Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare but potentially life threatening disease that can lead to intracranial haemorrhage (ICH) in babies during fetal development and the... Show moreFetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare but potentially life threatening disease that can lead to intracranial haemorrhage (ICH) in babies during fetal development and the neonatal period. ICH is associated with perinatal mortality and can lead to long-term neurodevelopmental impairment. If pregnancies at risk for FNAIT are identified upon antenatal screening, timely intervention could prevent the occurrence of fetal ICH. Implementation of population-based screening to prevent FNAIT is hampered by the lack of knowledge on the natural history, whom to treat and costs of case finding. We performed a large nationwide screening study and provide new evidence on the incidence of FNAIT. In addition, we confirm the value of risk factors for immunisation and severe disease. We describe current postnatal treatment strategies and the long-term outcome of cases that were affected by FNAIT. Based on these studies, we conducted a cost-effectiveness analysis comparing the situation with antenatal screening to the current situation without screening. In the general discussion, we evaluate the knowledge gained in this thesis and in the available literature guided by the principles from Wilson and Junger. We conclude that knowledge is available to all principles and nationwide screening for FNAIT during pregnancy seems warranted. Show less
Skeletal muscles are highly resilient due to the capacity to regenerate damaged muscle tissue. Despite the regenerative capacity, pathological conditions can lead to reduced muscle mass and... Show moreSkeletal muscles are highly resilient due to the capacity to regenerate damaged muscle tissue. Despite the regenerative capacity, pathological conditions can lead to reduced muscle mass and strength, also known as muscle wasting. Muscle wasting, seen in pathological conditions, is often progressive and concomitant with excessive or prolonged inflammation, fibrosis and fat infiltration. Aging is a risk factor for a large number of diseases that can result in muscle wasting. The prevalence of sarcopenia, an age-associated decline in skeletal muscle mass and strength in elderly, surges as life expectancy increases. In combination with muscle wasting caused by neuromuscular disorders, the burden of muscle wasting on society is significant. Gaining a better understanding of the cellular and molecular processes underlying muscle wasting conditions is critical for creating better treatments. Aging and thereby age-associated muscle wasting are multifactorial involving changes in different tissues and multiple cell systems. This thesis demonstrates how different omics approaches, like transcriptomics, proteomics and metabolomics, can elucidate the complexity of those molecular mechanisms and cellular processes involved in muscle wasting conditions. Employing a combination of different omics-techniques (multi-omics) specifically proved powerful and will continue to illuminate impaired mechanisms and consequently help to battle muscle wasting. Show less
This thesis describes the additional value of advanced echocardiographic techniques in patients with primary cardiac disease, resulting in mitral regurgitation, and secondary cardiac disease caused... Show moreThis thesis describes the additional value of advanced echocardiographic techniques in patients with primary cardiac disease, resulting in mitral regurgitation, and secondary cardiac disease caused by a systemic disease. In this thesis we focussed on patients with mitral regurgitation, specifically primary MR and functional MR (FMR), and patients with Systemic Sclerosis (SSc). The general introduction provides a background of MR and cardiac involvement in SSc and how conventional 2-dimensional (2D) echocardiography is currently used. The potential role of 2D speckle tracking echocardiography and 3-dimensional (3D) echocardiography together with customized software to create 4-dimensional (4D) mitral valve models is introduced. This thesis aims to provide new insights in diagnosis, disease progression and risk stratification in patients with MR and patients with SSc with the implementation of advanced echocardiographic techniques. Show less
In this thesis, the effectiveness and feasibility of two proactive care programs, implemented in the emergency department (ED) of Haaglanden Medical Center in The Hague are evaluated. The first... Show moreIn this thesis, the effectiveness and feasibility of two proactive care programs, implemented in the emergency department (ED) of Haaglanden Medical Center in The Hague are evaluated. The first part of the thesis focuses on a screening and intervention program for hazardous alcohol use in adult ED patients. Although in the subset of patients reached for follow-up, receiving an intervention was associated with reduced alcohol consumption after three months, many patients were not screened and less than half of eligible patients received an intervention. Moreover, risk factors for hazardous alcohol use were more common in unscreened than in screened patients. In the second part of the thesis, the effect of telephone follow-up after ED discharge for community-dwelling older patients on health-related outcomes, including unplanned hospital admissions and ED return visits within 30 days, is examined. As the intervention turned out not to be effective, we investigated reasons for unplanned ED return visits in older adults to assess whether post-ED discharge interventions are sufficiently attuned to the reasons for unplanned ED return.In conclusion, none of the interventions were effective. Moreover, feasibility of the programs was limited, as many eligible patients were not reached, due to both staff-related and patient-related reasons. Show less
