Thromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it... Show moreThromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it at the same time increases risk of bleeding. With nationwide data from Statistics Netherlands, antithrombotic therapy and relevant clinical outcomes were comprehensively examined in the patient population of atrial fibrillation, overall or among those with comorbid cancer. The results suggest the patient population was increasingly receiving anticoagulants, driven by the newly introduced medication- direct oral anticoagulant and guided by the CHA2DS2-VASc score, and meanwhile the patient population experienced fewer ischemic stroke and major bleeding. In spite of these promising changes, suboptimal medication adherence and potential underuse of anticoagulants remain directions for further improvement. Antithrombotic agent use during pregnancy was also examined in the general Dutch pregnant population, which featured a surge in antiplatelet prescriptions, and risk of preeclampsia/eclampsia decreased and several newborn outcomes improved simultaneously. Together, the studies presented in this thesis provide an overview of antithrombotic therapy in the Netherlands in recent years, providing insights for further improving this treatment and relevant patient outcomes. Show less
The outbreaks of AIDS and COVID-19 showed clearly how infectious viruses can influence people’s lives. Investigating the changes in the host metabolism may provide a paradigm shift to consider... Show moreThe outbreaks of AIDS and COVID-19 showed clearly how infectious viruses can influence people’s lives. Investigating the changes in the host metabolism may provide a paradigm shift to consider immune-metabolic interactions as therapeutic targets. The aim of this thesis is to examine the interplay between the immune system and metabolism during viral infections, such as HIV and coronavirus. These investigations will utilize metabolomic and lipidomic mass spectrometry techniques to gain a comprehensive understanding of the metabolic changes that occur during viral infections. To enhance the coverage of the lipidome, a new method will be developed. Show less
The emergence of complex diseases resulting from abnormal cell-cell signaling and the spread of infectious diseases caused by pathogens are significant threats to humanity. Unraveling the dynamic... Show moreThe emergence of complex diseases resulting from abnormal cell-cell signaling and the spread of infectious diseases caused by pathogens are significant threats to humanity. Unraveling the dynamic mechanisms underlying cell-cell signaling and infectious disease spreading is crucial for effective disease prevention and treatment. As science and technology advance, the availability and diversity of observational and experimental data related to these biological processes continue to grow. In this thesis, we integrate multisource data with dynamic modeling to investigate the biological mechanisms of Notch signaling in biological development and to develop prevention and control strategies for infectious diseases. Show less
Pulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades,... Show morePulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades, diagnosing PE is still a difficult process due to the non-specific symptoms, which can frequently overlap with symptoms of other cardiopulmonary diseases. Currently recommended diagnostic strategies for suspected acute PE consist of standardized assessment of the clinical pre-test probability (CPTP) using validated clinical decision rules (CDRs) and D-dimer testing. PE is considered safely ruled out in patients with a non-high CPTP and a normal D-dimer test. Imaging tests as computed tomography pulmonary angiography (CTPA) are required in the case of a high CPTP and/or abnormal D-dimer test to confirm the diagnosis. The first part of this thesis describes the challenges of diagnosing PE in general and in specific clinically relevant patient subgroups. Moreover, this part evaluates the diagnostic performance of non-invasive diagnostic strategies for suspected PE in specific relevant patient subgroups. The second part of this thesis focuses on venous thrombotic complications in hospitalized patients with COVID-19. Show less
