This thesis describes two studies on the efficacy and safety of vaccinations in patients stable autoimmune myasthenia gravis, one with tetanus revaccination and one with influenza vaccination. Of... Show moreThis thesis describes two studies on the efficacy and safety of vaccinations in patients stable autoimmune myasthenia gravis, one with tetanus revaccination and one with influenza vaccination. Of both vaccinations, the humoral response and clinical parameters of the disease are described. For tetanus revaccination, also the cellular response is described. Furthermore, the validation of a disease specific quality of life questionnaire is described. Show less
Neurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks... Show moreNeurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks of neurodegeneration are still not fully understood. In this thesis, we make use of bioinformatics approaches to analyze a high-resolution spatial gene expression atlas of the healthy human brain generated by the Allen Institute of Brain Science. Spatial transcriptomics allows examining the molecular and functional organization of the human brain and can be combined with neuroimaging data to identify brain regions and anatomical structures that are vulnerable to cell loss in neurodegenerative diseases. By combining both data modalities, we examined healthy molecular functions in brain regions associated with disease vulnerability based on neuroimaging features, namely gray matter loss within brain networks in individuals with Parkinson’s disease, Huntington’s disease, and individuals at risk of schizophrenia. With this thesis, we have shown that by applying data-driven computational methods we can explore the whole genome and find gene expression patterns informative of regional brain vulnerability in neurodegenerative diseases. Our methods can similarly be applied to unravel the molecular mechanisms in other neurodegenerative diseases, and potentially even reveal shared mechanisms between neurological disorders. Show less
Patients with diabetes mellitus have the highest mortality risk within the dialysis population. The presence of chronic kidney disease (CKD) in patients with diabetes is also strongly related to... Show morePatients with diabetes mellitus have the highest mortality risk within the dialysis population. The presence of chronic kidney disease (CKD) in patients with diabetes is also strongly related to impaired quality of life. Research is warranted to prevent progressive diabetic kidney disease, improve quality of life and reduce mortality in this vulnerable population. In order to improve survival, more knowledge about which patients have the highest mortality risk and which risk factors and co-morbid conditions contribute to this increased mortality risk is essential. In this thesis we focussed on clinical aspects of the relation between diabetes mellitus and kidney disease, from hyperfiltration to dialysis. In chapter 2 we assessed many different measures of glucose metabolism and their association with kidney function among Dutch middle-aged adults. In chapter three and four we compared survival of dialysis patients with diabetes mellitus as underlying cause of the renal failure versus dialysis patients with diabetes mellitus as a co-morbid condition only. In chapter five we aimed to develop a prediction model for 1-year mortality in diabetic dialysis patients. Furthermore in chapter six we compared survival after amputation in diabetic dialysis patients to non-diabetic dialysis patients. Show less
Pulmonary hypertension (PH) is a condition of increased blood pressure within the arteries of the lung (mPAP > 20mmHg) which affects approximately 1% of the global population. Chronic... Show morePulmonary hypertension (PH) is a condition of increased blood pressure within the arteries of the lung (mPAP > 20mmHg) which affects approximately 1% of the global population. Chronic thromboembolic pulmonary hypertension (CTEPH), group 4 PH, is characterized by unresolved pulmonary emboli and pulmonary vascular remodeling of both occluded and non-occluded vessels. The general aim of this thesis was to improve the understanding of CTEPH pathophysiology by focusing on patient endothelial cell (EC) behaviour and function. For this purpose, we isolated ECs from vascular material collected at pulmonary endarterectomy in patients with CTEPH (referred to as CTEPH-EC) and validated them as an in vitro model for studying endothelial pathology in CTEPH. In conclusion, we identified several abnormalities in CTEPH-EC that could play a role in pathological mechanisms driving CTEPH-specific vascular changes. We described alterations in key processes such as angiogenesis and migration, oxidative stress, metabolism and inflammation. Each of these processes may represent targets for novel therapies or biomarkers. Show less