This thesis reinforce that children born preterm are at risk for long-term impairments. Being able to predict who is at risk, by neonatal neuroimaging or early assessment, remains difficult,... Show moreThis thesis reinforce that children born preterm are at risk for long-term impairments. Being able to predict who is at risk, by neonatal neuroimaging or early assessment, remains difficult, especially in children who have milder forms of brain injury and/or experience milder difficulties at two years of age. Currently, most follow-up assessments use standardized outcome measures that might not show the full extent of a child’s daily functioning. Additional measurements and/or the implementation of qualitative research can be of great additional value. Show less
Conclusies1. De complexe interactie van anesthetica en neuromusculaire blokkeringsmiddelen op perifere chemosensitiviteit is nog maar ten dele begrepen.2. Gedurende verschillende fases van het... Show moreConclusies1. De complexe interactie van anesthetica en neuromusculaire blokkeringsmiddelen op perifere chemosensitiviteit is nog maar ten dele begrepen.2. Gedurende verschillende fases van het neuromusculaire blok is er een discrepantie tussen het niveau van neuromusculaire blokkade gemeten aan de bovenarm met compressomyografie en aan de m. adductor pollicis met elektromyografie.3. De huidige zorgen ten aanzien van de veiligheid van sugammadex betreffen vooral overgevoeligheidsreacties en hartritmestoornissen. In de huidige literatuur is bradycardie de meest gemelde ritmestoornis gerelateerd aan de toediening van sugammadex. Hartritmestoornissen die verband houden met de toediening van sugammadex kunnen gepaard gaan met anafylactische symptomen en potentieel levensbedreigend zijn.4. Wanneer anesthesie wordt gehandhaafd met sevofluraan tijdens laparoscopische nierchirurgie geeft diep neuromusculaire blokkade geen voordeel met betrekking tot chirurgische werkomstandigheden ten opzichte van een moderate neuromusculaire blokkade. Show less
Breast cancer is a heterogeneous disease with substantial variability in outcome, risk factors and response to treatment. Therefore, a better understanding of the factors influencing breast cancer... Show moreBreast cancer is a heterogeneous disease with substantial variability in outcome, risk factors and response to treatment. Therefore, a better understanding of the factors influencing breast cancer outcome could lead to improved prognostication and better stratification of patients into treatment subgroups. To this end, we investigated the association of hereditary genetic variants and non-genetic breast cancer risk factors with breast cancer outcome, and assessed the evidence of potential differential associations across specific tumor subtypes and patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment. We focused on two breast cancer outcomes, namely survival and risk of developing a second breast cancer in the contralateral breast (contralateral breast cancer).Based on data from a large international cohort of breast cancer patients, we found clear associations of several known lifestyle breast cancer risk factors with survival in breast cancer patients, independently from specific tumor subtype, and of coding hereditary genetic variants in five known breast cancer susceptibility genes with contralateral breast cancer risk. There was also evidence of association of coding hereditary genetic variants in three known breast cancer genes with breast cancer-specific survival (time to death due to breast cancer), although weaker than for contralateral breast cancer risk. These factors could be incorporated into prediction models for breast cancer outcome thereby potentially improving prognostic estimates and breast cancer counseling. In particular, the findings related to contralateral breast cancer risk are relevant to treatment decisions, follow-up and screening of breast cancer patients. Show less
Although COPD was originally thought to merely affect the airways and lungs, the attention of research has been shifted towards the high prevalence of cardiovascular disease in patients with COPD.... Show moreAlthough COPD was originally thought to merely affect the airways and lungs, the attention of research has been shifted towards the high prevalence of cardiovascular disease in patients with COPD. Up to one third of deaths in patients with COPD can be attributed to a cardiovascular cause. In particular, a strong association between COPD and acute myocardial infarction (AMI) has been emphasized and the need for adequate risk stratification in this population has been recognized. Identification of patients at risk of adverse events after AMI is frequently performed with cardiac imaging. Echocardiography permits early assessment of left- and right ventricular size and function, as surrogates of cardiac damage in the acute phase. Emerging advanced echocardiographic techniques such as speckle tracking strain imaging enable characterization of myocardial mechanics, which have been associated with prognosis. Assessment of left- and right ventricular longitudinal strain in patient with COPD might provide better risk stratification as compared to conventional echocardiographic parameters. COPD is also a known risk factor for atrial fibrillation. Structural atrial remodeling, particularly of the right atrium, is suggested to be an important pathophysiologic substrate. Echocardiography may provide an additional tool in characterization of atrial structure and function, leading to targeted treatments. Show less
