The studies described in this thesis contribute to the identification of biomarkers for risk stratification in systemic sclerosis (SSc). Luckily, nowadays many SSc prospective cohorts have been set... Show moreThe studies described in this thesis contribute to the identification of biomarkers for risk stratification in systemic sclerosis (SSc). Luckily, nowadays many SSc prospective cohorts have been set up worldwide which allows high-quality research. Given the rarity and the heterogeneity of the disease, relatively large cohorts are needed to draw valuable conclusions. For the studies described in the current thesis, I was able to incorporate data from the Leiden prospective SSc cohort and data from other prospective cohorts in Europe, which made it possible to strengthen the data. In this final chapter, I summarize the main findings of the studies presented in this thesis, put our findings in a broader perspective, discuss future perspectives and formulate research questions that are relevant to assess in the years ahead of us. Show less
The longevity of total knee implants may be impaired by aseptic loosening of the components within the bone. Aseptic loosening remains the leading cause of revision surgery. In the past decades,... Show moreThe longevity of total knee implants may be impaired by aseptic loosening of the components within the bone. Aseptic loosening remains the leading cause of revision surgery. In the past decades, many implant design aspects and surgical techniques have been changed in an attempt to decrease the risk of loosening. Given that radiostereometric analysis (RSA) is a highly accurate method to detect early implant migration which is predictive for late loosening, new implant designs should ideally be tested with RSA before widespread introduction onto the market. In this thesis, we present the results of four randomized controlled trials studying the effect of such changes in design on implant migration with use of RSA. We also pooled several RSA studies to be able to analyze the effect of other possible risk factors, including patient characteristics and surgical technique. We show that slight changes in implant design may increase the risk of loosening considerably, while other factors that are often thought to be associated with an increased risk (such as a high body mass index) do not appear to have a large effect. Show less
In dit proefschrift is gekeken naar de kwaliteit van uitname en naar de uitkomsten na transplantatie om zo goed mogelijk om te gaan met het tekort aan donororganen. Met de ET-DSRI kan de kans op... Show moreIn dit proefschrift is gekeken naar de kwaliteit van uitname en naar de uitkomsten na transplantatie om zo goed mogelijk om te gaan met het tekort aan donororganen. Met de ET-DSRI kan de kans op acceptatie voor een donorlever ingeschat worden. Daardoor kunnen er in een vroeg stadium maatregelen genomen worden om de kans op transplantatie te vergroten voor suboptimale levers. Alhoewel het aantal levers geschikt voor transplantatie geoptimaliseerd kan worden zal het tekort de komende jaren blijven bestaan. Daarmee zal ook de toewijzing van levers aan patiënten op de wachtlijsten complex blijven. De uitkomst na transplantatie is daarin een belangrijk punt. De resultaten beschreven in dit proefschrift laten zien dat statistische modellen een goede benadering kunnen geven van deze uitkomsten. Het toepassen van deze modellen zal leiden tot een meer evidence-based manier van het selecteren, toewijzen en daadwerkelijk transplanteren van levers in patiënten op de wachtlijst. Show less
The aim of this thesis is to identify emerging risk factors for VTE. To achieve this goal, we describe the supposedly causal role of statin and glucocorticoid use (i.e. two drugs that can influence... Show moreThe aim of this thesis is to identify emerging risk factors for VTE. To achieve this goal, we describe the supposedly causal role of statin and glucocorticoid use (i.e. two drugs that can influence inflammation) with changes in hemostasis and VTE risk. Systemic glucocorticoid use increases the relative risk of first VTE by more than three-fold and confers an 5% absolute risk of recurrent VTE per year. On the other hand, rosuvastatin use may reduce the risk of first VTE by 40%. Although the mechanisms behind this association are not fully elucidated, this thesis shows that rosuvastatin is capable of decreasing the thrombin generation potential by 10% in patients with a prior VTE. This thesis has shown that both statins and systemic glucocorticoids can affect the risk of VTE, improving the knowledge on the influence of these two commonly prescribed drugs on VTE pathophysiology. These findings have the potential to further refine the assessment of VTE risk since they highlight that the use of these drugs should be considered when evaluating the risk of VTE. Finally, this thesis provides insight into new therapeutic approaches since the results underscore that treatment strategies on VTE prevention in patients already taken statins, which may be sufficient for VTE prevention, are lacking. Treatment strategies to prevent glucocorticoid-associated VTE are also needed. Show less
