In this thesis, the monitoring of the immune system in balance and during active responses (by flow cytometry) plays a central role. In chapter 2.1 and 2.2, we investigated the optimal sample... Show moreIn this thesis, the monitoring of the immune system in balance and during active responses (by flow cytometry) plays a central role. In chapter 2.1 and 2.2, we investigated the optimal sample logistics for high-dimensional flow cytometry in clinical trials. In chapter 3.1-3.4, we monitored the longitidinal kinetics of circulating immune cells in humans after vaccination or bacterial challenge against Bordetella pertussis. Lastly, in chapter 4, we investigated the immune system in humans carrying a genetic variant of PLCG2 'p.P522R', which is associated with increased longevity and reduced chance of developing dementia. Show less
In response to the shortage of nursing staff and the so-called refugee crisis in 2015, two residential homes invited first-generation immigrants with a refugee background to participate in a... Show moreIn response to the shortage of nursing staff and the so-called refugee crisis in 2015, two residential homes invited first-generation immigrants with a refugee background to participate in a project for nursing education, orientation and internships. Between 2015 and 2018, a group of ten immigrants started working in a Dutch residential home and a group of seventeen immigrants in the German home. This dissertation investigates the social processes when these newcomers start working with the established staff, as well as the extent to which their mutual interactions and values of good care influence the enactment of geriatric care. Using ethnographic observations (305 hours), in-depth interviews (44) and six focus groups (24), the established care workers and immigrants were followed in both homes. The empirical data shows that institutional constraints, such as staff shortage, the imposition of professional norms, gossip used as a ‘weapon of the weak’, mutual suspicions of indifference, and collective images of ‘us’ versus ‘them’ affected the enactment of geriatric care. Their habitus stimulated them to tinker among each other as well as with different, sometimes conflicting, values of good care. However, both groups shared the feeling of ignorance by management, a pain of not mattering. Show less
This thesis is the result of several studies into the clinical and echocardiographic outcome of both open and hybrid surgical ventricular reconstruction for the treatment of ischemic cardiomyopathy... Show moreThis thesis is the result of several studies into the clinical and echocardiographic outcome of both open and hybrid surgical ventricular reconstruction for the treatment of ischemic cardiomyopathy. Additionally, predictors for a favorable outcome and important associated issues such as management and late outcome of functional mitral regurgitation and the use of LV ejection fraction as a selection criterium for indication for a implantable cardioverter defibrillator for the primary prevention ofventricular arrhythmias after surgical ventricular reconstruction were studied. In chapter 2 the early and late outcome of different types of open left ventricular reconstruction surgery by means of a meta-analysis are presented. Chapter 3 describesthe use of echocardiographic wall motion score index to predict mortality and functional results after surgical ventricular reconstruction for advanced ischemic heart failure. In chapter 4 the management of functional mitral regurgitation during left ventricular reconstruction is presented followed by a landmark analysis into the 10-year outcome of functional mitral regurgitation after left ventricular reconstruction. Chapter 5 discusses the use of the improved LV ejection fraction after SVR as an indication for a implantable cardioverter defibrillator for the primary prevention of ventricular arrhythmias after surgical ventricular reconstruction in heart failure patients. Chapter 6 discusses the early experience with a minimal-invasive hybrid transcatheter surgical ventricular reconstruction technique. First the technique of hybrid transcatheter left ventricular reconstruction is described. Followed by the preliminary results of this technique from 2 cardiac centres in the Netherland. Finally, the multicenter European results of hybrid less invasive reconstruction on clinical, functional and echocardiographic outcome are presented. Show less
Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic repression of the D4Z4 repeat resulting in misexpression of the repeat-encoded DUX4 gene in skeletal muscle. Two... Show moreFacioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic repression of the D4Z4 repeat resulting in misexpression of the repeat-encoded DUX4 gene in skeletal muscle. Two mechanisms are known to drive this D4Z4 epigenetic dysregulation: a contraction of the D4Z4 repeat or mutations in DNMT3B or SMCHD1, both epigenetic regulators of the repeat that are responsible for the establishment or maintenance of the repeat’s epigenetic repressive state in somatic cells. However, the aforementioned (epi)genetic changes lead to FSHD only if the individual also has a disease-permissive D4Z4 allele which allows for stable DUX4 expression in skeletal muscle. This disease permissivity of D4Z4 alleles has been attributed to the presence of a DUX4 polyadenylation signal adjacent to the D4Z4 repeat which is used for transcription termination. Despite knowing the root cause of FSHD, to date, there is no curative therapy available for FSHD and in some cases, the genetic etiology of the disease remains unknown. In this thesis, we identified a new FSHD disease gene called LRIF1 and performed its follow-up functional studies in human somatic cells and mouse embryonic stem cells. In addition, we also pursued a new targeted gene therapy for FSHD by employing CRISPR-based mutagenesis of the DUX4 polyadenylation signal. Show less
Door de verwachte toename van het aantal patiënten met verschillende chronische ziekten zullen de kosten en de complexiteit van de zorgvraag toenemen. Hierdoor kan de toegankelijkheid en... Show moreDoor de verwachte toename van het aantal patiënten met verschillende chronische ziekten zullen de kosten en de complexiteit van de zorgvraag toenemen. Hierdoor kan de toegankelijkheid en betaalbaarheid van de gezondheidszorg in het geding komen. Om de toegankelijkheid en betaalbaarheid van de gezondheidszorg te kunnen blijven waarborgen zullen we onze medische middelen zo effectief mogelijk moeten gebruiken. Dit proefschrift laat zien dat er nog steeds veel winst valt te behalen in het leveren van de juiste cardiale zorg voor de juiste patiënt op de juiste plek. Verbeteringen zijn mogelijk in eerste-, tweede- en derdelijns zorg. Wij geloven dat verticale integrale zorg het antwoord is op het managen en verdelen van de verwachte patiënten toestroom over de verschillende lijnen, en daarnaast de stijgende zorgkosten onder controle te houden. Show less
It is well known that military deployment can lead to mental health problems in veterans, but the long-term impact is still unclear. This thesis discusses the results of the PRISMO-study, a large... Show moreIt is well known that military deployment can lead to mental health problems in veterans, but the long-term impact is still unclear. This thesis discusses the results of the PRISMO-study, a large cohort study in a group of Dutch Afghanistan veterans with a follow-up period of ten years. It shows that at ten years post-deployment, 8% of the cohort reported severe symptoms of posttraumatic stress disorder (PTSD). Agoraphobia, anxiety, depression, and hostility symptoms are also reported more frequently at ten years post-deployment compared to pre-deployment. Furthermore, this thesis demonstrates the large heterogeneity in PTSD symptom development among veterans. Of note is the delayed onset group that experienced increasing symptom levels between five and ten years post-deployment and did not show significant symptom reduction. The results from this thesis also show that various psychological factors, such as social support, and biological factors, such as DNA methylation, are associated with the development of PTSD or other mental health symptoms after deployment. Combining these factors in a prediction model for PTSD symptoms has not led to a useful screening instrument. It does, however, offer important leads for the identification of risk factors for PTSD and the development of intervention programs. Show less
Greater acknowledgement of the value of assessing psychological factors and patient experiences after orthopaedic trauma may support policymaking regarding the provision of psychological therapies... Show moreGreater acknowledgement of the value of assessing psychological factors and patient experiences after orthopaedic trauma may support policymaking regarding the provision of psychological therapies as part of care. The first part focusses on factors associated with PROMs, such as pain intensity and depression, and with PREMs, such as satisfaction and communication effectiveness. The influence of psychological distress and family involvement is consistent and both minor and major trauma have a notable risk of developing symptoms of depression. In the second part of this thesis, the use of shorter and various questionnaires was evaluated for measuring patient experience to improve care. Given the mounting evidence of a common factor underlying PREMs as currently formulated, it might prove possible to measure patient experience using just a few questions, instead of measuring communication and satisfaction separately. In the last part, the use of pre-visit phone calls and software for emotion recognition was evaluated. Phone calls can replace in-person visits to establish the diagnosis and suggest treatment options. The ability to measure a patient’s mindset on the clinician’s face confirms that clinicians are registering the psychological aspects of illness, irrespective of whether they are consciously aware of them or not. Show less
