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Wednesday, May 23, 2012

Pediatric Inflammatory Bowel Disease: from a translational perspective Damen, G.M. 2010-04-14 Doctoral Thesis

Crohn’s disease (CD) and ulcerative colitis (UC), the two main subtypes of inflammatory bowel disease (IBD), are chronic relapsing inflammatory disorders of the gastrointestinal tract that have a peak age of onset in the second decade of life in children. There is strong evidence to support that dysregulation of the normally controlled immune response to commensal bacteria in a genetically susceptible individual drives IBD. Patients typically suffer from frequent and chronically relapsing flares, resulting in abdominal pain, diarrhea, rectal bleeding and weight loss. In CD, inflammation is transmural and often discontinuous. In UC, inflammatory changes typically involve the superficial mucosal and submucosal layers of the intestinal wall. CD most commonly involves the ileum and colon, but can affect any region of the gut. UC classically involves the rectum and inflammation may extend as far as the caecum in a typical continuous pattern. Patients with IBD may have various extra-intestinal symptoms such as oral ulcers, uveitis, arthalgias or arthritis and sclerosing cholangitis. IBD is heritable, 5 to 20% of the patients have a family history of the disease. This positive family history of IBD is more frequently observed in patients with CD than in UC. In IBD, there is a significantly higher rate of disease concordance in monozygotic twins compared with dizygotic twins.

Psoriasis: Comorbidity and Treatment Wakkee, M. 2010-04-15 Doctoral Thesis Dermatology

Psoriasis is universal in occurrence, although the worldwide prevalence varies between 0.6% and 4.8%.The prevalence of psoriasis in people of Caucasian descend is approximately 2%. In the Netherlands it is therefore estimated that approximately 300,000 people are diagnosed as having psoriasis. Its prevalence is equal in men and women and can first appear at any age, from infancy to elderly, although the mean age of development has suggested to be around 30 years old. Some studies suggest the presence of two forms of psoriasis related to the age at onset. Early onset psoriasis, which comprises approximately 75% of the psoriasis population, presents itself before the age of 40 mostly with a positive family history and with more severe disease. While late onset psoriasis presents itself after the age of 40 and may have a less severe clinical course. However, other studies were not able to confirm the presence of more severe psoriasis in those subjects with an early age of onset. The extent of body surface area affected by psoriasis is variable, but in most people the severity of their psoriasis is reasonably stable over time. Based on a patient survey the prevalence of moderate to severe psoriasis (i.e. more than 3% of the body surface area affected) was recently estimated to be approximately 17%. 

Population-based screening for colorectal cancer Hol, L. 2010-04-16 Doctoral Thesis Psychiatry

The incidence of colorectal cancer (CRC) shows considerable geographical differences around the world. The highest incidence rates are mainly seen in the Western world including North America, Australia/New Zealand, Western Europe, and Japan. Development countries report the lowest incidence rates. In Europe, CRC is the second most common diagnosed cancer in women and third in men (13% of all cancer cases in both women and men). Incidence rates are somewhat higher in men (1.2:1.0). The lifetime incidence of CRC in patients at average risk is approximately five percent. Incidence rates show demographic disparities over the last decades, with a gradual increase in South/Eastern Europe, stabilising numbers in North and West Europe, and a declining trend in the United States. Age is a major risk factor for the development of CRC. CRC rarely develops before the age of 40 (IKC), except in patients with a genetic predisposition. Incidence rates rapidly increase beyond the age of 50. In Europe, CRC ranked second (12% of all cancer related mortality) in terms of cancer related mortality 1, despite the significant increase in five-year survival in the last two decades. This improvement was in particular due to resection of rectal cancer with sharp dissection of the mesorectum en bloc with the rectum (total mesorectal excision) combined with pre-operative radiotherapy, and usage of new chemotherapeutic agents in various combinations. Additionally, improvement in outcome can be attributed to detection of the disease at an earlier stage due to screening and surveillance programmes.