In dit onderzoek hebben we de rol van thromboinflammatie onderzocht in verschillende hoog-risico populaties, zoals mensen met type 2 diabetes mellitus (T2DM) en patiënten met ernstige COVID-19, als... Show moreIn dit onderzoek hebben we de rol van thromboinflammatie onderzocht in verschillende hoog-risico populaties, zoals mensen met type 2 diabetes mellitus (T2DM) en patiënten met ernstige COVID-19, als ook naar verhoogd risico bij vrouwen in de Nederlandse samenleving. Thromboinflammatie is de verbinding tussen de gelijktijdige activatie van de stollingsroute en immuunrespons welke een belangrijke trigger vormt voor bloedvat schade, prominent in microvasculaire gezondheid. Als eerste laten we zien dat er genderspecifieke associaties zijn tussen het activatie potentieel van de stollingsroute en microvasculaire gezondheid met betrekking tot eventueel ontwikkelen van hartfalen. Het mechanisme van T2DM progressie varieert bij verschillende etniciteiten en we hebben aangetoond dat veranderingen in cholesterol functie (HDL) en lipiden profiel in het bloed een van de onderliggende mechanismen kunnen zijn die leiden tot versnelde ziekte progressie bij Zuid-Aziaten van Nederlandse afkomst met T2DM in vergelijk met Nederlandse blanke Europeanen met T2DM. Met nieuwe geavanceerde technieken vonden we ook dat bij patiënten met ernstige COVID-19 factoren in het bloed aanwezig zijn die schade aan de kleine bloedvaten en verhoogde stollingsactiviteit teweegbrengen. Ook bij deze patiënten zagen we dat veranderingen in HDL compositie een belangrijke rol in de ernst van de ziekte speelt. Samen geven de resultaten het belang aan van thromboinflammatie in verhoogd-risico populaties in versneld ontwikkelen van hartfalen, T2DM en COVID-19. Het onderzoek laat de noodzaak zien van vroege detectie in het proces, waarbij vroegtijdige interventies kunnen lijden tot preventie of het beter managen van het thromboinflammatoire ziekteproces.*************************************************************************In this study, we investigated the role of thromboinflammation in various high-risk populations, including individuals with type 2 diabetes mellitus (T2DM) and patients with severe COVID-19, as well as the increased risk in women in Dutch society. Thromboinflammation refers to the simultaneous activation of the clotting pathway and immune response, which is a significant trigger for vascular damage, particularly in microvascular health.Firstly, we demonstrated sex-specific associations between coagulation parameters and microvascular health. The mechanism of T2DM progression varies among different ethnicities, and we found that changes in cholesterol function (HDL) and lipid profiles in the blood could be underlying mechanisms leading to accelerated disease progression in South Asians of Dutch descent with T2DM compared to Dutch white Caucasian with T2DM.Using advanced techniques, we also identified factors in the blood of patients with severe COVID-19 that contribute to small blood vessel damage and increased clotting activity. We observed that changes in HDL composition played an important role in the severity of the disease in these patients.Overall, our results highlight the importance of thromboinflammation in high-risk populations in the accelerated development of heart failure, T2DM, and COVID-19. The research emphasizes the need for early detection in the process, where timely interventions can lead to prevention or better management of the thromboinflammatory disease process. Show less
The treatment of community-acquired pneumonia (CAP) is based on early diagnosis and swift initiation of appropriate antibiotic treatment. Despite effective treatment, CAP is still one of the... Show moreThe treatment of community-acquired pneumonia (CAP) is based on early diagnosis and swift initiation of appropriate antibiotic treatment. Despite effective treatment, CAP is still one of the leading causes of morbidity and mortality due to infectious diseases worldwide. This thesis aimed to identify strategies to optimise the treatment of hospitalised CAP patients outside an intensive care unit (ICU) setting with a focus on corticosteroid treatment. First, this thesis focused on the question whether oral adjunctive corticosteroid treatment improves outcomes in hospitalised CAP patients and tries to identify a subgroup of CAP patients, based on inflammatory status at admission, in whom the beneficial effects of adjunctive corticosteroid treatment outweigh the disadvantages associated with corticosteroid use. Next, this thesis investigated whether obesity and overweight are associated with worse clinical outcomes in a population of hospitalised COVID-19 patients who were all treated with the recommended 6 mg dexamethasone dose. Last, this thesis focused on optimising antibiotic treatment by exploring whether extensive microbiological testing facilitates early antibiotic alterations in CAP patients. Show less