Lyme borreliosis (LB) is caused by spirochetes that are part of the Borrelia burgdorferi sensu lato (s.l.) complex group. The most prevalent manifestation of LB is characterized by a red, migrating... Show moreLyme borreliosis (LB) is caused by spirochetes that are part of the Borrelia burgdorferi sensu lato (s.l.) complex group. The most prevalent manifestation of LB is characterized by a red, migrating skin lesion, also known as erythema migrans. If left untreated, then B. burgdorferi s.l. can disseminate through the body and infect other body parts such as the joints, the nervous system (Lyme neuroborreliosis (LNB)), the heart and/or other parts of the skin, although for the majority of cases LB resolves without treatment. The diagnosis of LB is based on the presence of clinical symptoms and, for most Lyme manifestations, should be supported by laboratory tests. The most widely used laboratory test is based on the detection of Borrelia-specific antibodies. The utility of antibody detection to support the diagnosis of LB, however, is hampered by a low sensitivity of antibody detection early in the infection, and the persistence of antibodies after a cleared infection. The research conducted in this thesis focused on the humoral and the cellular immune response to investigate whether LB diagnostics can be improved. As clear case-definitions are available for active LNB, well-defined patients with LNB were used as a proxy for patients with active LB.The research in this thesis has provided more insight into the added value and the pitfalls of laboratory tests for the diagnosis of LNB. It shows that the interferon-gamma enzyme-linked immunospot assay cannot be used for the diagnosis of LNB. Furthermore, it demonstrates the added value of elevated levels of the B-cell chemokine (C-X-C motif) ligand 13 in the cerebrospinal fluid for the diagnosis of LNB and that more research is necessary to investigate if an international reference standard can be established. Additionally, the research in this thesis underlines that a thorough validation of serological tests is important before its use in diagnostics and it illustrates that antibiotic treatment of an infection with B. burgdorferi s.l. is associated with discordant serological test results. The most important finding of the research conducted in this thesis; however, is the proposal of a diagnostic algorithm for LNB diagnostics. Such an algorithm should include tests that consider both the humoral as well as the cellular immune response as both may contribute to the diagnosis of LNB. By covering different aspects of the immune system, a concrete and feasible tool is provided that can better discriminate between an active and a previous infection with B. burgdorferi s.l., which and this will improve LNB diagnostics. Show less
In the young and healthy shoulder, cranially directed forces during abduction are counteracted by co-contraction of the rotator cuff muscles. In this way, it is prevented that the humerus moves... Show moreIn the young and healthy shoulder, cranially directed forces during abduction are counteracted by co-contraction of the rotator cuff muscles. In this way, it is prevented that the humerus moves cranially towards the acromion, thus entrapping subacromial tissues. During ageing however, shoulder tissues are subject to marked degeneration, which particularly concerns the rotator cuff muscles. This may have two consequences. First, due to reduced contribution of the upper parts of the rotator cuff to the abduction movement, the deltoid has to compensate, which results in a more cranially, instead of mediocranially directed force. Second, reduced stabilising force by the rotator cuff may jeopardise counteraction of cranial deltoid forces. These changes could lead to cranialisation of the humerus with painful compression of subacromial tissues, as observed in patients with Subacromial Pain Syndrome (SAPS). Previous studies have shown that by co-contraction of arm adductors, humeral-head depression may be accomplished, for the purpose of unloading subacromial tissues. In this thesis, we investigated the role of adductor co-contraction in the ageing asymptomatic population and in patients with SAPS. This has resulted in eight scientific publications with which the fundaments for evidence-based therapy in SAPS have been built, with as cornerstone training of adductor co-contraction. Show less
