Anorectal disorders are common in general practice and the incidence of chronic anal fissure is 2.5 cases per 1000 persons in the Netherlands. A chronic anal fissure (CAF) refers to a longitudinal... Show moreAnorectal disorders are common in general practice and the incidence of chronic anal fissure is 2.5 cases per 1000 persons in the Netherlands. A chronic anal fissure (CAF) refers to a longitudinal ulcer or tear in the squamous epithelium, generally located in the posterior midline with symptoms present for longer than 4-6 weeks or recurrent fissures. The classical symptom is pain during defecation, which may persist for hours, and has a significant impact on quality of life.Although some debate exists on the pathogenesis of CAF, it is assumed that pain causes an increased anal sphincter tone leading to ischemia which inhibits fissure healing, generating a vicious circle of pain and constipation.Pelvic floor dysfunction e.g., dyssynergia and/or increased pelvic floor muscle tone may also be an underlying cause and part of the pathophysiology and a reason for unresponsiveness to treatment.A digital rectal examination including examination of the pelvic floor muscles and a comprehensive evaluation of the pelvis and surrounding structures is important to determine the underlying cause of pain and pelvic floor dysfunction.According to current guidelines, the initial conservative management is comprised of fibre intake and/or use of laxatives, toilet behaviour, lifestyle advice, sitz baths, and ointments.In the Pelvic floor Anal Fissure (PAF) study, we demonstrated that pelvic floor physical therapy yields a significant and clinical benefit in the time course and should be advocated as adjuvant conservative treatment in patients with CAF. Show less
Even after thousands of years of experience in treating patients with TBI, decisions regarding the optimal treatment strategy remain difficult for both healthcare workers as policy makers. The... Show moreEven after thousands of years of experience in treating patients with TBI, decisions regarding the optimal treatment strategy remain difficult for both healthcare workers as policy makers. The first part of this thesis investigated the challenges of the treatment decision-making process in patients with (severe) TBI by focussing on three factors considered to be important in this process: patient outcome, in-hospital healthcare consumption, and in-hospital costs. The second part investigated the procedural difficulties in TBI research efficiency by focussing on the process of institutional review board approval and the use of informed consent procedures in patients with TBI with an inability to provide informed consent. Finally, we elaborate on the role of patient outcome and in-hospital costs in the acute treatment decision-making process in patients with severe TBI and make suggestions to optimize future research initiatives. Show less
In this thesis we aimed to investigate ways to optimize treatment strategies and the choice of treatment for individual patients, to be implemented in a worldwide context. Although major advances... Show moreIn this thesis we aimed to investigate ways to optimize treatment strategies and the choice of treatment for individual patients, to be implemented in a worldwide context. Although major advances have been made in the treatment of RA, it is still uncertain which treatment is the best choice for each individual patient. This can result in both overtreatment and undertreatment, increasing the burden of RA for patients as well as for society. In clinical trials and daily practice there appears to be a development towards earlier treatment, with higher dosages of medication and more stringent treatment targets. In part 1 of this thesis, some of these developments were investigated and challenged. In countries across the world, patients do not benefit similarly from recent advances in the treatment of RA. In part 2 of this thesis, we aimed to identify contributing factors to inequalities in access to treatment and care and clinical outcomes across countries, as a first step towards improvement. Show less
The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED)-study is a multicentre two-step randomized single-blinded clinical trial in 610 early... Show moreThe Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED)-study is a multicentre two-step randomized single-blinded clinical trial in 610 early rheumatoid arthritis (RA) and undifferentiated arthritis (UA) patients. Intensive induction therapy (methotrexate (MTX) and a tapered high dose of prednisone) was started in the first 4 months. Treatment adjustments aimed at clinical remission (Disease Activity Score (DAS)<1.6): if DAS<1.6, medication was tapered and stopped, if DAS≥1.6, medication was intensified or restarted. Patients not in DAS-remission after 4 months were randomized to triple therapy (MTX, hydroxychloroquine and sulfasalazine) with prednisone (arm 1) or MTX+adalimumab (arm 2).After 4 months 61% was in DAS-remission (early DAS-remission group). After 5 years, 48% were in DAS-remission and 22% in drug-free remission (DFR). Patients in early DAS-remission group had better functional ability and more often achieved DAS-remission and DFR than patients that were randomized, without differences between the arms. UA patients had lower DAS and less autoantibody positivity at baseline compared to the RA patients. DAS-remission percentages were comparable between RA and UA patients, but more UA patients did achieve DFR (33% vs 19%). Autoantibody (rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA)) negative patients more often achieved DFR. Show less
