Progress in prevention and prediction of venous thromboembolism in women:Focus on pregnancy and the postpartum period

Although women and pregnant women are increasingly included in studies and research, many knowledge gaps and clinically relevant issues remain unsolved for the pregnant population. The first part of the thesis (chapter 2-7) focuses on the incidence of (recurrent) venous thromboembolism (VTE) and superficial vein thrombosis (SVT) in pregnancy and the postpartum period. Chapter 3 presents the results of the largest, international, randomized controlled trial to date, the Highlow study, comparing an intermediate weight-adjusted dose of low-molecular-weight heparin (LMWH) to a fixed low dose of LMWH to prevent recurrent VTE in pregnant and postpartum women. Chapter 4 presents the results of a sub-analysis of the Highlow study about the number of women receiving neuraxial anesthesia and whether this differs between the two LMWH doses. Chapter 5 reports on the incidence of SVT and the risk of subsequent VTE in the pregnant population, which may help physicians to guide treatment decisions. Furthermore, we focus on the prognosis of VTE and pregnancy outcomes in special populations such as women with small for gestational age infants (chapter 6) and those with Budd-Chiari syndrome and/or portal vein thrombosis (chapter 7). The second part of the thesis (chapters 8-11), evaluates VTE in relation to women-specific health such as management and treatment strategies for heavy menstrual bleeding while using anticoagulation (chapter 8) and the risk of recurrence in women with a first VTE related to the use of estrogen-containing contraceptives (chapter 9 and 10)

Image analysis and in-silico simulation of acute ischemic stroke

Treatment of acute ischemic stroke (AIS) aims to restore the blood supply in the occluded artery to salvage the brain tissue at risk and improve clinical outcome of patients. We explored image analysis techniques to study the impact, causes, and constituents of ischemic lesion evolution in the subacute time window after treatment. We found that subacute lesion growth is associated with worse clinical outcome. We identified clinical risk factors of subacute lesion growth and showed that subacute lesion growth cannot be explained by edema evolution alone. We also evaluated the applicability of transfer-learning based Convolutional Neural Networks for segmenting follow-up lesions in posterior circulation AIS patients. We also explored in-silico tools to simulate and explain stroke and its treatment. We first described an in-silico trial (IST) platform that can leverage clinical data to generate virtual representations of patients; simulate stroke, its treatment, and the associated brain injury to estimate clinical outcome at population levels, similar to real-life clinical trials. We presented an automated pipeline to develop high resolution, patient-specific finite element vessel and thrombus models from radiological images that could serve as input to the in-silico treatment models. Finally, we validated the IST pipeline with real-life clinical trial data and simulated two exploratory trials to evaluate device performance in different clot types and compare the performance of two devices. Although in-silico techniques will not replace traditional clinical trials, they may potentially contribute towards establishing the efficacy of newer treatments

Making physical activity a walk in the park:The development and evaluation of a smartphone app-based just-in-time adaptive intervention to promote walking

Physical inactivity is a significant risk factor for non-communicable diseases, particularly affecting socioeconomically disadvantaged populations. This dissertation focuses on the importance of walking to combat inactivity. While walking apps have the potential to stimulate regular physical activity, they are underutilized by individuals from lower socioeconomic backgrounds. Using the Technology Acceptance Model, the first part of the dissertation explores factors influencing walking app use intention and usage across different socioeconomic segments. It highlights perceived ease of use and usefulness as key factors in driving walking app adoption, particularly for individuals with no prior app experience and lower socioeconomic position.Building on these findings, the second part of the dissertation introduces SNapp, an app-based just-in-time adaptive intervention designed to promote walking among socioeconomically disadvantaged Dutch adults. SNapp incorporates health behavior theory and dynamically tailors coaching content to individual users based on their content preferences, step count levels, and proximity to green spaces suitable for walking. A twelve-month randomized controlled trial evaluates the intervention's effects, showing positive outcomes only for users who perceived the app as useful for tracking and achieving daily walking goals. This dissertation highlights the potential effectiveness of walking apps in promoting physical activity, contingent on individual perceptions of ease of use and usefulness. To maximize impact, developers should collaborate with interdisciplinary teams, employ iterative development processes, and leverage advanced AI techniques to enhance these user perceptions. By incorporating these insights, developers can design more effective interventions to combat physical inactivity and associated health risks, particularly among socioeconomically disadvantaged populations

Mapping the ionised gas in active galactic nuclei with spectral-timing and spectroscopy