This thesis assesses multiple monitoring modalities that can be used in the peri-operative period to reduce respiratory adverse events associated with the use of anesthetic drugs, particularly... Show moreThis thesis assesses multiple monitoring modalities that can be used in the peri-operative period to reduce respiratory adverse events associated with the use of anesthetic drugs, particularly opioids and neuromuscular blocking drugs. Monitors of analgesia, neuromuscular block and ventilation are studied in both healthy volunteers and surgical patient populations to assess proof of concept, efficacy, feasibility of clinical use and effect on clinical outcomes. Show less
Persistent postpartum haemorrhage is a major cause of maternal mortality and severe morbidity after childbirth. Part I of this thesis discusses uncertainties in management of women with postpartum... Show morePersistent postpartum haemorrhage is a major cause of maternal mortality and severe morbidity after childbirth. Part I of this thesis discusses uncertainties in management of women with postpartum haemorrhage and opportunities to improve maternal outcome. Part II is a description of women with the highest risk of adverse haemorrhage-related outcomes: women with concurrent preeclampsia and women in whom the bleeding is refractory to first-line interventions to stop the haemorrhage. Part III of the thesis compares the outcomes after different strategies for fluid resuscitation and after different strategies for timing of plasma transfusion in these women. In part III we also discuss methodological challenges encountered in studies among women with severe postpartum haemorrhage, methods to deal with this time-dependent confounding. Show less
In this thesis we showed the clinical impact of several methodological issues that should be taken into account when studying chronic kidney disease progression and in order to find an answer to... Show moreIn this thesis we showed the clinical impact of several methodological issues that should be taken into account when studying chronic kidney disease progression and in order to find an answer to the question when to start dialysis. From a methodological point of view, the observations from this thesis provide several recommendations for future research with regard to studying associations of risk factors with CKD progression: the use of an inception cohort of incident patients, and using linear mixed effects models for analyses. Ultimately, patients with kidney failure could be subjected to dialysis. The optimal timing for dialysis initiation is unclear. Ideally, a randomized trial with all possible starting moments would be performed. However, this seems to be unfeasible due to the high patient number needed in each treatment arm. We have to rely on observational data, where methodological issues such as lead-time and immortal time bias arise. In this thesis, we showed the clinical impact of lead-time bias and how both types of bias were avoided by emulating a randomized trial using observational data in a pilot study. The methodology and recommendations provided in the thesis will be highly useful to find a more definitive answer in future research. Show less
The Dutch Audit for Treatment of Obesity (DATO) provides individual and composite outcome measures, assessing the short-term postoperative outcome after bariatric surgery, enable the possibility to... Show moreThe Dutch Audit for Treatment of Obesity (DATO) provides individual and composite outcome measures, assessing the short-term postoperative outcome after bariatric surgery, enable the possibility to identify outliers. Most importantly, individual hospitals can identify differences in outcome, whereas these may remain hidden in daily practice. This between-hospital variation may initiate an improvement cycle. This will probably result in hospital and surgical quality improvements leading to improved outcomes in bariatric surgery. Show less
This thesis provides an insight in the clinical aspects and therapy with neurostimulation in cluster headache patients. An unique cohort of Dutch cluster headache patients (LUCA - Leiden University... Show moreThis thesis provides an insight in the clinical aspects and therapy with neurostimulation in cluster headache patients. An unique cohort of Dutch cluster headache patients (LUCA - Leiden University Cluster headache neuro-Analysis programme) has been used to analyse different clinical aspects like drug-use, chronobiology and aura symptoms in cluster headache patients. Regarding neuromodulation: a case-report about occipital nerve stimulation and pregnancy is described here and a meta-analysis of non-invasive vagal nerve stimulation as acute treatment in both episodic and chronic cluster headache. Show less