The development of children's problem behaviors: A twin-singlton comparison and the influence of parental divorce Robbers, S.C.C. 2012-04-19 Doctoral Thesis

Twin-family studies have largely contributed to our understanding of the etiology of behavioral and emotional problems in childhood. From these studies we learned that almost every behavioral or psychological trait is ‘heritable’ to some extent. We also learned that both nature and nurture play important roles in the etiology of behavioral and emotional problems, and that these factors may act independently of one another as well as interactively (i.e., gene-environment interplay). Moreover, twin studies have given insight into the important distinction between environmental factors shared by siblings (e.g., parental socio-economic status) and those not shared by siblings (e.g., peer groups) (Boomsma, Busjahn, & Peltonen, 2002; Hudziak & Faraone, 2010). An important assumption that is made when using twin data is that results from twin samples can be generalized to singleton populations. However, the validity of this assumption needs to be examined. 

The Manchester Triage System in paediatric emergency care Veen, M. van 2010-04-16 Doctoral Thesis

In the first part of the thesis performance of the Manchester Triage System in paediatric emergency care was evaluated. In chapter 1 we reviewed the literature to evaluate realibility and validity of triage systems in paediatric emergency care. The Manchester Triage System was used to triage patients when presenting at the emergency department of a general teaching hospital and the emergency department of a university paediatric hospital. The system’s reliability was evaluated in chapter 2. Its validity and specific patients groups for which validity was not optimal were discussed in chapter 3. Chapter 4 evaluates patient problems for which the MTS performs severe under-triage. The second part focuses on improvements of the MTS. Chapter 5 focuses on the value of temperature as discriminator in triage systems. The MTS was modified for patient groups with a low validity and the effect of the modification on the reliability and validity are studied in chapter 6. In the third part of this thesis we assess the ability of the MTS to safely identify low urgent patients. In chapter 7 determinants of hospitalisation for low urgent patients were evaluated. Chapter 8 reports about compliance and effect on costs when low urgent children, when presenting to the ED are referred to the general practitioner cooperative. Chapter 9 provides a summary of the findings and the future prospects. 

The Dutch Living Donor Kidney Exchange Program Klerk, M. de 2010-04-22 Doctoral Thesis

Kidney transplantation is the optimal option for patients with an end-stage renal disease. The first successful transplantation with a living genetically related donor has been performed since 26 October 1954, when an identical twin transplant was performed in Boston. In the years that followed, efforts to enable non-twin transplants unfortunately failed because effective immunosuppression was not yet available. It took until the early sixties after the discovery of azathiopirine that also deceased donor kidney transplantations became possible. In the eighties of the last century the wait time for a kidney transplant was approximately one year. Since that time the success rate of organ transplantation has significantly improved which attracted large numbers of transplant candidates. As the number of deceased organ donors did not increase, the wait time on the list steadily grew and at the moment patients in most Western countries face wait times up to 5 years before a deceased donor kidney is offered. Unfortunately an increasing proportion of them will never be transplanted because their clinical situation deteriorates to such an extent that they are delisted or die on the wait list. For the Netherlands we estimate that this proportion is approximately 30%. A strategy to expand the kidney donor pool includes the use of non-heart beating (NHB) donors. Educational programs in the Netherlands have resulted in an increase in the number of kidney transplants derived from NHB donors from almost 20% in the year 2000 to 43% in 2004, while in the years that followed the numbers of NHB donors stabilized. So the NHB donors have not led to expansion of the deceased kidney donor pool. Possibly substitution from heart beating to non heart beating donation procedures took place, resulting from pressure on the facilities of intensive care units. In the Netherlands, it has been suggested that the main reason for our failure to increase the number of deceased organ donors is the lack of donor detection. This is certainly not the case; both in 2005 and in 2006 almost all potential donors in the Netherlands (96%) were recognized as such and for the vast majority (86%) our national donor registry was consulted. The problem is not donor detection but the high refusal rate by the next of kin, which is inherent to our legal system. Our organ donation act dictates an opt-in system, and therefore all adult citizens are asked to register their consent for the use of their organ for transplantation purpose after death. In the Netherlands approximately 25% of the adults are now registered as potential donors, 15% have explicitly refused and thus for 60% it remains unknown. Especially in case of potential donors of the latter category high refusal rates up to 70% haven been found. Apparently next of kin argue that while the possibility was given to everybody to register as donor, their relative did not do so, therefore they are unaware of consent and thus reluctant to give permission for donation. We feel that an opt-out organ donation system would be very much helpful to expand the deceased kidney donor pool. However, we are aware that even if all potential deceased donors became actual donors, there still would be a shortage of donor kidneys. Therefore the use of kidneys from living donors is an obvious way to go. These transplants result in a superior unadjusted graft survival compared to deceased donor kidneys. It has been calculated that the difference in 10 years survival between living and deceased donor kidney transplantation is 34 %. 