The post-thromotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) are the most feared long term complication of a deep venous thrombosis (DVT) and pulmonary embolism (PE)... Show moreThe post-thromotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) are the most feared long term complication of a deep venous thrombosis (DVT) and pulmonary embolism (PE) respectively. We have reviewed the literature on arguments for and against routine screening of CTEPH in patients after an episode of an acute PE. The incidence of CTEPH is relevant in this evaluation. In a systematic review and meta-analysis we showed a CTEPH incidence of 0.56% in all comers and of ~3% in the survivors. We showed that a very recent developed screening algorithm, the InShape II algorithm, is sensitive and reproducible for detecting early CTEPH in the course of an acute PE. Beside this, most patient who were diagnosed with CTEPH in the course of an acute PE already showed signs of CTEPH on the initial CT scan made for PE diagnosis.In the last chapter we focus on PTS in the course of a DVT. In patients included in the MEGA database the 0-1 year incidence was 21.8%, after 8 years of follow-up an additional 7% developed PTS. During follow-up PTS symptoms improves in almost 70% of patients. Show less
In this thesis the impact of donor and recipient risk factors and the development of risk models in liver transplantation was investigated. These models can be used for multiple purposes, including... Show moreIn this thesis the impact of donor and recipient risk factors and the development of risk models in liver transplantation was investigated. These models can be used for multiple purposes, including risk indication, outcome prediction and benchmarking between transplant centers. As such, several steps have been made towards evidence-based liver allocation and proper selection of liver allografts in times of organ shortage and the current system of severitybased liver allocation (by MELD the score). Further refinement of these models is necessary in order to optimize donor to recipient matching and achieve an objective, transparent and well-informed system of liver allocation. Altogether, the efforts made here to improve waitlist and transplantation outcomes, are meant for the individual transplant candidate on the liver transplant waitlist and as a whole, for the transplant community. Show less
The main objective of this thesis was to improve cardiovascular risk assessment in primary care. Chapter 2 provides evidence that coded diagnosis from general practice electronic health... Show moreThe main objective of this thesis was to improve cardiovascular risk assessment in primary care. Chapter 2 provides evidence that coded diagnosis from general practice electronic health records are a feasible and valid alternative to self-report to define diabetes cases in epidemiological studies. Based on the results of focus group discussions with research participants confronted with an incidental finding, as described in Chapter 3, we concluded that a detailed study protocol is needed on the disclosure of incidental findings before recruitment of participants. We gave several recommendations to improve the disclosure of incidental findings. Our findings in Chapter 4 suggest that it is important to inform the general practitioner and the research participants about the individual cardiovascular test results. Only participants with an estimated intermediate of high cardiovascular risk should receive a recommendation to consult their general practitioner. In Chapter 5, we concluded that inviting patients with overweight or obesity for cardiovascular risk assessment can help to identify a substantial additional group of patients at increased cardiovascular risk. In Chapter 6, we did not find evidence that cardiovascular risk assessment can be improved when non-invasive markers of hepatic steatosis are added to an established risk estimation system. Show less
This dissertation aimed to identify opportunities to slow down disease progression and improve health-related quality of life (HRQOL) in patients with chronic kidney disease (CKD). Biopsychosocial,... Show moreThis dissertation aimed to identify opportunities to slow down disease progression and improve health-related quality of life (HRQOL) in patients with chronic kidney disease (CKD). Biopsychosocial, patient-centred and self-regulation perspectives were employed and enabled this dissertation to shed light on the importance of patients’ health behaviours and illness perceptions in the treatment of CKD. Taken together, this dissertation indicates that patients in early CKD stages are in need of behavioural support to cope with the broad range of barriers that they experience when reducing sodium intake. The results demonstrate that a multicomponent patient-centred self-regulation program would fit patients' needs, and can reduce risk factors for disease progression and improve psychosocial outcomes. Furthermore, this dissertation suggests that support strategies should be implemented to increase the impaired HRQOL that many patients experience during predialysis care. The results underline the need for personalized treatment approaches in light of the differences between patients in relation to their HRQOL and how their HRQOL evolves over time (e.g., differences with regard to age and cardiovascular disease). Moreover, illness perceptions were found to be key factors in HRQOL and disease progression, and therefore, treatment strategies in predialysis care should take into account patients’ illness perceptions as well. Show less