The first part of this thesis identified patients at low risk for recurrent events or death after STEMI. It was observed that asymptomatic patients with a LVEF>45% after one year can safely be... Show moreThe first part of this thesis identified patients at low risk for recurrent events or death after STEMI. It was observed that asymptomatic patients with a LVEF>45% after one year can safely be referred to the GP with mortality rates after STEMI that come close to the rate in the general population.The second part focused to identify high-risk subpopulations to improve risk stratification. Despite current standards of care aimed at achieving targets for LDLc and other traditional risk factors, STEMI patients remain at high risk of new cardiovascular events. Valuable effort should therefore be made to further reduce residual cardiovascular risk by using additional more discriminating and more refined treatments targets like apoB and apoB/apoA1 ratio. Furthermore, novel biomarkers were identified to improve risk stratification and select high risk sub-populations. GDF-15, a more general marker for disease severity in STEMI patient demonstrated to have an additional prognostic value beyond identified risk factors and other cardiac biomarkers such as cTn and NT-proBNP.Lastly, the third part of this thesis showed that a dedicated pre-hospital triage protocol is an effective tool to select patients for admission at the cardiac emergency department. Overcrowding is a major public health problem and this thesis shows that the introduction of dedicated cardiac emergency departments can potentially reduce the caseload of the general emergency department. Show less
In this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying... Show moreIn this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying it independently of the rheumatologist’s opinion. Our findings likely add knowledge to what axSpA really is. Future studies will learn us how much of these insights will translate into a better recognition of the disease in clinical practice and in better classifying them for research purposes. Since SpA is a slowly progressing disease, several years are needed to see meaningful changes in imaging abnormalities of the axial skeleton, which poses methodological challenges. We have shown that thoughtful analytical approaches, that make best use of imaging data, are helpful in better estimating progression, in unravelling its determinants and in clarify which outcomes are best to monitor disease. Efforts are made to further improve outcome measurement in axSpA, including the development of new imaging techniques, which can benefit from our proposed solutions to long-term imaging scoring. Show less
Corneal diseases are among the leading causes of reversible blindness worldwide. When conservative treatment options fail, many eyes can be treated with corneal transplantation. Historically, full... Show moreCorneal diseases are among the leading causes of reversible blindness worldwide. When conservative treatment options fail, many eyes can be treated with corneal transplantation. Historically, full thickness corneal transplantation, in which all corneal layers are replaced, has been the mainstay of care in the treatment of corneal endothelial disorders. In the past two decades, however, there has been a trend towards the selective, less invasive replacement of only the diseased, rather than all corneal layers. These partial thickness corneal transplantations are known as lamellar keratoplasties. Lamellar keratoplasty has significantly improved the clinical outcomes, such as visual acuity, after transplantation. Since its introduction in 1998, lamellar keratoplasty has evolved from Deep lamellar endothelial keratoplasty to Descemet membrane endothelial keratoplasty (DMEK). Globally, however, there is only one donor cornea available for 70 people in need. This shortage inspired further refinement of conventional DMEK and led to the development of adapted DMEK-techniques, which may increase the availability of endothelial donor grafts. This thesis focuses on donor tissue preparation for DMEK and evaluates the feasibility and clinical outcomes of DMEK, DMET, Hemi-DMEK and Quarter-DMEK in the management of corneal endothelial disorders. Show less
Corneal transplantation still represents the elected method for the treatment of corneal endothelial pathologies. However, the worldwide shortage of donor corneas induced the exploration of... Show moreCorneal transplantation still represents the elected method for the treatment of corneal endothelial pathologies. However, the worldwide shortage of donor corneas induced the exploration of approaches to use the donor tissue more efficiently or to be more independent from donor tissue. This thesis will illustrate the improvements of new strategies for cell-based corneal endothelial regeneration, alternative to corneal endothelial surgical transplantation, by bridging the gap between in vitro experiments and clinical models. In the studies described, we first address the establishment of a GMP-compliant protocol for in vitro hCEC culture for clinical application and then we focus on endothelial cell sheet transplantation, describing both in vitro and in vivo applications of expanded CEC-carriers constructs made by biocompatible materials. Show less