This thesis addresses the pathophysiology of stress related diseases, taking two rare diseases, in which the hypothalamic-pituitary-adrenal axis and cortisol play a key role, as a model for stress... Show moreThis thesis addresses the pathophysiology of stress related diseases, taking two rare diseases, in which the hypothalamic-pituitary-adrenal axis and cortisol play a key role, as a model for stress vulnerability of the brain and the eye. The second aim of this thesis is to describe the organization of thromboprophylaxis management, and the outcome evaluation and quality of care for patients treated for Cushing’s syndrome. For more informatie, please refer tot he summary in the pdf of the thesis. Show less
To improve the predictive capability of pre-clinical models and reduce the use of animal models in drug discovery and disease modelling, advanced in vitro models are being developed. These... Show moreTo improve the predictive capability of pre-clinical models and reduce the use of animal models in drug discovery and disease modelling, advanced in vitro models are being developed. These microphysiological systems (MPS) or “Organs-on-Chip” (OoC) are being developed to include all aspects of the human physiology to improve the in vitro cellular response. OoCs combined with differentiated human induced pluripotent stem cells (hiPSC) allow the use of cells with patient specific genotypes and aid the development of personalized and precision medicine.In this thesis, the development of tractable models of the vasculature is described. These models allow for the combination of hiPSC-derived vascular and tissue specific cells with haemodynamics to recapitulate essential stimuli of blood vessels. Show less
To communicate with one another, cells in the body release signaling molecules called cytokines. The effects of these cytokines have been demonstrated to be extremely important for a successful... Show moreTo communicate with one another, cells in the body release signaling molecules called cytokines. The effects of these cytokines have been demonstrated to be extremely important for a successful immune response, but surprisingly little is known about how cytokines act in space and time. In this thesis, I describe the development of a set of new techniques that allow the efficient identification of cells that have encountered cytokine signals. Subsequently, I investigate the spreading of cytokines such as IFNγ and TNFα in in vivo cancer models and describe how activated cytotoxic T cells, which form a key compartment of our immune system, can profoundly modify the tumor microenvironment by the generation of widespread cytokine gradients. Show less
Cutaneous lymphomas originate from cancer of the lymphocytes in the skin without lymph node/organ involvement at time of diagnosis. There are many types of cutaneous lymphomas, with this thesis... Show moreCutaneous lymphomas originate from cancer of the lymphocytes in the skin without lymph node/organ involvement at time of diagnosis. There are many types of cutaneous lymphomas, with this thesis focusing on CD30-positive cutaneous lymphomas, consisting of a spectrum with lymphomatoid papulosis (LyP) on one side, and primary cutaneous anaplastic large cell lymphoma (C-ALCL) on the other. LyP is characterized by multiple skin lesion that resolve spontaneously, and C-ALCL by a solitary or grouped tumor that persists. This thesis shows that approximately 15% of LyP patients develop a second skin lymphoma/blood cancer, but also have an increased risk of developing other cancers (squamous cell carcinoma/melanoma/colon/lung/bladder cancer). At molecular level, a subcategory of patients was found in C-ALCL with ALK translocations, suggestive of a systemic lymphoma. It appears that these patients also have a favorable prognosis and can be treated with radiotherapy. The optimal dose of radiotherapy was also demonstrated (8 Gray). In addition, different types of mutations (PI-3-K/MAPK/G pathways) seem to occur in C-ALCL compared to more aggressive lymphomas (JAK-STAT). C-ALCL patients with ≤5 tumors are best treated with radiotherapy, and patients with >5 lesions with methotrexate. Targeted therapies remain for patients not responding to methotrexate or with systemic involvement. Show less