This study investigated the prevalence of child maltreatment in a cross-cultural perspective, the changes in prevalence estimates in Vietnam over time, child and family risk factors of maltreatment... Show moreThis study investigated the prevalence of child maltreatment in a cross-cultural perspective, the changes in prevalence estimates in Vietnam over time, child and family risk factors of maltreatment, and possible consequences of child maltreatment. We administered questionnaires and a working memory test to 1,851 secondary and high school students (12-17 years old) in four Northern provinces of Vietnam. We compared current Vietnamese prevalence estimates with those from the Dutch prevalence study on child maltreatment (NPM-2010) and from a prevalence study in Vietnam 10 years ago to achieve a cross-cultural and chronological comparison. We found that although there was a decrease in emotional and physical abuse over time, all types of child maltreatment were still highly prevalent, ranging from 2.6% for sexual abuse to 31.8% for emotional abuse. Most types were more common in Vietnam than in the Netherlands. Only the past year sexual abuse prevalence in Vietnam was lower. Single parenthood, being a boy, and older age were risk factors for child maltreatment. Child maltreatment was related to negative child well-being aspects with the largest effect on emotional functioning. Our study draws a clearer picture on child maltreatment in Vietnam. It highlights the importance of prompt responses to child maltreatment. Show less
In this thesis we show the results of the AT-AGE study, a two-center, population based case-control study in Leiden, the Netherlands and Burlington, Vermont, US, in which consecutive patients aged... Show moreIn this thesis we show the results of the AT-AGE study, a two-center, population based case-control study in Leiden, the Netherlands and Burlington, Vermont, US, in which consecutive patients aged 70 years and older with deep venous thrombosis (DVT) in the leg or a pulmonary embolism (PE), were identified. The AT-AGE study was specifically designed to optimise the participation-rate in the older population. Therefore, we performed home visits to all participants. We showed that conventional risk factors such as immobilisation due to hospital admission, and also immobility at home, due to for instance infection and minor injury, increase the risk of venous thrombosis. Also genetic risk factors, such as Factor V Leiden (FVL, rs6025) and the prothrombin 20210A mutation (PT20210, rs1799963) increase the risk of venous thrombosis. We report the presence of age-specific risk factors: functional impairment, low hand grip strength and venous insufficiency, such as varicose veins and leg oedema. Also we identified new high risk groups in older people, e.g., recent hospital discharge in which preventive measures could be of special interest. Show less
In this thesis the epidemiology of suicidal ideation and suicide attempts (together referred to as 'suicidality') in Huntington's disease (HD) is investigated and coping styles and support... Show moreIn this thesis the epidemiology of suicidal ideation and suicide attempts (together referred to as 'suicidality') in Huntington's disease (HD) is investigated and coping styles and support strategies that may serve to help suicidal HD mutation carriers are explored. Suicidality frequently occurs in HD, with a 1-month prevalence of up to 20%. Mutation carriers who were most likely to currently experience suicidal ideation or suicidality had a shorter disease duration, were anxious, aggressive, previously attempted suicide, used antidepressants, and had a depressed mood. The presence of a depressed mood and use of benzodiazepines were the only significant independent predictors of incident suicidal ideation or suicidality. Biological parameters, in particular functioning of the immune system and the hypothalamus-pituitary-adrenal axis were not found to be associated with suicidality in HD. In a qualitative study it was shown that suicidal HD mutation carriers generally used four strategies to cope with suicidality: talking about suicidality, employing self-management activities, using medication, and discussing end-of-life wishes. Lastly, in a meta-analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide. Effect estimates differed substantially among different populations, but none of the included studies investigated this association in HD. Show less
978-94-6182-393-9 The first part of this thesis identified several high-risk sub-populations to improve the care and risk stratification of patients with ST-elevation myocardial infarction (STEMI).... Show more978-94-6182-393-9 The first part of this thesis identified several high-risk sub-populations to improve the care and risk stratification of patients with ST-elevation myocardial infarction (STEMI). It was observed that common patient characteristics such as female gender, cancer and age have a strong impact on the delay to reperfusion therapy and the prognosis after STEMI. Furthermore, the historically devastating complication of out-of-hospital cardiac arrest continues to have an impact of the STEMI population. Angiographic determinants of the occurrence and prognosis of out-of-hospital cardiac arrest were identified, which may improve the care of these high-risk patients. The second part of this thesis investigated the use of second generation drug-eluting stents (DES) for the treatment of coronary heart disease. Among the second generation DES, everolimus-eluting stents showed superior results compared to Endeavor zotarolimus-eluting stents in a real world cohort of STEMI patients. A randomized acute MI trial subsequently established the non-inferiority of the everolimus-eluting stent to the first generation sirolimus-eluting stent, with results suggesting superiority. However, these stents performed similarly during long term follow-up, both in patients with and without STEMI. Low rates of stent thrombosis and similar efficacy confirmed the usefulness of both stents in the full range of coronary heart disease. Show less