Economic evaluations of health technologies: insights into the measurement and valuation of benefits Bobinac, A. 2012-05-11 Doctoral Thesis

Economic evaluations have been applied in the field of healthcare for several decades with the principle aim of improving the economic efficiency of resource allocation, i.e., help maximizing benefits from available (and constrained) resources. Broadly speaking, “economic evaluation is the comparative analysis of alternative courses of action in terms of both their costs and consequences” (Drummond et al., 1997). Economic evaluations became reasonably well-accepted in the decision-making process within the systems of different countries because they offer a promise of a systematic and transparent framework for deciding which intervention - among alternative interventions - to fund from a restricted budget. That is, once efficacy and effectiveness have been established, decision-makers can decide between competing interventions based on their relative cost-effectiveness and thus maximize the aggregate (value of) health benefits attained. 

Recovery after total hip or knee arthroplasty: physical and mental functioning Dikmans-Vissers, M.M. 2012-05-10 Doctoral Thesis

Musculoskeletal complaints are extremely common and have important consequences for the individual and society. The most prevalent chronic musculoskeletal disease is osteoarthritis (OA). OA is a disease of the articular joint and can lead to severe disability. In Western adult populations it is one of the most frequent causes of pain and stiffness, loss of function and disability. With regard to the major joints, OA is most prevalent in the knee and hip joint. In the Netherlands, in 2007 about 312,000 persons had knee OA and 238,000 persons had hip OA. Based on demographic development it is expected that the absolute number of persons with OA will increase by about 52% between 2007 and 2040. If the expected increase of patients with obesity is also taken into account, the prevalence of OA will become even greater. The initial treatment of OA consists of pain medication, physical therapy, and lifestyle recommendations. These treatments aim to suppress the symptoms and to improve or maintain functioning. When conservative treatment fails to alleviate pain and dysfunction caused by knee or hip OA, total knee arthroplasty (TKA) and total hip arthroplasty (THA) are cost-effective surgical options that can provide significant pain relief and improvement in physical functioning. The number of TKA and THA procedures performed in the Netherlands has increased substantially in the last decades. Between 1996 and 2008 the annual number of TKAs placed in the Netherlands in patients with a primary diagnosis of OA increased from 4,046 to 11,881, an increase of almost 300%. During this same period, the number of THAs placed in the Netherlands increased from 16,803 to 17,401 procedures. Because of the aging of the Western population, together with the increasing number of people with overweight and the improvements in surgical techniques, these numbers are expected to increase even further. 

Red Wine Polyphenols and Vascular Function Botden, I.P.G. 2012-05-09 Doctoral Thesis

Hippocrates, the father of modern medicine, said many centuries ago: “let food be your medicine.” Today, this quote still shows its value, amongst others by the !nding that red wine consumption attributes to a healthy life style, reducing the risk to develop cardiovascular diseases. Cardiovascular diseases are one of the leading causes of death in many economically developed countries as well as in emerging economies.1 It has become a global epidemic problem, with type 2 diabetes, hypertension and, obviously, aging as one of the major risk factors. Red wine might interfere with one or more of these factors, and thus contribute in the prevention of cardiovascular diseases. 

