In this thesis we examined patient readiness for shared decision making (SDM) about treatment. We first assessed associations between patient-related characteristics and the occurrence of SDM.... Show moreIn this thesis we examined patient readiness for shared decision making (SDM) about treatment. We first assessed associations between patient-related characteristics and the occurrence of SDM. Overall, we did not find consistent associations between characteristics such as age or education level, and the extent to which SDM occurred (measured from the perspective of patients, clinicians, or observers). Second, we assessed what patients need to be ready, i.e., enabled and well-equipped, to participate in SDM about treatment. We identified a wide range of skills, cognitions, and emotions. For instance, patients need to be able to understand the relevant information, be able to and dare to express themselves in consultations with clinicians, and experience an adequate amount of time to talk to clinicians and to consider the options. Finally, we developed a questionnaire, the ReadySDM. The aim of the ReadySDM is to retrospectively measure the extent to which patients felt ready for SDM during a treatment decision-making process. The questionnaire has the potential to identify novel insights into patients’ support needs and ways to enhance SDM in daily practice. Show less
Drug candidates with a covalent binding mode have gained interest since the approval of multiple covalent anticancer drugs, but were long avoided due to concerns regarding promiscuous reactivity... Show moreDrug candidates with a covalent binding mode have gained interest since the approval of multiple covalent anticancer drugs, but were long avoided due to concerns regarding promiscuous reactivity with off-target proteins. In this dissertation, the scope and versatility of the newly discovered in situ thiol–alkyne reaction is evaluated: the nonactivated alkynes exhibit an unprecedented target reactivity with excellent thiol selectivity, thus potentially outperforming currently used cysteine-reactive warheads. Chapter 1 starts with the history of (ir)reversible covalent inhibition, the reactivity of (non)activated alkynes, and the serendipitous discovery of the thiol–alkyne reaction. Established technologies for direct detection of covalent protein–drug adducts are reviewed in Chapter 2, and in Chapter 3 a detailed guide for the evaluation of (ir)reversible covalent inhibitors to obtain relevant kinetic parameters is provided, accompanied by kinetic simulations and step-wise protocols for enzymatic activity assays. In Chapter 4, the nitrile warhead in reversible CatK inhibitor odanacatib (ODN) is replaced with alkyne warheads to investigate whether it an irreversible covalent adduct is formed with cysteine protease cathepsin K (CatK) despite having a small recognition element. In Chapter 5, we evaluate if nonactivated alkynes can target noncatalytic cysteine residues by replacing the irreversible covalent acrylamide warhead in EGFR/HER2 inhibitor neratinib by an alkyne warhead. In Chapter 6, the impact of substituents on the alkyne warhead is explored using a panel of ubiquitin-based ABPs bearing substituents on the propargylamide warhead. Finally, the most important findings are summarized in Chapter 7, and placed in the context of covalent drug discovery. Show less
Mental health problems among children and youths are common and have numerous negative consequences for young people and their social network. Therewith, these problems pose a social issue. GPs... Show moreMental health problems among children and youths are common and have numerous negative consequences for young people and their social network. Therewith, these problems pose a social issue. GPs play an important role in early detection and management of these problems. Insight into their clinical decision- making and, as a result, way of working would be helpful to develop methods for providing children and youths with the help they need. Previous literature suggest many doctors(-to-be), of whom some are or will become GPs, have (lived) experience related to mental health problems themselves. Previous studies also suggest having (lived) experience influences GPs’ clinical decision-making, and consequently their way of working. It would have clinical benefits for GPs and patients to explore this process. This thesis is constructed of four different articles, each contributing to answering the main question: ‘How do GPs decide on child and youth mental health problems and what is the influence of their(lived) experience regarding these problems on this decision?’ Article 1: How do GPs make decisions regarding mental health problems in children and youths? For answering this subquestion, a mixed methods design was used: interviews among 14 and an online survey among 15 GPs. GPs were asked about their clinical decision-making process on children and youths with mental health problems using three vignettes describing children and youths with mental health problems representative of clinical practice. The findings suggest GPs differ with regards to their decision- making regarding child and youth mental health problems, and that their decision-making is influenced by factors related to 1) the GP, for example if the GP approaches the problem somatically or psychosocially, if the GP considers themself competent enough to solve the problem with regards to their interest in and knowledge about youth mental health care, 2) the child and its social context, for example if the child or youth has psychiatric (co)morbidity, if the problem is likely to solve itself and if the problem could be assessed as being complex and 3) the GPs’ collaboration with other youth care providers, for example if GPs have existing collaboration agreements with these youth care providers and how they view their collaboration. Article 2: Can GPs’ decisions on child and youth mental health problems be supported by means of a decision-support method?For answering this subquestion, a literature search was conducted to retrieve studies that involved clinical decision support methods for GPs’ clinical decision-making related to mental health problems among children and youths. This systematic review yielded 25 studies on 18 clinical decision-support methods, divided into computer-based methods (such as MyGRaCE), telecommunication methods (such as CAP PC) and methods with a combination of components related to computer-based methods and telecommunication methods (such as Collaborative care for depression intervention). The article provides insight into (possible) beneficial clinical implications of clinical decision-support methods. These methods could give more insight into possible mental health problems, they could provide structured information which can be used by the GP and/or parents during their next consultation with the child or youth, and they could also decrease time and costs spent by the primary care practice and the GP. There are also less beneficial clinical implications, such as an inability for some computer-based methods to be used in emergency situations, when time is short, problems for children and youths when using computer-based methods because of their mental status, and impediment to discuss certain topics freely because the decision-support method gives too much direction to the consultation. The article describes certain considerations for GPs when choosing a decision-support method, which may indirectly have a positive impact on the implementation of such methods into general practice. For example, the GP can take into account their way of working, user flexibility of the method for the GP, the child/youth and their parent(s) with regards to understandability and ease of use, if the GP already uses a clinical decision-support method, if the GP already has collaboration agreements with youth care providers, as well as their own attitude and knowledge regarding mental health problems among children and youths.Article 3: Do doctors-to-be, among whom future GPs, have (lived) experience regarding mental health problems? Study focused on preclinical medical students.For answering this subquestion, self-report questionnaires were sent to 1311 preclinical medical students of Leiden University Medical Center to measure burnout-, depression- and anxiety-related symptoms. The article concludes that symptoms related to mental health problems are common among preclinical medical students. Burnout-related symptoms were found in 46%, depression-related symptoms in 27% and anxiety- related symptoms in 29% of preclinical medical students. Burnout-related symptoms among preclinical medical students were correlated with a sleep duration of less than 6 hours per night, low happiness and a high need for recovery after a day of study. Depression- and anxiety-related symptoms were mainly correlated with low optimism, low happiness, and a high need for recovery after a day of study. These findings suggest preclinical medical students are at risk to develop mental health problems, which can inspire universities to come up with preventive interventions.Article 4: Do doctors-to-be, among whom future GPs, have (lived) experience regarding mental health problems? Study focused on medical interns.For answering this subquestion, self-report questionnaires were sent to 709 medical interns of the same institution mentioned in article 3 to measure burnout-related symptoms. Burnout-related symptoms were found in 30% of medical interns. Burnout-related symptoms among medical interns were related to low dedication with regards to work, a high work pace and quantity, a high need for recovery after a day of work and low optimism. These correlates could be used to prevent mental health problems among medical interns by making adjustments to the medical curriculum. The articles of this thesis suggest GPs’ decision-making on mental health problems in children and youths is multifactorial and consists of objective and subjective components. Furthermore, decision-making seems to differ between GPs, which may be an explanation why there are a variety of clinical decision support methods. Some clinical decision support methods