The aim of this set of studies was to provide more insight in individual characteristics that influence care-giving abilities, in particular precursors of harsh and abusive parenting. We examined... Show moreThe aim of this set of studies was to provide more insight in individual characteristics that influence care-giving abilities, in particular precursors of harsh and abusive parenting. We examined how different subtypes of childhood abuse were related to child abuse potential in adulthood. Emotional neglect in childhood was related to child abuse potential, which is in line with earlier research showing the long-lasting effects of emotional maltreatment and neglect in childhood. With regard to the effects of oxytocin on the neural basis of parenting, we used fMRI to examine how oxytocin influenced emotion recognition using pictures of both adult and infant faces, taking experiences of maternal love withdrawal into account as potential moderator. Oxytocin enhanced neural activity in regions involved in emotion processing, such as the IFG, insula and STG. Our findings regarding the moderating role of experiences of maternal love withdrawal are inconsistent for emotion recognition in adult faces and in infant faces. Lastly, a new paradigm (LISSA) to observe sensitivity in response to standardized infant cues was developed and tested. Our results show that sensitivity can be reliably assessed using this procedure, making the LISSA a promising method for future research and clinical practice. Show less
The scope of the work described in this thesis is to examine whether potential transfusion related and clinical risk factors modulate the risk of alloimmunization in a general, previously not... Show moreThe scope of the work described in this thesis is to examine whether potential transfusion related and clinical risk factors modulate the risk of alloimmunization in a general, previously not transfused, non alloimmunized population of transfusion recipients. In these studies we emphasize the methodological aspects of observational research in clinical transfusion medicine Show less
Background As maintenance of lifestyle change and risk factor modification following completion of cardiac rehabilitation (CR) has been shown to be notoriously difficult, we developed a brief self... Show moreBackground As maintenance of lifestyle change and risk factor modification following completion of cardiac rehabilitation (CR) has been shown to be notoriously difficult, we developed a brief self-regulation lifestyle program for post-CR patients. Design Randomized-controlled trial. Method Following completion of CR 210 patients were randomized to receive either a lifestyle maintenance program (n=112) or standard care (n=98). The program was based on self-regulation principles and consisted of a motivational interview, 7 group sessions and home assignments. Risk factors and health behaviors were assessed at baseline (end of CR), and 6 and 15 months thereafter. Results ANCOVAs showed a significant effect of the lifestyle program after 6 months on blood pressure, waist circumference and exercise behavior, only the latter of which remained significant at follow-up (15 months). Mediation analysis demonstrated that the treatment effect on exercise behavior could be explained by an effect on self-regulation skills. Furthermore, the lifestyle intervention program was associated with a 12% reduction in self-reported cardiac hospital admission rates. In addition, patients in the intervention group had significantly fewer uncontrolled risk factors as compared to the control group. However, there was only a long-term beneficial intervention effect on obesity and physical inactivity, but not on other individual risk factors (increased waist circumference, raised blood pressure, raised TC/HDLC-ratio and smoking). Conclusion This trial indicates that a relatively brief, theory-based lifestyle program is capable of inciting and maintaining improvements in exercise adherence. It is suggested that patients may need ongoing attention and guidance, for example in the form of (internet-based) booster sessions, as long-term consolidation of changes is arduous. Show less
This thesis describes the epidemiology of emerging infections with Clostridium difficile. Outbreaks of severe disease with high mortality were found to be associated with certain types of this... Show moreThis thesis describes the epidemiology of emerging infections with Clostridium difficile. Outbreaks of severe disease with high mortality were found to be associated with certain types of this bacterium and type specific risk factors were identified. Moreover, highly discriminatory typing techniques were useful in understanding clonal disseminations across healthcare institutions. Show less