Darmkanker is met name een ziekte van de oudere patiënt en voor de grootste groep patiënten is chirurgie de aangewezen behandeling. Echter, oudere patiënten hebben meer risico op complicaties,... Show moreDarmkanker is met name een ziekte van de oudere patiënt en voor de grootste groep patiënten is chirurgie de aangewezen behandeling. Echter, oudere patiënten hebben meer risico op complicaties, waardoor zij mogelijk minder goed herstellen van een operatie.Omdat geriatrische kenmerken voorspellend zijn voor postoperatieve uitkomsten,vragen goed geïnformeerde behandelbeslissingen om geriatrische kennis. Preoperatieve interventies in een oncologisch-geriatrisch zorgpad kunnen mogelijk bijdragen aan een beter postoperatief herstel, mits er een goede selectie van deze patiënten plaatsvindt. Show less
This thesis is about the role of spreading depolarization (SD) in subarachnoid hemorrhage (SAH) as explained in Chapter 1.Chapters 2 and 3 use a rat model of SAH, SD induction and SD-inhibitor... Show moreThis thesis is about the role of spreading depolarization (SD) in subarachnoid hemorrhage (SAH) as explained in Chapter 1.Chapters 2 and 3 use a rat model of SAH, SD induction and SD-inhibitor valproate. They suggest a direct association between SD and lesion growth after experimental SAH, which can be counteracted by valproate.Chapter 4 explores the application of MRI techniques to monitor SD induced in rats. Balanced-steady-state-free-precession (b-SSFP) captures more detail than gradient-echo MRI. Diffusion-weighted multi-spin-echo (DT2) scans allowed for simultaneous recording of hemodynamic and diffusion changes.Chapter 5 describes a trend towards less DCI in SAH patients using SD-inhibiting drugs, but that did not result in a better clinical outcome. This suggests a possible protective effect of SD-inhibition on DCI but an unclear possible detrimental effect on other factors that affect clinical outcome.Chapter 6 found, in an ischemic stroke cohort, no statistically significant differences in the percentage of incomplete circles of Willis between migraine and non-migraine patients.Chapter 7 provides a general discussion of the findings from chapter 2-6. Show less
Cutaneous lymphomas are hematological malignancies that present in the skin without evidence of extracutaneous disease at the time of diagnosis. This thesis explores the pathogenetic basis of... Show moreCutaneous lymphomas are hematological malignancies that present in the skin without evidence of extracutaneous disease at the time of diagnosis. This thesis explores the pathogenetic basis of common and rare cutaneous lymphoma entities (i.e. tumor-stage mycosis fungoides, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T‐cell lymphoma, blastic plasmacytoid dendritic cell neoplasm) by studying them using next-generation sequencing approaches. These studies had a special focus on structural genomic alterations (i.e. genomic rearrangements, copy number alterations), since a detailed examination of this type of genetic defects in cutaneous lymphomas using high-resolution techniques had been largely neglected in prior molecular studies. The body of work presented in this thesis expanded the understanding of the pathogenetic basis of four different cutaneous lymphoma entities. Firstly, it showed that structural genomic alterations play important roles in the pathobiology of cutaneous lymphomas. Secondly, it identified recurrently affected genes and cellular processes/pathways in each of the analyzed malignancies. Finally, it provided molecular insights that may be instrumental for the development of novel therapies in the future. Show less
In this thesis, we focus on recipients of donation after circulatory death (DCD) kidneys in the first months after transplantation. DCD kidney transplant recipients have an increased risk of early... Show moreIn this thesis, we focus on recipients of donation after circulatory death (DCD) kidneys in the first months after transplantation. DCD kidney transplant recipients have an increased risk of early complications post transplantation such as acute rejection and delayed graft function (DGF). A sensitive and specific biomarker to monitor the occurrence of an acute rejection episode or (the resolution of) DGF is unfortunately not available to date. For a definite diagnosis, a kidney allograft biopsy remains the so-called ‘golden standard’. A percutaneous kidney biopsy is, however, an invasive procedure with a risk of bleeding complications. Guidance in daily clinical practice by a simple but reliable marker is needed, and can help to monitor regular resolution of DGF and/or identify intercurrent problems