The cores of most galaxies harbour a supermassive black hole. The process of its growth, manifested by the accretion of the surrounding material, is connected with the formation of a complex environment and the release of substantial amounts of energy. As a result, this region near the central black hole can reach luminosity far exceeding that of the host galaxy. These compact yet energetic cores of galaxies are called active galactic nuclei (AGNs). Spectroscopic observations of AGNs unveil several characteristic components shaping this region and often allow for placing general constraints on their spatial structure. Detailed mapping of this environment remains, however, a challenging task. Yet it is an essential one, as uncovering the underlying geometry and physical processes forming AGNs is key for understanding not only the black hole growth but also the impact AGNs have on their surroundings: observations reveal a tight connection between the supermassive black hole and the properties of its host galaxy. A crucial role in this connection is believed to be played by outflows of photoionised gas accelerated away from the central region. Despite being detected in most AGNs, the fundamental physical properties of these outflows are largely unconstrained, which poses a longstanding challenge to understanding these phenomena. In this thesis, I aim to overcome it by harnessing the power of photoionisation modelling of the ionised gas combined with the analysis of the time-dependent behaviour of the observed spectral features

Preterm birth:Risk factors and treatment

Preterm birth, defined as a delivery before 37 completed weeks of gestation, is a major cause of neonatal mortality and morbidity worldwide. The pathogenesis of preterm birth is complex and largely unknown, and understanding of risk factors remains poor. Ideally, identification of risk factors will lead to effective interventions that reduce or prevent preterm birth. The first part of this thesis studies population trends in the Netherlands and studies risk factors for preterm birth.Once clinical symptoms of threatened preterm birth occur at a viable gestational age, it is challenging to prevent preterm birth. Treatment is then aimed at safe delivery and improvement of neonatal outcome. The second part of this thesis focuses on improving neonatal and long-term outcomes in threatened preterm birth, specifically the effectiveness of tocolysis (inhibiting labor). We state that, although tocolytics are widely used, there is currently no evidence to routinely administer tocolytics in threatenend preterm birth

Shared decision-making in maternity care:Health literate-sensitive support for healthcare professionals and clients

Dit proefschrift beschrijft hoe zorgverleners en cliënten in de geboortezorg kunnen worden ondersteund bij ‘gezondheidsvaardig samen beslissen’. Dit betekent dat samen beslissen wordt afgestemd op vaardigheden van cliënten om informatie te vinden, begrijpen, beoordelen en toe te passen (gezondheidsvaardigheden). Ondersteuningsbehoeften van zorgverleners en cliënten werden in kaart gebracht en samen met hen werd een training en een gesprekstool ontwikkeld en geëvalueerd. Zorgverleners bleken de meeste moeite te ervaren met het beoordelen of een cliënt de verstrekte informatie begrepen heeft. De terugvraagmethode of bestaande beslisondersteuning werden nog zelden toegepast. Cliënten met beperkte gezondheidsvaardigheden hadden problemen in het vinden van betrouwbare informatie, het begrijpen van medische terminologie, het begrijpen van kans-informatie en het vormen van voorkeuren op basis van informatie over voor- en nadelen. Huidige keuzehulpen leken tot op zekere hoogte ondersteuning te bieden bij het begrijpen, beoordelen en toepassen van informatie, maar er is ruimte voor verbetering, met name in de presentatie van informatie. De training en gesprekstool die wij ontwikkelden, hebben potentie om gezondheidsvaardig samen beslissen te ondersteunen in de geboortezorg. Zowel zorgverleners als cliënten waren positief over het gebruik van de gesprekstool. De training had in een gesimuleerde setting positieve effecten op de mate van samen beslissen, zowel zelf gerapporteerd door zorgverleners als door ons geobserveerd. Ook zagen we een effect van de training op het daadwerkelijk gezondheidsvaardig communiceren, zoals het gebruik van eenvoudige taal. De resultaten beschreven in dit proefschrift kunnen worden gebruikt om zorgverleners beter in staat te stellen om gezondheidsvaardig samen beslissen systematisch in de praktijk toe te passen

Evolution of sexual signals:Within and between species variation in a dual function sex-pheromone component in two noctuid moths

Sexual signals are key components in mate attraction and mate choice. Sexual attraction through sex pheromones is best studied in moths, where females emit species-specific pheromone blends. This species-specificity stems from the presence/absence and ratios of the different components. For example, the two closely related noctuid moth species Heliothis subflexa and Heliothis virescens produce similar sex pheromone blends, with one major difference: acetate esters (hereafter referred to as “acetates”). Only H. subflexa females produce acetate in their sex pheromone blend which play a dual function: attracting conspecific males, while repelling the sympatrically occurring species, H. virescens. Moreover, H. subflexa females produce high acetate levels when H. virescens are present, but low in their absence.In this thesis I investigated both within and between species variation in acetate levels, by studying the genetic architecture responsible for this variation and looking at the potential costs associated with high acetate levels. We identified a few candidate genes that are involved in acetates variation in two previously found QTLs. In addition, we selected for high and low levels of acetate in H. subflexa and investigated how this affected the pheromone blend. Finally, we investigated whether the production of high acetate levels comes with a cost, by rearing the two selection lines under food stress conditions. Our results indicate that 1) intra- and inter-specific variation in acetate levels can be explained by a combination of shared and unique genetic factors and 2) high levels of acetate come with a fitness cost under stressful conditions