This thesis elaborates the occurrence of venous thrombosis in cancer patients. Cancer is known to be associated with venous thrombosis with a spectrum of clinical manifestations varying from deep... Show moreThis thesis elaborates the occurrence of venous thrombosis in cancer patients. Cancer is known to be associated with venous thrombosis with a spectrum of clinical manifestations varying from deep vein thrombosis of the leg and pulmonary embolism, recurrent thrombophlebitits saltans et migrans (also called Trousseau__s syndrome) to disseminated intravascular coagulation and arterial embolism. The causes of venous thrombosis can be divided in environmental risk factors such as bed rest, surgery, plaster cast, trauma, long-distance travel, oral contraceptives or pregnancy and puerperium and genetic risk factors such as factor V Leiden and prothrombin 20210A mutation. Various factors may contribute to the development of venous thrombosis in cancer patients, and circulating mucins as well as circulating microparticles which express active TF on their surface may provide a missing link between cancer and thrombosis in (adeno) carcinoma patients. Treatment options include vitamin K antagonists and low-molecular-weight heparins, and the long-term use of these heparins in prevention of venous thrombosis may improve the outcome in comparison with oral anticoagulants. Further research is needed to better understand the morbidity and mortality associated with thrombosis in cancer patients and to optimize strategies of prevention and treatment Show less
To improve quality of cancer care treatment-related information is needed. This could be acquired by registries. Since January 1984, the Leiden University Medical Center (LUMC) collects... Show moreTo improve quality of cancer care treatment-related information is needed. This could be acquired by registries. Since January 1984, the Leiden University Medical Center (LUMC) collects prospectively more than 200 relevant clinical and pathological parameters of women with cervical cancer treated in the LUMC. The purpose of this thesis was to use the treatment-related information of this database, to get inside information and to become aware of possibilities for improvement in the current treatment procedures, in order to monitor the quality of treatment. Furthermore, when results of cancer treatment in terms of survival are good it is also important to focus on the sequelae of the treatment. The incidence of lymphedema, urinary and colorectal dysfunction has been reported with variable rates and sexual dysfunction after radical hysterectomy has been shown to occur in about 25% of the patients. Furthermore, a study assessed by vaginal plethysmography, showed that radical hysterectomy seems to be associated with a disturbed vaginal blood flow response during sexual arousal. The second purpose of this thesis was to monitor the sequelae of the treatment of women with a history of early stage cervical cancer in order to have measures in attempts to improve the quality of life. Show less
Osteoarthritis (OA) refers to a heterogeneous group of conditions. This thesis focuses on OA with a hereditary background; Familial OA at multiple joint sites and radiological hand OA at middle age... Show moreOsteoarthritis (OA) refers to a heterogeneous group of conditions. This thesis focuses on OA with a hereditary background; Familial OA at multiple joint sites and radiological hand OA at middle age. The main objective is to identify risk factors that play a role in the development of OA in order to gain further insight in the aetiology of OA. The secondary objective is to investigate factors that determine the outcome in OA. This thesis provides evidence that familial clustering of symptomatic OA is most prominent for hand and hip OA. In search for genetic risk factors, we present data suggesting that a proportion of the genetic susceptibility for OA at multiple sites is encoded by variation in innate cytokine activity. Further, we find HLA-DR antigens to be associated with radiological hand OA. In addition to genetic risk factors, this thesis demonstrates that other systemic risk factors such as hormonal status and local factors, to be important in the susceptibility of familial OA at multiple sites, underscoring the multicausal etioliology of this phenotype. Finally, this thesis addresses the resulting disability from OA. Using the International Classification of Functioning, Disability and Health as framework, we show illness perceptions and mental health to be important modifying factors in OA in the hands and lower extremities. Show less
This thesis examines different risk factors, in relation to restenosis after Percutaneous coronary interventions (PCI), with its main focus on genetic markers. Restenosis is the main drawback of... Show moreThis thesis examines different risk factors, in relation to restenosis after Percutaneous coronary interventions (PCI), with its main focus on genetic markers. Restenosis is the main drawback of PCI. Genetic variance poses an opportunity to enhance stratification of individuals who will be more prone to develop restenosis. Restenosis is a multifactorial process, therefore only limited part of the number of candidate genes that are potentially involved in restenosis can be described. Since the inflammatory reaction is known to be highly important in restenosis, our study has its main focus on inflammatory markers. To examine various candidate genes and their polymorphisms we made use of the GENetic DEterminants of Restenosis (GENDER) study, a multicenter follow-up study, including 3,104 consecutive patients, who were successfully treated with PCI. In the different chapters we describe the study population and the clinical and genetic factors investigated. Furthermore, we made use of a mouse model to improve our understanding of restenosis. Our results have contributed to a better understanding of the restenotic process, they could provide novel therapeutic targets as well as contribute to development of improved risk stratification of patients who are scheduled for elective PCI, thereby creating the opportunity to individualize treatment in the future. Show less