The main objective of this thesis was to evaluate the role of new advanced multimodal CT imaging techniques in acute ischemic stroke.Important findings are that collateral assessment with dynamic... Show moreThe main objective of this thesis was to evaluate the role of new advanced multimodal CT imaging techniques in acute ischemic stroke.Important findings are that collateral assessment with dynamic CT angiography (CTA) better predicts radiological outcome and clinical outcome compared with conventional single-phase CTA. Dynamic CTA also enabled us to study dynamic cortical venous outflow in stroke which had not been described before. We have shown that venous outflow, as assessed with dynamic CTA, is a new predictor of functional outcome in acute large vesselvanterior circulation stroke. By combining the extent and velocity of optimal CVF, we observed a decreased risk of poor outcome in patients with good and fast optimal CVF. Moreover, we have demonstrated an interaction between IAT treatment effect and cortical venous filling which could potentially be useful for future treatment decision-making. Show less
Narcolepsy is a disorder of the regulation of sleep and wakefulness, with as its major features excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and... Show moreNarcolepsy is a disorder of the regulation of sleep and wakefulness, with as its major features excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. The first part of this thesis concernes an overview of the pathophysiology, symptoms and treatment of narcolepsy type 1. The second part elaborates some pathophysiological aspects, focussing on the autoimmune hypothesis of narcolepsy. The third part focuses on alterations of temperature regulation and on measuring treatment effects of symptomatic treatment on sustained attention, i.e. vigilance. Show less
The general aim of this thesis is to investigate small fiber neuropathy in sarcoidosis and to asses whether ARA290 is a possible new agent to treat the neuropathic complaints in sarcoidosis... Show moreThe general aim of this thesis is to investigate small fiber neuropathy in sarcoidosis and to asses whether ARA290 is a possible new agent to treat the neuropathic complaints in sarcoidosis population. The results of the various ARA290 trials in painful sarcoidosis are discussed. Painful neuropathy is common, difficult to treat complication.The limited efficacy of current treatment options dictates a rationalized design of novel compounds. ARA290 treatment was consistently associated with a significant improvement of neuropathic pain symptoms in sarcoidosis patients, evidenced by a decrease in pain scores on validated questionnaires. Moreover,ARA290 treatment resulted in significant increases in corneal nerve fibers, improved sensory pain thresholds,improved quality of life and physical functioning. Given the excellent safety profile while reducing neuropathy symptoms,the prospects of ARA290 treatment in sarcoidosis related neuropathy seem promising.The long lasting beneficial effects of ARA290 on both pain related and non pain related symptoms in sarcoidosis patients prompt additional studies on potential disease modifying properties of ARA290. The data collected so far suggest that ARA290 will be equally effective in SFN associated with other syndromes, including diabetes mellitus. Show less
Parents are increasingly viewed as key to successful child (semi-) residential treatment. Positive outcomes for both the parents as the child with a psychiatric disorder are more likely to occur... Show moreParents are increasingly viewed as key to successful child (semi-) residential treatment. Positive outcomes for both the parents as the child with a psychiatric disorder are more likely to occur when effective levels of therapeutic alliances exist between team members and parents. Unfortunately, it remains unclear from the literature, how the establishment of the parent-treatment team alliance best contributes to child residential treatment outcome. Therefore, a more systematic approach is needed to help practitioners.The aim of this thesis is threefold: 1. Development of assessment strategies (instruments) of the parent-team alliance, 2. Longitudinal investigation of the relation between parent-team therapeutic alliance and semi-residential treatment outcome factors and 3. Examining the effect of strengthening the parent-team alliance on (semi-) residential treatment outcomes. Routine Outcome Monitoring was implemented at five semi-residential treatment units of Curium-LUMC, a Centre for Child and Adolescent Psychiatry. All newly admitted children and their parents, 46 children (6-12 years old) in total, were included in the ROM assessment. Results showed: 1)Alliance instruments are capable of assessing the parent-team alliance; 2)Parent-team alliance, parental stress and child'symptoms are interconnected, and 3)A structured investment of team members in the parent-team alliance strenghtens this alliance and positively indfluences childs'symptoms. Show less