Physical activity and fitness in older adults with intellectual disabilities Hilgenkamp, T.I.M. 2012-05-09 Doctoral Thesis

This thesis describes the results of the 'Healthy ageing and intellectual disability"-study concerning the theme 'Physical activity and fitness'. In this study, 1050 older adults with intellectual disabilities were included, and measured with an extensive battery of tests, including pedometers, physical fitness tests, daily functioning and mobility. Reliability and feasibility of instruments new to this population were studied and proved to be acceptable. Results of the measurements showed that this group is mostly inactive and had low physical fitness levels. 

Risk assessment of cervical disease by hrHPV testing and cytology Kocken, M. 2012-05-02 Doctoral Thesis

As cervical cancer is an important health problem worldwide with over a half million patients a year and as it is the fourth most common cause of cancer-related death in women, improving the prevention of this disease is a continuing and important process. A major reduction of cancer incidence and mortality has occurred in countries with cervical cancer screening. Because cervical cancer develops through different premalignant stages it can be detected in a premalignant stage, allowing treatment before these stages would be able to develop into cervical cancer. Chapter 1 gives a general introduction about the cervix, human papillomavirus (HPV), the model(s) of cervical carcinogenesis and different measures that are taken to prevent cervical cancer. These measures include screening, triaging of abnormal test results, colposcopic examination, treatment and post-treatment surveillance. In the vast majority of cervical cancers a persistent infection with high-risk HPV types (hrHPV) has been proven to be the causative agent in their carcinogenesis. Besides almost all cervical squamous cell carcinomas, approximately 95% of all cervical adenocarcinomas (ACs) are caused by a transforming infection with a hrHPV type. The remaining ACs are rare and sometimes seem hrHPV-unrelated, which could be caused by detection error or because these tumours are indeed caused by another, not HPV-related carcinogenic mechanism. Chapter 2 describes the attribution of hrHPV in cervical clear-cell adenocarcinoma (CCAC), relatively rare tumours (<<1% of all cervical carcinoma). These tumours have a bimodal age distribution with one peak in the early twenties and another after menopause and are characterised by clear cytoplasm and Hobnail cells. In approximately 60% of the cases this tumour has been associated with intrauterine exposure to diethylstilbestrol (DES), a synthetic oestrogen in the past (falsely) used to prevent miscarriages. In this study of 28 women with CCAC, of whom 15 were DES-exposed in utero, hrHPV was found in 13 (46.4%) tumours. However, after performing immuno-histochemistry with p16INK4a and p53 to distinguish transient hrHPV infections from transforming, carcinogenic infections, only three carcinomas remained in which a causal relation of hrHPV and CCAC was plausible. This demonstrated a very limited role of hrHPV in the carcinogenesis of CCAC. None of the hrHPV-associated tumours were found in women prenatally exposed to DES. In DES-unrelated tumours only a minority (20-25%) seemed hrHPV mediated. In the Dutch population-based screening programme approximately 2.5% of screened women have borderline or mild dysplasia (BMD, PAP2/3a1). These women are retested after 6 months with either cytology of a combination of both cytology and HPV (co-testing), and after 18 months with cytology. If the tests remain abnormal, women are referred for colposcopy. However, not all women with BMD comply with this protocol. Many studies have examined the short-term value of hrHPV-testing in predicting the cumulative risk of CIN3+. In Chapter 3 we have evaluated the long-term cumulative CIN3+ risk in a group of 342 women with an abnormal cytological test result (≥ BMD). These women were followed for a time period of 17 to 19.5 years after detection. Immediate hrHPV-testing clearly stratified the CIN3+ risk; almost all CIN3+ lesions (97.1%) were found in women who tested hrHPV positive. Almost half of all hrHPV-positive women were infected with HPV16; these women had a significantly higher CIN3+ risk than women infected with other hrHPV types. This risk difference between HPV16-positive women and women positive for other hrHPV types, was only found in younger women (<30 years). In older women (≥30 years) the risks in both age groups were similar. The 5-year CIN3+ risk was lower in women who had cleared the virus within 