such as acute rejection episodes. In the current thesis we investigated risk factors of acute rejection and DGF. In addition, the most promising biomarkers of kidney injury according to current literature (i.e. KIM-1, NGAL, TIMP-2, IGFBP7) were investigated in the prediction of DGF and acute rejection. Furthermore, we used an alternative approach in the search for biomarkers by analyzing smaller molecules with Nuclear Magnetic Resonance (NMR) spectroscopy.We still have not found the ‘perfect’ biomarker to monitor acute rejection DGF after kidney transplantation, however of all biomarkers investigated TIMP-2 showed the greatest potential. Using the approach of metabolomics, we were able to identify new biomarkers. Further studies are needed to confirm and validate these results and evaluate their usefulness in daily clinical practice. Show less
The research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the... Show moreThe research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the detrimental connection between them. The thesis consists of two parts. Part 1 describes multiple experimental stroke research projects in mice in which we set out to: (I) improve the methodology of stroke research, and (II) unravel the stroke-migraine connection using diff erent research strategies, methods, and transgenic mouse models. The mouse models express human pathogenic mutations found in CADASIL, RVCL-S and FHM1 and represent the clinical spectrum of monogenic disorders linking ischemic stroke and migraine. Part 2 includes multiple clinical projects in which we set out to study a large cohort of ischemic stroke patients with and without migraine in search for means to investigate stroke characteristics and vascular pathology. Show less
The fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved... Show moreThe fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved identification of patients with an unfavourable prognosis, early in their treatment course, which may facilitate proactive approaches to improve outcomes. We discussed two conceptually distinct constructs of predictors of prognosis in order to improve the identification of patients with an unfavourable prognosis. First, the level of control of the chronic condition as a predictor could reflect to some extent the presence of a multitude of other risk factors. Second, information on early treatment response had better predictive ability for long-term outcomes and so acts as a proxy for treatment effectiveness. Treatment effectiveness depends on different aspects e.g. adequateness of initial treatment and/or drugs, the mutual trust between clinician and patient and behavioral aspects such as treatment adherence. Treatment response adds an insight that can be acted upon; guiding personalized decisions in the treatment plan. In conclusion, this thesis leads to improvement of personalized medicine and thereby could increase the efficient use of healthcare resources, with the early identification of patients at risk of an unfavourable prognosis. Show less
Red blood cell transfusions are still the cornerstone of supportive care in many hemato-oncological patients. A chronic and underestimated side-effect of red blood cell transfusions is iron... Show moreRed blood cell transfusions are still the cornerstone of supportive care in many hemato-oncological patients. A chronic and underestimated side-effect of red blood cell transfusions is iron overload, which is associated with increased morbidity and mortality. This thesis focuses on red blood cell transfusion strategies and the management of iron overload due to frequently administered red blood cell transfusions. A nationwide survey showed a large variation in red blood cell transfusion practice throughout the Netherlands. This is probably due to the lack of high grade evidence-based guidelines. In a meta-analysis was demonstrated that a restrictive red blood cell transfusion strategy was safe and could lead to fewer side-effects and reduced costs in hemato-oncological patients. In order to diagnose iron overload, tissue biopsy is still the golden standard. Due to its risk of complications, tissue biopsies are not likely to be performed in this patient group. In this thesis, we assessed the value of bone marrow iron scores in frequently transfused acute myeloid leukemia patients. We concluded that bone marrow iron scores on routinely performed bone marrow aspirate specimens could guide iron-lowering therapy and/or transfusion strategies in an early stage. Finally, in a large European registry we showed that toxic iron species as non-transferrin bound iron and labile plasma iron are associated with inferior overall survival in lower-risk myelodysplastic syndrome patients. Likewise, treatment with iron chelation therapy led to an improvement in overall and progression-free survival in lower-risk myelodysplastic syndrome patients. Show less