have been implemented in the context of research into general practice, like MyGRaCE, CHICA, Mobiletype, Youth StepCare, consultation-liason method(between GPs and psychiatrists), telepsychiatry consultation practice and the MC3 Program. A clinical implication is GPs can choose a decision-support method which match their personal style of clinical decision-making. However, the validity, trustworthiness and usability of available methods need to be further explored. A clinical implication with regards to medical students’ mental health comprises universities provide accessible proactive mental support to preclinical medical interns and medical interns, because many do not seek help themselves. Furthermore, universities could stimulate a stigma-reducing educational environment, for example in collaboration with the department of (Child- and Adolescent) Psychiatry. Therefore, medical students could be equipped with effective strategies to cope with mental health problems. Also, they might be made aware of their vulnerability, so that they may know their subjectivity and use their personal experiences in practice. The results of this thesis invite more (longitudinal) research on the diagnostic precision, predictive value and cost-efficiency of clinical decision-support methods. Furthermore, more research is needed on the prevalence of mental health problems among graduated doctors, like GPs, and possible effects of these problems on their way of working, their decision-making and their contacts with patients. Strengths of this thesis include exploration of a relatively unknown research area, namely GPs’ clinical decision-making regarding mental health problems among children and youths. Therefore, this thesis used multiple research methodologies and it used a practical scope. This thesis also contains several limitations, such as inclusion of a small GP population, as well as self-selection bias in the studies on preclinical medical students, medical interns and GPs. Finally, interpretation of the results of this thesis was impeded because the research has been conducted in one university, because cause and effect of results could not always be disentangled and because of low statistical power. Because having mental health problems may influence GPs’ clinical decision-making, one could explore how (future) doctors work, study and relax. Therefore, it is recommended to strive for educating balanced doctors: persons who, in collaboration with their colleagues, are – through reflection – aware of their needs and wants between professional boundaries. Show less
Adverse drug reactions on sexual functioning (sADRs) may seriously decrease a person's quality of life. This topic is barely discussed in healthcare practice, partly because of little knowledge... Show moreAdverse drug reactions on sexual functioning (sADRs) may seriously decrease a person's quality of life. This topic is barely discussed in healthcare practice, partly because of little knowledge about the association between drugs and sexual function. Research in this thesis supplements this knowledge with quantitative methods, identifying drugs associated with sADRs and taking the first steps in characterizing the population with these drugs in use. In the second part of the thesis, qualitative methods were used to describe the current practice and the potential role of healthcare providers regarding sADRs in primary care, especially in the community pharmacy. With the acquired knowledge, materials have been developed for primary healthcare providers to discuss and agree on local policy about sADRs in their own region. Initial experiences with these materials showed greater awareness of the subject among the healthcare providers concerned. Show less
The aim of this thesis is to develop noise robust electrical properties tomography (EPT) reconstruction methods that are free from tissue transition artifacts to support clinical applications for... Show moreThe aim of this thesis is to develop noise robust electrical properties tomography (EPT) reconstruction methods that are free from tissue transition artifacts to support clinical applications for complex tissue structures such as the brain. In particular the contrast-source inversion approach is pursued. This focus of this thesis is on the reconstruction of the electrical properties from the transmit field of radiofrequency coils most frequently available in magnetic resonance imaging. Show less
This research concerns the role of metabolic sensor AMPK, which is activated during low energy levels, and known to suppress the activation of some immune cells. I studied how AMPK regulates the... Show moreThis research concerns the role of metabolic sensor AMPK, which is activated during low energy levels, and known to suppress the activation of some immune cells. I studied how AMPK regulates the function of dendritic cells (DCs), immune cells that are key regulators of the adaptive immune response. Key findings include that drug-induced AMPK activation in DCs results in metabolic rewiring that leads to immunosuppressive DCs. Furthermore, we show that the AMPK signaling axis in DCs is important for protection against obesity-induced inflammation, while AMPK in DCs inhibits the anti-tumor immune response and thereby promoting tumor growth. Therefore, AMPK activation in DCs may be a promising strategy for the generation of therapeutic tolerogenic DCs, while AMPK inhibition may be beneficial for DC-based cancer therapies. Together, these findings contribute to a better understanding of AMPK as regulator of immunity and tolerance in dendritic cells. Show less