Glioma, a malignant brain tumor, is a serious condition with a large impact on patients’ life expectancy and Health-Related Quality of Life (HRQoL). This thesis aimed to improve knowledge on the... Show moreGlioma, a malignant brain tumor, is a serious condition with a large impact on patients’ life expectancy and Health-Related Quality of Life (HRQoL). This thesis aimed to improve knowledge on the prediagnostic symptoms, tmeasurement of HRQoL and care in the end-of-life phase of glioma patients.Regarding prediagnostic symptoms in glioma patients, it was found that several symptoms such as fatigue or headache were relatively common before diagnosis, but not more common than in patients with other conditions. Therefore, identification of patients with glioma in general practice based on their symptomatology seems extremely difficult.For the measurement of HRQoL in glioma it was demonstrated that patients, proxies and healthcare neuro-oncology professionals were overall positive about their routine implementation of its assessment in clinical practice. Regarding the timing of the measurements, the scores were not influenced by assessment either before or after the consultation with the physician.With respect to the optimization of care in the end-of-life phase, a feasibility study on the disease-specific Advanced Care Program was conducted among patients with glioblastoma, the most malignant type of glioma and their nearest. The relatively positive results of that study in terms of satisfaction warrant the need for a larger, controlled study. Show less
There is no consensus in diagnoses nor treatment of type B ankle fractures. This thesis investigates multiple type of radiologic diagnostics, in order to safely exclude instable type B ankle... Show moreThere is no consensus in diagnoses nor treatment of type B ankle fractures. This thesis investigates multiple type of radiologic diagnostics, in order to safely exclude instable type B ankle fractures. Stable type B ankle fractures, with a MCS < 6 mm on the mortise view, can safely be managed conservatively with performance of the weightbearing radiograph within a week. When using of the gravity stress radiograph, the cut-off value of MCS ≥ SCS + 3mm should be applied, while for the weightbearing radiograph the MCS ≥ SCS + 2 mm is advised. The results of ultrasound are promising and should be further investigated. Show less
Bone and joint disorders have an enormous personal- and societal impact. Diagnosis and treatment of these disorders are most efficient if targeted screening, accurate diagnosis, and targeted... Show moreBone and joint disorders have an enormous personal- and societal impact. Diagnosis and treatment of these disorders are most efficient if targeted screening, accurate diagnosis, and targeted treatment are available. To enable targeted screening, the population at risk must be well-defined, and categorized if required. Subsequently, screening- and diagnostic methods must have good, or excellent predictive value and finally, treatment must target the disease, thus spare healthy tissues and processes and thereby avoid adverse events.The aim of this thesis is to gain new insights about the diagnostic process- and treatment of pathological conditions of the bone and joints, namely male urological cancer-induced bone loss and inflammatory arthritis. Show less
Endometrial cancer (EC) is the most common gynaecological cancer in developed countries. Standard treatment consists of surgery (hysterectomy and bilateral salpingo-oophorectomy) followed by either... Show moreEndometrial cancer (EC) is the most common gynaecological cancer in developed countries. Standard treatment consists of surgery (hysterectomy and bilateral salpingo-oophorectomy) followed by either no adjuvant treatment, vaginal brachytherapy (VBT) or external beam radiotherapy (EBRT) with or without chemotherapy. The type of adjuvant treatment is based on clinicopathologic risk factors as age, FIGO-stage, histologic type and grade, myometrial invasion and lymph-vascular space invasion. In the recent years, knowledge has been gained on molecular risk factors in EC and four different molecular subgroups with distinct prognosis have been defined. The implementation of these subgroups into the treatment guidelines is being investigated in the PORTEC-4a trial. In this trial women with high-intermediate risk EC are randomised to either VBT versus an experimental arm in which a molecular-integrated risk profile is used to guide adjuvant treatment. With the improved patient selection women with favourable prognosis can be spared unnecessary treatment, while those with unfavourable prognosis are treated with more intensive treatment (EBRT). Besides the improvement of patient selection, radiotherapy techniques have developed as well. Modern radiotherapy techniques can increasingly spare healthy tissues with comparable outcomes and less toxicity. These developments will lead to better results and higher(er) quality-of-life for women with EC. Show less