Platelet transfusions are used to provide hemostatic capacity to patients with decreased number or functionality of platelets. The aim of this thesis was to expand knowledge about the safety and... Show morePlatelet transfusions are used to provide hemostatic capacity to patients with decreased number or functionality of platelets. The aim of this thesis was to expand knowledge about the safety and efficacy of platelet transfusions in general and in particular in cardiac surgery patients. In this thesis we found that cardiac surgery patients receiving an platelet transfusion shortly after cardiopulmonary bypass experienced less blood loss than patients who did not receive an early platelet transfusion. However, early platelet transfusion was not associated with more reinterventions, thromboembolic complications, infections, multi-organ failure, or mortality. Furthermore, we discovered that PAS-C as storage medium for platelets is associated with more favorable outcomes than plasma with regard to transfusions reactions, but not with regard to in vitro hemostatic measurements. Furthermore, we observed that fresh platelet concentrates are associated with more favorable outcomes than older platelet concentrates: less transfusions reactions in the whole transfused population, better hemostatic measurements in vitro, and less blood loss and mortality in cardiac surgery patients. Show less
How to define the preclinical Alzheimer's Disease state in otherwise healthy elderly. How to best select otherwise healthy elderly for clinical trials participation with a disease modifiying... Show moreHow to define the preclinical Alzheimer's Disease state in otherwise healthy elderly. How to best select otherwise healthy elderly for clinical trials participation with a disease modifiying compound. Difference between healthy elderly and subjects in the preclinical AD stage on biomarker level. Difference in cognitive performance in healthy subjects compared to neurodegenerative disease profiles. Show less
Pathogenic variants in PALB2 and CHEK2 are associated with an increased risk of breast cancer. By contrast, for missense variants of uncertain significance (VUS) in these genes, the associated... Show morePathogenic variants in PALB2 and CHEK2 are associated with an increased risk of breast cancer. By contrast, for missense variants of uncertain significance (VUS) in these genes, the associated breast cancer risk is often unclear. To aid in their clinical classification, functional assays that determine the impact of missense VUS on PALB2 and CHK2 protein function have been performed in this thesis. By means of these functional analyses, numerous missense VUS (in both PALB2 and CHEK2) have been identified that are, from a functional viewpoint, just as damaging as known pathogenic (i.e., truncating) variants. In agreement, we observe that the level of impaired protein function correlates with the degree of increased breast cancer risk. Overall, these findings suggest that damaging PALB2 and CHEK2 missense VUS are associated with a risk of breast cancer similar to that of protein-truncating variants in these genes. This indicates the urgency of expanding the functional characterization of missense VUS in both PALB2 and CHEK2 to further understand the associated cancer risk. Show less
The global obesity pandemic is one of the most significant long-term challenges for healthcare in the current era. Obesity is strongly associated with disrupted glucose and lipid metabolism, a pro... Show moreThe global obesity pandemic is one of the most significant long-term challenges for healthcare in the current era. Obesity is strongly associated with disrupted glucose and lipid metabolism, a pro-inflammatory state of the immune system, and has a causal role in the development of cardiometabolic diseases. The medical science is challenged to find new targets in the fight against this worldwide silent pandemic.We investigated how the gut microbiota influences local and systemic lipid metabolism and immune system of the host and the relationship to pathophysiology of atherosclerosis. The central question was "Does the gut microbiota have a anti-atherogenic potential?" Our studies have shown that oral administration of the bacterium A. muciniphila positively influences the host's lipid metabolism. In addition, oral administration of this bacterium triggers an anti-inflammatory immune response. These findings suggest that A. muciniphila has anti-atherogenic potential. Furthermore, we provided critical insights into two commonly accepted and widely used research methods in cardiometabolic and microbiome research, namely Bone Marrow Transplantation (BMT) and 16S rRNA sequencing. These insights should be taken into account in the research design and interpretation of the research data when applied. In another study, we demonstrated that the gut microbiota increases the cytokine reactions of immune cells after BMT. This phenotype can be transferred to immune cells of healthy controls through Fecal Microbiota Transplantation, implying that this phenotype is independent of BMT-induced gut damage, leaky gut syndrome, and microbiota-mediated. In summary, our studies show that the gut microbiota has anti-atherogenic potential by playing a causal role in the modulation of lipid metabolism and the host's immune system. Show less