Cancer immunotherapy has experienced remarkable advances in the last decades. Striking clinical responses have been achieved for several solid cancers, particularly cancer types with a high... Show moreCancer immunotherapy has experienced remarkable advances in the last decades. Striking clinical responses have been achieved for several solid cancers, particularly cancer types with a high mutation burden, which placed tumour-mutated antigens (neoantigens) centre stage as targets of tumour immunity and cancer immunotherapy. Neoantigens can be presented in complex with HLA molecules on the tumour cell surface, where T cells with the correct specificity can recognize the neoantigen as ‘non-self’ which will trigger killing of the tumour cell by the T cell. In theory, cancers with a low/moderate mutation burden that present neoantigens in complex with HLA class molecules could still be eligible for T cell-mediated immunotherapy. This thesis, describes the finding that neoantigen-specific T cells are present in mismatch-repair proficient (MMR-p) colorectal cancer patients, a low mutation burden cancer type. Moreover, CD39 and CD103 were found as cell surface markers that pinpoint the T cell population that contains the neoantigen-specific T cells. In addition, subsequent metastasis of a melanoma patient cohort were studied and revealed that also at advanced, late-stage disease, neoantigen-directed T cell therapy is, in theory, still applicable. Taken together, the studies reveal potential for the development of neoantigen-directed cancer immunotherapy for a broader patient population. Show less
Targeted therapy using EGFR inhibitors cetuximab and panitumumab has anti-tumor efficacy in colorectal cancer, though only in patients without a KRAS mutation in their tumor. This thesis aims to... Show moreTargeted therapy using EGFR inhibitors cetuximab and panitumumab has anti-tumor efficacy in colorectal cancer, though only in patients without a KRAS mutation in their tumor. This thesis aims to give insight on several aspects of EGFR inhibitors en RAS mutations in colorectal cancer. It reviews aspects of mutational analysis, aims to find ways to restore sensitivity to EGFR inhibitors in patients with KRAS mutated colorectal cancer and discusses the distinctive skin toxicity of cetuximab en pantiumumab. Show less
Oxygen supplementation is a cornerstone of supportive medical treatment for critically ill patients. We studied self-reported attitudes towards oxygen therapy and actual clinical practice of ICU... Show moreOxygen supplementation is a cornerstone of supportive medical treatment for critically ill patients. We studied self-reported attitudes towards oxygen therapy and actual clinical practice of ICU clinicians. We found that clinicians are concerned with oxygen induced lung injury and will change mechanical ventilation settings accordingly. However, we performed a large, randomized trial assessing whether a conservative oxygenation strategy resulted in reduced mortality compared to a liberal oxygenation strategy and found there was no significant difference in mortality between the two groups. This thesis has brought to light an important problem of studying ICU patients regarding the consent procedure. We had to exclude patients because no consent had been obtained, losing valuable data and risking selection bias. Afterwards we asked patients how they experienced participating in the trial and most were not aware of their participation but did agree with their participation. This challenges the feasibility of informed consent in critically ill patients. Moreover, we researched disturbances in the homeostasis of sodium and found that an increase in serum sodium was associated with mortality, even in patients with normonatremia and moderate hyponatremia. This challenges the assumption that correcting hyponatremia would lead to lower mortality. Show less
This thesis explores the 4 pillars of Primary Healthcare (PC), the innovations that have been implemented to improve them, and the role digital technologies may have had as part of these... Show moreThis thesis explores the 4 pillars of Primary Healthcare (PC), the innovations that have been implemented to improve them, and the role digital technologies may have had as part of these innovations, with a focus on their impact in the management of chronic conditions. This thesis seeks to identify the optimal way to incorporate digital technologies in PC and how they could improve the PC consultation, in particular, and the PC field in general. It is composed of three parts: the first revises the concept of PC and explores interventions to improve it; the second part, delves into the role digital technologies have had in improving PC and looks at how apps may impact the treatment of chronic conditions. And the third, explores the digital competencies required for PC professionals to use these technologies. Show less