Clavicular fractures are among the most common fractures of the shoulder. Displacement or comminution of the fracture fragments may lead to shortening of the clavicle, but could also cause mal... Show moreClavicular fractures are among the most common fractures of the shoulder. Displacement or comminution of the fracture fragments may lead to shortening of the clavicle, but could also cause mal-union or non-union of the clavicle and might lead to poor functional outcome. These fracture characteristics are therefore important in clinical decision making. The diagnostic aspects of clavicular fractures are evaluated in the first part of this thesis, whereas the second part describes studies on treatment and clinical outcomes. The third part of these thesis focuses on the complex biomechanics of the shoulder after a displaced midshaft clavicular fracture. The findings on diagnostic aspects underline the importance of fracture characteristics for classification and of two-view radiography for treatment decisions for clavicular fractures. Clavicular shortening after a midshaft clavicular fracture is deemed the most important factor in deciding whether or not to operate, but no clinically relevant changes after clavicular shortening in the scapular kinematics and functional outcome were demonstrated. Clavicular shortening should therefore not be used as the only reason to justify operative treatment. Show less
Clostridium difficile is a spore-forming bacterium, the toxin-producing strains of which cause colitis. Risk factors are antibiotics, advanced age and severe comorbidity. C. difficile infection ... Show moreClostridium difficile is a spore-forming bacterium, the toxin-producing strains of which cause colitis. Risk factors are antibiotics, advanced age and severe comorbidity. C. difficile infection (CDI) has been regarded as mostly a hospital-acquired infection. Preventing relapses is considered the biggest challenge in CDI management. In this thesis, we show that CDI occurs in Dutch general practices, often in patients without contact with hospitals. Also, we show that the emerging virulent strain PCR ribotype 027 has not become dominant in European hospitals, but community-associated type 078 has become highly prevalent. Furthermore, we found that cystic fibrosis outpatients are frequently colonized with C. difficile, though mostly with nonpathogenic strains. Thus, acquisition of C. difficile in the community appears more important than previously thought. Next, we show that renal failure at the time of diagnosis predicts relapses. In addition, patients who fail to develop antibodies against C. difficile toxins have a higher chance of relapse. We describe an experimental product derived from the milk of cows vaccinated against C. difficile and its toxins, which might prevent relapses. The last part of the thesis consists of the European guideline for CDI treatment and its recent update Show less
In contrast with the intuitive feeling of physicians many worrisome MRI findings do not correlate with patient outcome in patients with sciatica. Physicians should for example not automatically... Show moreIn contrast with the intuitive feeling of physicians many worrisome MRI findings do not correlate with patient outcome in patients with sciatica. Physicians should for example not automatically ascribe persistent or recurrent symptoms of sciatica to the presence of abnormalities visible on MRI. This thesis enables physicians to reshape the mindset of many persons thinking that knowing imaging findings can only be good. Seeing MRI abnormalities of patients with sciatica should not always be believing. Show less
