alignment between social science and legal practice about behavioral change
Get PDFThis dissertation aimed to gain a better understanding of the alignment between social scientific research and the law, specifically where law aims to shape behavior. Based on semi-structured interviews with legal practitioners, this research found that on a conceptual level, there is an alignment between the experiential knowledge of legal practitioners and social scientific research: practitioners and researchers distinguish similar concepts relevant for how law may shape behavior. On a substantive level, there is more misalignment as legal practitioners differ among themselves and pay less attention to underlying processes of how law may shape behavior. Moreover, based on the interviews, the research shows that practitioners vary greatly in their views on how valuable and useful social science is for their practice. The last part of this dissertation researched to what extent social scientific research influences decision-making on preventing crime. It found that participants who read information about the lack of evidence for the deterrent effect of more severe punishment were less inclined to double sentences than people who did not, regardless of how science was presented or information about victim harm was given. In general, this dissertation shows the insights in the complex relationship between legal practice and social scientific research. It holds important implications for both research and legal practice: it shows that there is a surprising alignment that can function as a starting point to increase the knowledge exchange between social science and legal practice. It seems that these are not two distinct areas, but rather two parallel worlds
New insights in managing homozygous and severe heterozygous familial hypercholesterolaemia in children
Get PDFThis thesis delves into the management of familial hypercholesterolaemia (FH) in children, focusing on homozygous FH (HoFH) and severe heterozygous FH (HoFH). Part I explores the correlation between genotype and phenotype. It reveals that null pathogenic variants correlate with more severe phenotypes than defective variants, highlighting the importance of genetic testing for accurate diagnosis and treatment. Part II assesses several lipid-lowering treatments (LLTs), emphasizing monoclonal antibodies targeting PCSK9 and potential therapies such as inclisiran and evinacumab. It discusses ongoing trials and future perspectives, for children with HoFH and children with HeFH and high LDL-C levels or statin intolerance. Most important, it evaluates lipoprotein apheresis as a treatment for HoFH, showing its effectiveness in lowering LDL-C levels and improving cardiovascular outcomes and provides clinical practise recommendations for integrating lipoprotein apheresis in the management of children with HoFH. Part III addresses various aspects of FH management. It emphasizes optimal counselling for couples at risk of having a child with HoFH, investigates elevated Lp(a) levels in children with HoFH and explores the use of CTCA for assessing cardiovascular risk in HeFH and assessing efficacy of lipid-lowering treatments in HoFH. This research contributes valuable insights into the management of HoFH and severe HeFH, highlighting the need for personalized approaches and ongoing research to improve LDL-C goal attainment and cardiovascular outcomes for affected individuals
Sustainable strategies for appropriate urinary tract infection management
Get PDFUrinary tract infections (UTIs) belong to the most common infectious diseases worldwide and are often treated with antibiotics. However, not all patients with positive urine tests require antibiotic treatment. Particularly, patients with asymptomatic bacteriuria (ASB), a positive urine culture without symptoms of a UTI, are often inappropriately treated, partly due to frequent urine testing across various healthcare settings. This inappropriate treatment is an example of low-value care. De-implementation strategies target reducing low-value care. We conducted a de-implementation strategy consisting of education and feedback about ASB to reduce its overtreatment in emergency departments. Although the percentage of patients with ASB who were overtreated with antibiotics was not significantly reduced, the number of urine tests ordered was lower after the implementation of the strategy.Further, we evaluated the long-term effects of a de-implementation strategy that was used to reduce the inappropriate use of catheters, another example of low-value care. We showed that the effect of de-implementation can be sustained for at least five years.In primary care, healthy women with uncomplicated UTIs (i.e., cystitis) can recover spontaneously without antibiotics. However, most women receive antibiotic treatment, even though general practitioners are encouraged to facilitate conversations with women about both antibiotic and non-antibiotic treatment options. We used qualitative studies to investigate the management of urinary tract infections in primary care and identified several barriers and facilitators influencing the decision-making process.Overall, individual and system-wide approaches are necessary to decrease low value care in the diagnostic and therapeutic management of patients with UTIs and ASB
Macrophage immunity in ANCA-associated vasculitis