Our immune system is supposed to protect us from infections, but it can also attack our own tissues if not properly controlled. This can lead to autoimmune diseases like rheumatoid arthritis (RA).... Show moreOur immune system is supposed to protect us from infections, but it can also attack our own tissues if not properly controlled. This can lead to autoimmune diseases like rheumatoid arthritis (RA). People with RA have antibodies to the body’s own proteins (self), but it is not known how they arise. The data described in this thesis show that these antibodies cross-react with self-proteins carrying different post-translational modifications, suggesting that multiple proteins may be involved in the initial loss of the immune system’s ability to discriminate between self- and foreign-proteins. As another unique feature, these antibodies carry additional sugars at an unexpected site in the molecule. Our data show that these sugars (variable domain glycans) can prevent binding to potential self-proteins, affect complement activation, and set the threshold for immune B-cell activation. In addition, our data show that the abundance of these sugars increases toward disease onset and predicts the development of chronic, persistent disease or the chance of subsequent remission. Taken together, these sugars may help B cells to escape the tight control mechanism in our body that are in place to prevent the development autoimmunity. This new “sugar mechanism” could be beneficial for diagnosis and future treatment. Show less
Physical Activity (PA) is one of the most important lifestyle factors influencing human health. The general and disease-specific health benefits of PA are well known to the general population and... Show morePhysical Activity (PA) is one of the most important lifestyle factors influencing human health. The general and disease-specific health benefits of PA are well known to the general population and to those people living with rheumatic musculoskeletal diseases (RMDs). The importance of PA as an intervention for the management of RMDs has been endorsed by various stakeholders, e.g. the World Health Organisation and the European Alliance of Associations for Rheumatology/EULAR. The early translation of research evidence into clinical care benefits patients with RMDs greatly.This thesis is focused on the effects and promotion of PA and exercise on people with RMDs, and particularly those with axial Spondyloarthritis (axSpA).The overall aim of this thesis was to document the journey from the development of the EULAR PA recommendations for people with RMDs (including axSpA) to the practical implementation of a concept for group exercise therapy for people with axSpA living in Switzerland that conforms to these recommendations. Show less
The high standard of Dutch hemophilia care and the availability of prophylaxis provide an opportunity to focus on health outcomes beyond mortality. Using both qualitative and quantitative methods,... Show moreThe high standard of Dutch hemophilia care and the availability of prophylaxis provide an opportunity to focus on health outcomes beyond mortality. Using both qualitative and quantitative methods, this thesis defined, measured and quantified relevant health outcomes for persons with hemophilia. In the first part of this thesis we showed that communication and information provision about treatment options and prophylaxis regimes may support persons with hemophilia in their decisions about current and future treatment products. This will likely result in improved bleeding outcomes. In the second part, we took the first steps towards value-based health care for hemophilia by defining a standard set of ten relevant health outcomes, including instruments to measure these outcomes. Routine measurement of the standard set may be implemented in clinical practice in order to further improve hemophilia care that adds value for patients. Already, the high standard of care has resulted in near-normal socio-economic participation of Dutch persons with hemophilia. Development of more sophisticated data collection tools will help to monitor relevant health outcomes over time. Show less
Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favourable efficacy and toxicity profile.... Show moreTreosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favourable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationship between systemic treosulfan exposure, early and long term clinical outcome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant diseases is unresolved. In this thesis we aimed to answer these questions. We found a relationship between the level of exposure to treosulfan and acute toxicity, but we found no relationship with the risk of rejection, survival and long-term endocrine complications. A personalized dose of treosulfan can therefore be useful to reduce toxicity in children, but because the toxicity profile of treosulfan is generally relatively mild, it will not be necessary in most cases. This is beneficial, because measuring blood levels is not always available in every hospital. Future research should focus on specific disease categories or patient groups that may benefit from treosulfan monitoring. More research is also needed on the late complications of treosulfan, such as dental, neurocognitive, hair, eye and lung problems, as this aspect becomes increasingly important as more (very young) patients undergo stem cell transplantation. Show less