The role of oxidative stress in development of antimicrobial resistance in <i>E. coli</i>

Antibiotics are extensively utilized in the veterinary sector for various applications, including treatment and prevention of microbial infections, as well as the promotion of livestock growth in various low- and middle-income countries. As a result, more antibiotics are used to treat animals than to treat human disease. This widespread use of antibiotics causes the emergence and dissemination of resistance among veterinary or environmental microorganisms. In response to antibiotic-induced stress, bacteria activate various general or specific responses, leading to physiological adaptations, genetic mutations, and the acquisition of exogenous genes, resulting in the development of resistance. This study investigates whether bacterial stress responses, particularly oxidative stress and stringent responses, influence the de novo acquisition of antimicrobial resistance through genetic mutations. Our findings demonstrate that reactive oxygen species (ROS) under aerobic conditions and reactive metabolic byproducts under anaerobic conditions accelerate the de novo acquisition of antibiotic resistance in E. coli by activating the SOS response, consequently initiating DNA damage-repair mutagenesis. Additionally, the knockout of (p)ppGpp synthetase RelA impedes the acquisition of resistance to bactericidal antibiotics by lowering growth rate and ROS production. Both oxidative stress and stringent responses play pivotal roles in de novo acquisition of antimicrobial resistance. Furthermore, our study reveals that oxidative stress and stringent responses exert notable influence on the fitness costs associated with resistance development. This study provides important theoretical support for a comprehensive understanding of the mechanisms by which antibiotics acquire de novo resistance to identify potential drug targets and advance the development of new antibiotic candidates and adjuvants

Physical performance in patients undergoing transcatheter aortic valve implantation (TAVI)

Severe aortic valve stenosis is a common heart valve disease that can be treated with transcatheter aortic valve implantation (TAVI), which is the preferred treatment option for older and frailer patients. Physical performance is a crucial outcome for many of these patients. This thesis aimed to describe the physical performance, dietary intake, and physical activity of TAVI patients as a first step towards developing an intervention to enhance physical performance.The thesis findings indicate that, on average, most patients improve their physical performance after TAVI, but one in three patients experiences a clinically significant decline. Muscle strength also typically decreases in most patients after TAVI. Furthermore, pre-procedural low physical performance and muscle quality are independent predictors of mortality after TAVI.In the second part of the thesis, it was highlighted that most TAVI patients fail to meet the required protein intake, do not adhere to most dietary guidelines, and do not meet the guidelines for minimal required physical activity.Finally, the thesis examined the barriers and facilitators of behaviour change and found that many TAVI patients are ambivalent about changing their behaviour. Additionally, adherence to home-based cardiac rehabilitation among older patients was studied, and we observed adherence in two-thirds of these patients.In conclusion, the thesis emphasizes the need for interventions focused on protein intake, diet quality, and physical activity. The thesis proposes an intervention that should be tested for feasibility and effectiveness in future research

Neutrophils in the spotlight:In dendritic cell-driven adaptive immunity

The daily challenge of dodging pathogenic infections is carried out by the two arms of our immune system: the innate and the adaptive immune system. Innate immune cells, like neutrophils and dendritic cells (DCs), form the first line of defense against invading pathogens. Neutrophils are the most abundant cell type of the innate immune system and they can directly kill invading pathogens, a non-specific and rapid response. DCs are important orchestrators of adaptive immune responses, by adequately activating them, while maintaining immune tolerance against autoantigens and harmless antigens, e.g., dietary nutrients. The induction of peripheral tolerance by DCs and how neutrophils are able to shape DC-driven T cell development is explained. The current knowledge on the effects of tolerogenic adjuvants vitamin D3 (VD3), vitamin A-derivative retinoic acid (RA) and corticosteroid dexamethasone (DEX) on both DCs and neutrophils is described. In this thesis, we investigated the effects of these adjuvants on neutrophils and on DC-driven T cell development. We demonstrate that tolerogenic adjuvants VD3 and RA that could be used in DC-targeting therapies inhibit T helper 17 cell development, while they can also directly affect neutrophils. While DEX shows inhibitory effects on the function of stimulated neutrophils, RA increases neutrophil function. Therefore, we envision that combining a tolerogenic adjuvant-loaded DC-targeting nanoparticle with DEX treatment could be a valuable treatment strategy for patients with chronic inflammatory diseases. This treatment would promote a tolerogenic adaptive immune response while reducing the harmful effects of neutrophils as seen in some autoimmune diseases, including rheumatoid arthritis