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 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%.
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.
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.
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 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.
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.
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.
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.
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.