Monique Krystyna van der Kooij shows that a combination of treatments enhancing the immune system can conquer metastasized melanoma in heavily pre-treated patients. Immunotherapy is not a new... Show moreMonique Krystyna van der Kooij shows that a combination of treatments enhancing the immune system can conquer metastasized melanoma in heavily pre-treated patients. Immunotherapy is not a new concept. However, in Leiden a milder, and therefore better tolerated preconditioning regimen is used before the immune cells are administered. This milder preconditioning, in combination with the patient’s own immune cells and an immune checkpoint inhibitor is unique. This thesis shows that this combination is safe and preliminary data also show that some patients have (lasting) clinical responses. A second important finding described in this thesis is that treatment with immune checkpoint inhibitors can safely be prescribed to patients with common autoimmune diseases. Approximately 1 in 10 metastatic melanoma patients suffer from such an autoimmune disease. Until now clinicians were hesitant to prescribe these immune checkpoint inhibitors out of fear of unleashing the autoimmune disease. Showing that this is not the case made it possible for this large group of patients to gain access to this often-successful treatment. However, immune checkpoint inhibitor monotherapy is not indicated for all patients with metastatic melanoma. Patients with uveal melanoma do not benefit from this type of treatment, and do suffer from the adverse events. Show less
The aim of this thesis is to explore fear of choking and fear of falling in people with Huntington's disease (HD) and their caregivers. Dysphagia and falls are common in HD and may lead to fear of... Show moreThe aim of this thesis is to explore fear of choking and fear of falling in people with Huntington's disease (HD) and their caregivers. Dysphagia and falls are common in HD and may lead to fear of choking and fear of falling. However, knowledge about this is mostly lacking, as well as knowledge about the relationship between cognitive and emotional factors and these types of fear. The study confirms that fall prevalence (29% over a 30-day period) and prevalence of dysphagia symptoms (90%) are high. However, a prevalence of about 50% is also reported for fear of choking and fear of falling in people with HD. However, their informal caregivers report the most fear. Severity of dysphagia symptoms was a predictor of fear of choking, and anticipatory awareness of fall risks and gender were found to be predictors of fear of falling. In most individuals with HD, a combination of preventive measures was used.Future research can improve both management of dysphagia and fear of choking and management of falls and fear of falling. Because questioning people with HD is sometimes difficult, due to speech and cognitive difficulties, diagnostic tools may be sought to facilitate this, such as wearable electronic devices. Show less
This thesis describes studies of individuals with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms at the Leiden NPSLE clinic. A diverse range of studies, including... Show moreThis thesis describes studies of individuals with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms at the Leiden NPSLE clinic. A diverse range of studies, including laboratory, radiological, clinical and patient´s reported outcomes are presented.The Leiden NPSLE clinic is a tertiary referral center for patients with SLE and neuropsychiatric (NP) symptoms. In the NPSLE clinic, patients are assessed by a multidisciplinary team. Thereafter, clinical, radiological and laboratory measures are weighed in a consensus meeting to correctly attribute the NP symptoms: related to lupus activity (NPSLE) or not. This extensive and standardized assessment of NPSLE, a rare and heterogenous disease lacking a gold standard, is unique and creates the opportunity to explore many aspects of NPSLE in well-defined phenotypes.In the first part of this thesis, we evaluate both classification and treatment of patients withSLE and NP symptoms. The second part of this thesis focuses on a diverse range of clinicaloutcomes of NPSLE, including both morbidity and mortality. The last part of this thesisassesses potential biomarkers for (specific manifestations of) NPSLE. Show less
The prevalence of cardiovascular diseases has increased in the last decennia. This thesis studied the potential relationship between oxidative stress and cardiovascular diseases. The first part of... Show moreThe prevalence of cardiovascular diseases has increased in the last decennia. This thesis studied the potential relationship between oxidative stress and cardiovascular diseases. The first part of the thesis focused on anti-oxidants, which are scavengers that protect against oxidative damage. We studied the association between several lifestyle factors, diet, physical activity, sleep, alcohol intake and smoking, and antioxidant levels both in blood and urine. Subsequently, we investigated whether a higher concentration of antioxidants leads to a decrease in ischaemic stroke occurrence. Next, we aimed to study a possible cause of oxidative damage and its effect on cardiovascular disease. Mitochondrial dysfunction is one of the mechanisms that may underly this effect. Mitochondria are an important source of Reactive Oxygen Species (ROS), as an inevitable byproduct of their essential role in energy production. A disbalance in ROS production and scavenging might result in oxidative damage. Thus, we investigated the causal association between mitochondrial dysfunction and stroke using the Mendelian Randomization method. Finally, we studied how socio-demographic traits could modify the causal association between CVD risk factors and coronary artery disease. Show less