6 months than in women with persistent hrHPV infections (2.2% versus 56.0%), with the highest risks for women with a persistent HPV16 infection (67%). We stratified the CIN3+ risks according to referral cytology and found that both women with BMD and women with >BMD referral cytology had an increased risk of developing CIN3+ within the first 5 years after detection. This risk was twice as high in women with >BMD compared to women with BMD (45% versus 22%). In the subsequent 5 years an increased risk (3.5%) remained for women with >BMD, while for women referred with BMD this risk was with 0.7% similar to that of the general population. Immediate (or delayed, i.e. after 6 months) hrHPV testing clearly stratified the risk in women with BMD; the 5-year risk in hrHPV-negative women was 0.01%, and in hrHPV-positive women 37.5%. Therefore we support the strategy to refer hrHPV-negative women with BMD to routine screening and to refer those who are hrHPV positive for additional testing or colposcopy. When these women do not develop CIN3+ within 5 years, they also may be referred to population-based screening. Additional (baseline) hrHPV-testing in women with >BMD did not result in a group with a risk low enough to refrain from colposcopy, therefore we do not advocate hrHPV testing in this group and advise to refer all these women for colposcopy. As their CIN3+ risk is elevated for at least 10 years, long-term monitoring is required. Chapter 4 focuses on women treated for high-grade cervical disease (CIN2/3). As over 10% of treated women will develop residual/recurrent (post-treatment) high-grade cervical disease, they are closely monitored by cytological testing after treatment. Most published studies concern the risk-assessment of developing post-treatment disease up to a maximum of two years. Currently, treated women in the Netherlands are referred to population-based screening when they have three consecutive negative cytological test results after treatment. This means that it would take at least another three years before women are invited for population-based screening again. In order to evaluate the safety of the current regimen, long-term follow up data is essential. Also because in several other countries yearly follow-up for up to 10 years after treatment. As successful treatment is associated with the elimination of hrHPV, hrHPV testing has been suggested as an improvement in post-treatment surveillance. In Chapter 4.1 a multi-cohort study is described that includes 435 women followed between 5 and 21.5 years after treatment. Different post-treatment test algorithms were analysed; sole cytological testing, sole hrHPV-testing and combined testing with both cytology and hrHPV (co-testing). The overall 5-year CIN2+-risk in this cohort was 16.5%. However, in women who tested consecutively negative for cytology (at 6,12 and 24 months after treatment) this risk was lowered to 2.9% and even to 1.0% in women who tested negative for co-testing at both 6 and 24 months after treatment. The risk of developing CIN3+ in treated women with three consecutive negative cytological test results is similar to the risk of developing high-grade cervical disease in women who test negative for cytology (PAP1) in population-based screening. However, by adding hrHPV-testing to post-treatment surveillance, a better risk-assessment could be reached with even fewer visits. In order to judge the results found in this multi-cohort study, studies which compared different surveillance methods (cytology, hrHPV or co-testing), tested six months after treatment, were systematically reviewed in Chapter 4.2. After a bibliographic database search, relevant studies published between January 2003 and May 2011 were identified by two reviewers with a multi-step process. Then the selected studies were methodological assessed with a modified version of the QUADAS tool (QUality Assessment of Diagnostic Accuracy Studies). Eventually, only eight out of 2410 identified studies remained, incorporating 1513 treated women. The sensitivity of hrHPV testing to predict post-treatment CIN2+ was significantly higher than of cytology (relative sensitivity 1.15; 95%CI 1.06-1.25), while the specificity of these tests was similar (relative specificity 0.95, 95%CI 0.88-1.02). The sensitivity of co-testing was the highest (95%), however this combined test had the lowest specificity (67%). In summary, this review supports the inclusion of hrHPV testing in post-treatment monitoring protocols. The general discussion in Chapter 5 summarizes the findings of this thesis and discusses possible future prospects and clinical consequences.