This dissertation aimed to examine the ethnic socialization context in the upbringing of Chinese-Dutch children, specifically three social-contextual factors: parents, children’s books, and the... Show moreThis dissertation aimed to examine the ethnic socialization context in the upbringing of Chinese-Dutch children, specifically three social-contextual factors: parents, children’s books, and the COVID pandemic. Results reveal that Chinese-Dutch children evaluate their ingroup and the White outgroup most positively, followed by the Middle Eastern and North African (MENA) outgroup, and the Black outgroup least positively. Stronger maternal endorsement of multiculturalism is associated with lower child ethnic prejudice (in terms of less ingroup preference). In addition, results demonstrate maternal self-report ethnic-racial socialization strategies and the observed behaviors that reflect color-evasiveness and white normativity. Furthermore, results show an overrepresentation of White authors, illustrators, and characters, and a preference for light skin color in East Asian characters in illustrations in Chinese children’s books, suggesting a form of current postcolonial influences on Chinese children’s literature. Furthermore, results indicate ethnicity-related attitude differences among mothers participating after than before the COVID outbreak, with higher perceived discrimination and stronger ethnic identity. A lower ingroup rejection among Chinese-Dutch children was found in the post-COVID-outbreak group than in the pre-COVID-outbreak group. This dissertation can foster a better understanding of the interethnic relations in the underrepresented Chinese group and elucidate the ethnicity-related consequences of the pandemic in this group. Show less
Immunoglobulin G (IgG) antibodies can exert their functions via both Fab-mediated neutralization and Fc-mediated effector functions, both of which are crucial for protective immunity in COVID-19.... Show moreImmunoglobulin G (IgG) antibodies can exert their functions via both Fab-mediated neutralization and Fc-mediated effector functions, both of which are crucial for protective immunity in COVID-19. Importantly, effector functions and resulting inflammatory responses are impacted by the structure of N-glycans linked to the Fc-tail of IgG. Studying antibody glycosylation in emerging infectious diseases such as SARS-CoV-2 allows to gain insight into specific glycan signatures at the early stages of infection, and to investigate whether these reflect how the disease would progress. For example, low fucosylation is a common glyco-phenotypic signature of IgG1 produced against the spike (S) protein of severely ill SARS-CoV-2 infected patients early on in their disease course, but has likewise been described in other disease settings, where the antigen is presented in the context of host-cell membranes (Chapter 2). In this thesis, antibody glycomics signatures of SARS-CoV-2 infection and vaccination have been explored using an established liquid chromatography – mass spectrometry-based method relying on affinity-isolation and proteolytic digestion of both total and anti-S IgG. In Chapter 3, the glycosylation of SARS-CoV-2 anti-S IgG antibodies were found to be vastly skewed relative to total IgG and to change in a highly dynamic fashion. Moreover, IgG glycosylation was shown to be an early severity marker and showed patient stratification potential, with predicting power for intensive care admission within a hospitalized patient population. Early detection of a pro-inflammatory glycosylation pattern may provide a broader intervention window and decrease the number of ICU-admissions. Furthermore, anti-S IgG1 glycosylation levels obtained with LC-MS show promise to supplement clinical parameters and biomarkers of inflammation, that have together been used for the severity score calculation of hospitalized COVID-19 patients. Similarly to SARS-CoV-2 infection, antibodies generated against the spike protein upon BNT162b2 mRNA vaccination also induced a transient afucosylated anti-S IgG1 response in antigen naïve individuals, albeit to a lower extent than in severely ill patients, exemplifying the influence of the type of immunization on antibody glycosylation (Chapter 4). Upon vaccination, the observed initial, mild afucosylated response was additionally accompanied by low fucosyltransferase (FUT8) expression in antigen-specific plasma cells. Furthermore, the observed initial anti-S IgG afucosylation signature may aided mounting a stronger immune response, as indicated by its correlation with antibody amounts following the second vaccination dose. Given the impact of glycosylation on antibody function, deciphering theunderlying regulatory mechanisms influencing IgG glycosylation will be of great importance to better understand the inflammatory potential, vaccine efficacy and protective capacity of vaccine- or pathogen-induced IgG in both body fluids and tissues in the future.In Chapter 5 and 6, the reaction steps of a previously developed linkage-specific sialic acid derivatization workflow were studied in more detail. Key players in such reactions are catalyst, of which novel types with different physico-chemical properties were introduced in Chapter 5. In Chapter 6, prior lactone formation was found to be a prerequisite for subsequent amidation of α2,3-linked sialic acids, which proceeds via direct aminolysis of the C2 lactone. Together, these new insights will be beneficial for the rational optimization of high-throughput (MALDI-)MS-based glycomics and glycoproteomics workflows relying on linkage-specific sialic acid derivatization. Show less