Long-term survival for univentricular heart patients with a Fontan circulation is nowadays excellent, with the majority of patients expecting to reach adulthood. Nevertheless, a general attrition... Show moreLong-term survival for univentricular heart patients with a Fontan circulation is nowadays excellent, with the majority of patients expecting to reach adulthood. Nevertheless, a general attrition rate remains present and the majority of Fontan patients will be faced with significant morbidity. However, no Fontan patient is the same and there is a need for better understanding which patients will do worse, ideally by (early) identification of adverse factors that can be optimized. In this thesis, the role of flow efficiency in the TCPC was thoroughly investigated leading to multiple new insights. A novel three-dimensional blood flow MR sequence (3D flow MRI) was developed and shown to be superior to conventional 2D and 4D flow MRI sequences which could potentially lead to a more widespread use. Adverse flow patterns associated with reduced flow efficiency were shown at multiple areas within the TCPC which were related to adverse energetics. Increased 4D flow MRI derived energetics in turn are associated with reduced exercise capacity and increased levels of liver fibrosis/venous congestion. A focus on conduit size adequacy demonstrated that the currently used 16-20mm extracardiac conduits become undersized for teenage and adolescent Fontan patients. Undersized conduits proved to be an important factor leading to reduced flow efficiency, especially during exercise conditions. Achievement of optimal blood flow in Fontan patients may ultimately lead to improved long-term outcome. Show less
Although urbanization has long been associated with human development and progress,recent research has revealed that urban environments can also result in significant inequalitiesin many areas... Show moreAlthough urbanization has long been associated with human development and progress,recent research has revealed that urban environments can also result in significant inequalitiesin many areas including health. In particular, urban areas in low and middle incomecountries (LMIC), often see a widening gap in economic growth which contributes to healthdisparities between wealthy and underprivileged children. Several studies have establishedthe association between socioeconomic status (SES) and child health, showing that childrenof low-income parents had poorer health status. The rise of non-communicable diseases,the persistence of communicable disease, and the challenge of re-emerging diseases arecurrently a burden in developing countries. Given the rapid increases of urbanization andurban poverty in several developing countries including Indonesia, it is important to elaborateto what extent SES affects child health. We have done so, in relation to outcome of BCGvaccination, atopic sensitization, and intestinal barrier function. We have also investigatedthe interaction between intestinal parasitic infections and bacterial gut microbiota in orderto be able to delineate the contribution of this interaction on the function of intestinal barrier. Show less
The aim of this thesis was to assess the efficacy (part 1) and tolerability (part 2) of antiseizure medications (ASMs) in glioma patients with epilepsy. In addition, we aimed to get insight into... Show moreThe aim of this thesis was to assess the efficacy (part 1) and tolerability (part 2) of antiseizure medications (ASMs) in glioma patients with epilepsy. In addition, we aimed to get insight into the ASM prescription behavior and treatment policy in brain tumor-related epilepsy (part 3).First-line levetiracetam seems to be the most efficacious ASM in glioma patients, with favourable tolerability. This is demonstrated in multicenter retrospective observational cohort studies, a systematic review, and is the opinion among the vast majority of European neuro-oncology professionals. Enzyme-inducing AMSs should be avoided in glioma patients due to the high risk of adverse effects. ASM use was not independently associated with neuropsychiatric symptoms in glioma patients, but alternative factors seem to pose a greater risk for developing neuropsychiatric symptoms. If patients experience uncontrolled seizures on ASM monotherapy, levetiracetam combined with valproic acid has better efficacy than other ASM combinations in glioma patients, while toxicity is similar. Subsequently, potential add-on ASMs in glioma patients experiencing uncontrolled seizures on ASM dual therapy include clobazam, lamotrigine, and lacosamide. Show less