Het doel van de dissertatie van David Gast is: het onderzoeken in hoeverre voedingssupplementen (vitaminen, mineralen en omega-3 vetzuren) in de praktijk gebruikt kunnen worden als interventie voor... Show moreHet doel van de dissertatie van David Gast is: het onderzoeken in hoeverre voedingssupplementen (vitaminen, mineralen en omega-3 vetzuren) in de praktijk gebruikt kunnen worden als interventie voor het verminderen van agressief gedrag bij mensen met een verstandelijke beperking (Chapter 1). Daartoe zijn verschillende studies verricht, te beginnen met een onderzoek naar de kwaliteit van voedingspatroon(Chapter 2). De tweede studie is een focusgroep onderzoek, waarin wordt onderzocht in hoeverre professionals en cliënten in de gehandicaptenzorg een interventie met voedingssupplementen accepteren als interventie voor moeilijk verstaanbaar gedrag (Chapter 3). De derde en vierde studies zijn RCT’s waarin het effect van voedingssupplementen wordt onderzocht op agressief gedrag bij respectievelijk gedetineerden (Chapter 4), en mensen met een verstandelijke beperking (Chapter 5). Het laatste onderzoek (Chapter 6) is een meta-analyse van de door ons gevonden studies naar het effect van een interventie met multivitaminen- mineralen op agressief gedrag. Om toekomstig onderzoek met voedingssupplementen in een kwetsbare populatie te faciliteren hebben we de door ons geleerde lessen geordend en van kanttekeningen voorzien (Chapter 7). Tot slot volgt een samenvatting en algemene discussie over de inhoud van de dissertatie (Chapter 8). Show less
Cardiovascular healthcare is continuously evolving. Biochemical,-and surgical discoveries from past decades improved patient survival to outstanding heights. However, with an ever growing aging... Show moreCardiovascular healthcare is continuously evolving. Biochemical,-and surgical discoveries from past decades improved patient survival to outstanding heights. However, with an ever growing aging patient population and scarce resources, cardiovascular healthcare has to become more value-driven. Value Based Healthcare (VBHC) research is becoming increasingly important in that matter, which questions the relevance (i.e. value) of contemporary evidence-based interventions in relation to patients’ health status and personal preferences.It is difficult to obtain a comprehensive view of ‘valuable outcome’ for both patients and professionals as individual and subjective perspectives on the value of treatment are ever present. This thesis presents a methodological ‘toolbox’ to assess clinical cardiovascular care, unravel the ‘value of care’ for its stakeholders and develop it further in a meaningful way. Patients were assessed on a national level using claims data, which enables insight into care patterns and helps unravel if that which is perceived as valuable by the professional (i.e. guideline evidence), is truly applied in daily practice. Second, cardiovascular care on a local hospital level is qualitatively assessed via Human Factors (HF) science, a novelty in clinical research. In line with VBHC, it helps to understand how the patient and professional experience healthcare within a certain context. Show less
The subject of the dissertation is the investigation and mapping of Nikolay Ivanovich Pirogov, the founder of “modern medicine” in Imperial Russia in the 19th century, Soviet Union and the Russian... Show moreThe subject of the dissertation is the investigation and mapping of Nikolay Ivanovich Pirogov, the founder of “modern medicine” in Imperial Russia in the 19th century, Soviet Union and the Russian Federation. Pirogov lived from 1810-1881 and is briefly and incorrectly only known in the world history of medicine as a military surgeon. He was a professor of applied anatomy and surgery from an early age, being the first to administer anaesthesia (ether) on the battlefield in the Caucasus during the summer of 1847. He was above all a scientist and teacher. He was also a member and correspondent of the Imperial Russian Academy of Sciences, and forerunner of the International Red Cross. He wrote many (text)books with different disciplines as subject. Research shows that he is a late student of the Leiden Medical School from the 18th century.The question is: why is Herman Boerhaave, who lived in the late 17th – early 18th century, more famous than Nikolay I. Pirogov, who lived in the 19th century from 1810-1881. Show less
