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
Due to the increased incidence of breast cancer and improved survival, more women are at risk of developing contralateral breast cancer (CBC). The aim of this thesis was to explore risk factors... Show moreDue to the increased incidence of breast cancer and improved survival, more women are at risk of developing contralateral breast cancer (CBC). The aim of this thesis was to explore risk factors associated with CBC. We observed significant associations for a polygenic risk score of common germline variants (PRS313) and for different adjuvant systemic therapy regimens with (subtype-specific) CBC risk. These factors may be incorporated in CBC risk prediction models together with other known and available risk factors. For support of clinical decision making more biological information is needed to understand CBC development in women with invasive breast cancer and DCIS. As a first step towards implementation of a risk prediction model, we performed an exploratory interview study, which showed that patients had varying preferences for graphical presentation of probabilities in a CBC prediction model. In future studies, the prediction model should be incorporated in a decision support tool and implemented in clinical practice. This tool can then help to better identify women at high risk of CBC who may benefit from prophylactic surgery, while the estimates can also be used to reassure patients who are at low risk of developing CBC. 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
In this thesis the risk factors of venous thrombosis will be discussed in the general and particularly the elderly population. The goal of this thesis is to provide insights on risk factors of... Show moreIn this thesis the risk factors of venous thrombosis will be discussed in the general and particularly the elderly population. The goal of this thesis is to provide insights on risk factors of thrombosis in the elderly population, in order to advance our basic understanding of physiological age-related changes that increase the risk of venous thrombosis and which may ultimately lead to improved personalized interventions. In this chapter firstly background information will be provided on risk factors for venous thrombosis, focussing specifically on age as a risk factor. Secondly, the role of veins and venous valves in the development of venous thrombosis will be discussed and thirdly, global assays as a potential tool to identify patients at high risk for venous thrombosis will be considered. The study populations used in this thesis will discussed, and an outline of this thesis will be provided. 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
Patients with deep vein thrombosis or pulmonary embolism remain at risk for recurrent venous thrombosis. This risk is pronounced in the first months after the acute episode and declines in... Show morePatients with deep vein thrombosis or pulmonary embolism remain at risk for recurrent venous thrombosis. This risk is pronounced in the first months after the acute episode and declines in subsequent years. Although the existence of an extensive list of risk factors may seem reassuring, it does not come close to give us all the answers: many people have several of these risk factors but never develop thrombosis; others suffer from thrombosis but have none. Therefore, the challenge that we are facing today is not to just add more risk factors to this list but rather to integrate them all in a causal model that allows us to understand how and when thrombotic disease develops. The idea behind “the thrombosis potential model” is that an individual is at risk for venous thrombosis throughout life, which is reflected in the ‘thrombosis potential’ and that each risk factor contributes to increase the potential. Only when the combination of thrombosis risk factors reach a certain potential, venous thrombosis will occur. In this thesis, the thrombosis potential model will be applied to several known risk factors for venous thrombosis to better understand why first and recurrent venous thrombosis can develop in an individual patient. Show less
The pathogenesis of OA is largely unknown; however, several risk factors are known to contribute to disease development. Treatment modalities are currently limited to alleviation of symptoms. In... Show moreThe pathogenesis of OA is largely unknown; however, several risk factors are known to contribute to disease development. Treatment modalities are currently limited to alleviation of symptoms. In order to develop better treatment modalities, increase of the understanding of the underlying mechanisms leading to OA development may provide targets for disease modification. Furthermore, knowledge regarding appropriate outcome measures that can be applied in OA research has to be increased for adequate assessment of potential treatment effects. Therefore, part I of this thesis describes studies aiming to increase the understanding of mechanisms underlying the association between known risk factors and OA, especially focussing on obesity in relation to OA in weight-bearing and non-weight-bearing joints. Furthermore, it was investigated which specific structural abnormalities on specific locations within the knee joint could best discriminate presence of symptomatic OA, and impact of knee OA and its modifiable or preventable risk on health-related quality of life was evaluated. Part II of this thesis describes two systematic reviews, assessing available instruments for measurement of the domains pain, physical function, patient global assessment and imaging in hand OA in order to enable recommendations for use in clinical trials. 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
Venous thrombosis is a disease that occurs in 1-2 per 1000 people per year. At the time of their first venous thrombosis, approximately 50% of women are exposed to reproductive risk factors (oral... Show moreVenous thrombosis is a disease that occurs in 1-2 per 1000 people per year. At the time of their first venous thrombosis, approximately 50% of women are exposed to reproductive risk factors (oral contraception, postmenopausal hormone therapy, pregnancy and the puerperium). In this thesis, we showed that these women are at particularly high risk of venous thrombosis if they have previously experienced an episode of superficial vein thrombosis, or are over the age of 50 years (Chapters 2 and 3). There is no known male counterpart to female reproductive risk factors. Nevertheless, the incidence of venous thrombosis is approximately similar in men and women. In this thesis we established that, once female reproductive risk factors are taken into account, men have an approximately twofold higher risk of both first and recurrent venous thrombosis than women (Chapters 4 and 5). Further to these findings, in Chapter 6, we reviewed the literature on sex-specific risk factors for venous thrombosis. We hypothesized that sex-specific genetic risk factors, an excess in overweight and smoking, or hypercoagulable changes such as microalbuminuria may explain the higher risk of venous thrombosis in men than in women. 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
H2: Hensgens MP, Goorhuis A, Notermans DW, van Benthem BH, Kuijper EJ. Decrease of hypervirulent Clostridium difficile PCR ribotype 027 in the Netherlands. Euro Surveill. 2009 H3: Hensgens MP,... Show moreH2: Hensgens MP, Goorhuis A, Notermans DW, van Benthem BH, Kuijper EJ. Decrease of hypervirulent Clostridium difficile PCR ribotype 027 in the Netherlands. Euro Surveill. 2009 H3: Hensgens MP, Keessen EC, Squire M, Riley TV, Koene MG, de Boer E, Lipman LJ, Kuijper EJ. Clostridium difficile infection in the community: a zoonotic disease? Clin Microbiol Infect. 2012 H4: Hensgens MP / Goorhuis A, van Kinschot CM, Crobach MJ, Harmanus C, Kuijper EJ. Clostridium difficile infection in an endemic setting in the Netherlands. Eur J Clin Microbiol Infect Dis. 2011 H5: Hensgens MP, Goorhuis A, Dekkers OM, Kuijper EJ. Time-interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012 H7: Hensgens MP, Goorhuis A, Dekkers OM, van Benthem BH, Kuijper EJ. Outcome of nosocomial Clostridium difficile infections; results of a multicenter cohort study. Clin Infect Dis. 2013 H8: Hensgens MP / Bauer MP, Miller M, Gerding DN, Wilcox MH, Dale AP, Fawley WN, Kuijper EJ, Gorbach SL. Renal failure and leukocytosis are predictors of a complicated course of Clostridium difficile infection (CDI) if measured on day of diagnosis. Clin Infect Dis. 2012 H9: Hensgens MP, Kuijper EJ. Clostridium difficile infection due to binary toxin positive strains. Emerg Infect Dis. 2013 H10: Hensgens MP, Dekkers OM, Goorhuis A, Le Cessie S, Kuijper EJ. Predicting a severe course of Clostridium difficile infection at the bedside. Clin Microbiol Infect. 2012 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