In dit proefschrift is gekeken naar de afweercellen die een rol spelen bij het ontstaan van alvleesklierkanker of als reactie teweeg worden gebracht door de tumor. daarnaast hebben we oude... Show moreIn dit proefschrift is gekeken naar de afweercellen die een rol spelen bij het ontstaan van alvleesklierkanker of als reactie teweeg worden gebracht door de tumor. daarnaast hebben we oude chemotherapeutica onderzocht op alvleesklierkanker cellen in vitro. Show less
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by a progressive loss of motor function. Despite the strives into growing knowledge on ALS, fundamental... Show moreAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by a progressive loss of motor function. Despite the strives into growing knowledge on ALS, fundamental obstacles remain into understanding disease causation and nominating drug targets for a cure. With this work, we widen our understanding of ALS through the analysis of single-nuclei RNA-sequencing dataset of patients’ and control motorcortices. We show intrinsically higher expression of ALS-related genes in Extratelencephalic Neurons accompanied by selective vulnerability of subsets of cortical motor neurons. These changes are found with alterations in oligodendrocytes and microglia that widen our knowledge of cell-to-cell interactions in ALS. We use hiPSC-derived in vitro systems to model the molecular changes identified. Secondly, we offer a wide view on models of human brain cells in a dish to encompass protocols useful for modelling complex cell-to-cell interactions in ALS. Moreover, we describe a human in vitro system for the study of motor neuron that is highly reproducible, scalable and high-throughput. This new method allows the assessment of multiple cell lines in the same dish and could provide insights into heterogeneity in human populations and mechanisms disrupted in disease. We then use these models to further dissect molecular mechanisms disrupted in ALS. We undertake a discussion onto the future of the field and hopefully the opening to a more holistic approach to the understanding of ALS, where multidisciplinary techniques and the use of different models might expand our perspectives on the disease. Show less
This thesis aims to advance anti-cancer therapy development through a comprehensive exploration.In Chapter 1, the focus is on understanding the immune system's role in breast cancer and... Show moreThis thesis aims to advance anti-cancer therapy development through a comprehensive exploration.In Chapter 1, the focus is on understanding the immune system's role in breast cancer and chemotherapy response. It examines the paradoxical roles of immune cells and macrophages, seeking novel biomarkers and immunomodulatory strategies.In Chapter 2, the impact of the adaptive immune system on HER2+ breast cancer is explored. Contrary to other breast cancer types, the adaptive immune system neither suppresses nor promotes spontaneous HER2-driven tumorigenesis or metastasis formation.Chapter 3 investigates the relationship between chemotherapy and the adaptive immune response using GEMMs. The study highlights that the endogenous adaptive immune system's role in chemotherapy response might not be as vital as previously believed when utilizing tumor cell line transplantation models. This finding leads to a reevaluation of the conventional understanding of the immune system's involvement in chemotherapy response.Chapter 4 focuses on macrophage-targeted cancer therapy. In non-immunogenic breast cancer, CSF-1R inhibition enhances chemotherapy, especially with platinum drugs. Intratumoral type I interferon activation drives their synergistic impact. Also, neutralizing immunosuppressive neutrophils is crucial for a strong anti-tumor immune response.In Chapter 5, the thesis discusses how its findings align with existing research and suggest clinical applications. Show less
The aim of this dissertation was to identify gaps in knowledge and room for improvements in certain aspects of the current system of prevention and care regarding RBC alloimmunization in pregnancy.... Show moreThe aim of this dissertation was to identify gaps in knowledge and room for improvements in certain aspects of the current system of prevention and care regarding RBC alloimmunization in pregnancy. The focus in this thesis was to evaluate the performance of new measures in the prevention program, the follow-up with laboratory monitoring in alloimmunized pregnancies and the counseling of pregnant women and their partners, in cases of RBC alloimmunization. Show less
Pancreatic surgery today involves a wide variety of surgical and non-surgical medical disciplines. Several aspects to improve the multidisciplinary management of patients undergoing pancreatic... Show morePancreatic surgery today involves a wide variety of surgical and non-surgical medical disciplines. Several aspects to improve the multidisciplinary management of patients undergoing pancreatic surgery were identified, implemented and used to design future studies. More than 15 medical disciplines were involved during the studies involved in this thesis. Highly needed further improvement of outcome of pancreatic patients can be made by multidisciplinary collaborations on a hospital, regional, national and international level. Show less