Get PDFThis thesis examines the pathophysiology of the systemic autoimmune disease ANCA-associated vasculitis (AAV), focusing on both acute and long-term effects. Part I explores the role of macrophages in renal inflammation. Despite being the primary infiltrating immune cells in early glomerular lesions, their exact functions have long remained unknown. Chapter 2 reviews the role of monocytes and macrophages in AAV pathophysiology. Chapter 3 presents a single-cell RNA sequencing study using kidney biopsies from AAV patients and controls, revealing increased proportions of CD163+ macrophages, primarily classical monocyte-derived macrophages expressing specific pro-inflammatory mediators, alongside a distinctive SPP1+ macrophage subset linked to lipid metabolism and fibrosis.Part II delves into the pathophysiology and risk factors for cardiovascular disease. Chapter 4 reveals alterations in monocyte phenotype during active disease, while intrinsic adhesion and migration capacities remain unchanged. This chapter also delineates differences between the PR3-AAV and MPO-AAV subtypes. Chapter 5 identified risk factors for cardiovascular events in AAV, such as age, HbA1c levels, the presence of diabetes mellitus, and cardiovascular history. Part III emphasizes the high risk of AAV recurrence and the need for reliable biomarkers. Chapter 6 evaluates the value of monitoring ANCA levels, revealing a moderately elevated odds of a disease relapse within 6 and 12 months of an ANCA rise. A larger effect was found by examining the odds of a positive test during an episode of recurrent inflammation. Collectively, this research enhances our comprehension of AAV's inflammatory cascade, offering prospects for enhanced diagnostics and targeted therapeutics
Promoting oral health care for people with disabilities:Tools for oral health professionals
Get PDFIn this thesis, various aspects of oral health care for people with disabilities are evaluated, aiming to equip oral health professionals (OHPs) with tools to provide appropriate care to these patients. Although the primary focus is on individuals with intellectual and developmental disabilities (IDD), the research aims to improve oral health care for all people with disabilities. The research design includes two systematic reviews, an observational study, a qualitative study, a controlled clinical trial, and a secondary analysis to address the research questions.The thesis concludes that OHPs in primary care can play an important role in promoting oral health care for people with disabilities. This includes familiarizing patients with disabilities with the dental setting, and providing continuity of care through preventive guidance, monitoring, and management of oral diseases. Additionally, timely referrals to specialized clinics should be ensured when necessary.To support OHPs in tailoring their care to the specific needs of their patients with disabilities, the thesis identifies tools in the following areas:*Toothbrushing: A triple-headed manual toothbrush is a valuable addition to the range of available toothbrushes. *Adolescents with mild ID: Structure (influencing toothbrushing and intake frequency), Anxiety (impeding dental visits), and Support (provided by support workers) are pivotal factors influencing the oral health behavior of adolescents living in residential care. *Restorations: Atraumatic Restorative Treatment (ART) is an effective restorative treatment technique for patients with disabilities*Tooth agenesis in Down syndrome: The Tooth Agenesis Code (TAC) is a valuable tool to ensure clear communication about tooth agenesis
Novel targets for prevention and inhibition of proliferation and metastasis of esophageal adenocarcinoma
Get PDFEsophageal adenocarcinoma (EAC) is a highly malignant disease with a dismal prognosis. In the Western world, EAC presents a growing number of new cases, which poses a health challenge in recent years. Novel molecular treatments to improve patients’ outcomes are an unmet medical need. Barrett’s esophagus (BE) is a metaplastic condition that predisposes for EAC. Non-dysplastic BE (NDBE) accounts for a large proportion of the BE population and carries a relatively low risk for developing EAC. The challenge for NDBE is the difficulty to estimate its malignant progression risk. This often leads to overtreatment and frequent endoscopic examinations, thereby generating a healthcare burden. In this thesis, BE patients and EAC patients’ specimens were used for RNA sequencing, gene expression, gene variation and protein expression analyses. This thesis found that upregulation of the PXR signaling and downregulation of certain immune pathways are promising factors to identify NDBE with high risk of malignant progression. This thesis largely focuses on the inhibition of tumor growth and development of metastasis of EAC cells. Hereto, we used novel llama derived single domain antibodies (VHHs), which are directed against the Bone Morphogenetic Proteins: BMP2 and BMP4. Multiple in vitro and in vivo models were established to explore and validate the effect of VHHs on inhibiting the malignant behavior in EAC. This thesis found that in mouse models targeting BMP2/4 with our novel anti-BMP2/4 VHHs is an attractive molecular therapy for inhibition of tumor growth and prevention of metastasis in EAC. Further studies on clinical trials are warranted