This thesis describes the outcomes an possibilities of drug-tapering in rheumatoid arthritis (RA) patients treated to target. Data from the BeSt cohort were used, in which early RA patients were... Show moreThis thesis describes the outcomes an possibilities of drug-tapering in rheumatoid arthritis (RA) patients treated to target. Data from the BeSt cohort were used, in which early RA patients were randomized to 4 treatment arms: initial monotherapy, sequential or step-up, or initial combination therapy, with prednisone or TNF-blocker infliximab. The disease activity score (DAS) was measured every three months and treatment was changed or added to in case of insufficient response (DAS >2.4). This thesis shows that continued low disease activity steered treatment is possible and leads to maintenance of good functional ability in the majority of patients during 8 years of follow-up. Initial combination therapy is beneficial in the first months of treatment but is not associated with better longer-term results, except in anti-citrullinated protein antibodies positive patients. Initial combination therapy with TNF-blo cker infliximab can be successfully discontinued in over 50% of early RA patients, and in around 20% of all patients, all medication can be stopped when prolonged remission is achieved. Show less
__The non-displaced scaphoid fracture: evaluation of diagnostic modalities & conservative treatment__ Over de diagnostiek en de behandeling van scafo_dfracturen bestaat nog veel verschil van... Show more__The non-displaced scaphoid fracture: evaluation of diagnostic modalities & conservative treatment__ Over de diagnostiek en de behandeling van scafo_dfracturen bestaat nog veel verschil van mening. Een onjuiste of vertraagd ingestelde behandeling kan leiden tot ernstige complicaties. R_ntgenfoto mist een groot deel van de scafo_dfracturen. De botscintigrafie kan gebruikt worden om deze fracturen zichtbaar te maken. Een botscintigrafie is echter invasief en maakt gebruik van radioactief materiaal. Een MRI of CT zou wellicht de botscintigrafie kunnen vervangen. Dit proefschrift beschrijft twee prospectieve studies, waarbij in de eerste studie de botscintigrafie werd vergeleken met de MRI. In de tweede studie werd de botscintigrafie vergeleken met de CT. Beide onderzoeken konden niet aantonen dat de MRI en CT de botscintigrafie kan vervangen. Het probleem is dat beide onderzoeken scafo_dfracturen missen. Ook is onderzocht of een zogenaamde 'clinical prediction rule' te ontwikkelen was, om de a priori kans op een ware fractuur bij een pati_nt met de verdenking op een scafo_dfractuur te verhogen. Analyse liet zien dat er drie voorspellers significant waren: extensie < 50%, supinatiekracht < 10% en het hebben van een fractuur in de voorgeschiedenis. Tenslotte is de behandeling van scafo_dfracturen geanalyseerd. Gekeken is of een kortere behandeling mogelijk was. Normaal wordt een scafo_dfractuur 12 weken ge_mmobiliseerd met een gips. Lange immobilisatie kan klachten veroorzaken. Wij hebben onderzocht of de scafo_dfractuur ook te behandelen is middels een gipsimmobilisatie van 6 weken. Hiervoor werden 98 pati_nten geanalyseerd en na 6 weken bleek 80% te zijn genezen. Wat ook bleek is dat de localisatie met name invloed had op de functionele uitkomst van de behandeling. Om deze functionele uitkomst in beeld te brengen gebruikten we een DASH-score (Disabilities of the Arm, Shoulder and Hand score). De gemiddelde DASH-score was 6 voor 13 distale pool en 5 voor 44 middenpool fracturen. Concluderend kunnen wij stellen dat voor het opsporen van scafo_dfracturen bij pati_nten met een klinische verdenking hierop, de botscintigrafie nog steeds de gouden standaard is. Niet gedisloceerde scafo_dfracturen van de distale middenpool dienen conservatief behandeld te worden middels gipsimmobilisatie gedurende 6 weken. Show less
Major advances have been made in the treatment of rheumatoid arthritis, a potentially chronic disabling disease which poses a large burden on both patients and society. By early start of disease... Show moreMajor advances have been made in the treatment of rheumatoid arthritis, a potentially chronic disabling disease which poses a large burden on both patients and society. By early start of disease-modifying antirheumatic drugs, including methotrexate as a prominent drug, the use of combination therapies including prednisone or biologicals, and tight control of disease activity, many patients are able to reach a state of clinical remission and some can even taper and stop antirheumatic therapy. Challenges lie in correctly identifying the earliest manifestations of the disease, starting the right treatment sufficiently early, tailored to the individual patient, and setting the optimal treatment goal at which to steer therapy adjustments. This thesis has made a start towards tackling several of these challenges and discusses further necessary steps that may lead to a fundamental change in the outlook of patients with rheumatoid arthritis. Show less
Large variation between hospitals and pathology laboratories was demonstrated in adherence to the guidelines. This is associated with type and volume of hospitals and pathology laboratories.... Show moreLarge variation between hospitals and pathology laboratories was demonstrated in adherence to the guidelines. This is associated with type and volume of hospitals and pathology laboratories. However, not all variation could be explained by these characteristics. The aim of this thesis was to identify factors influencing quality of care by investigating the variation in guidelines adherence of patients with colon and rectal cancer in the Netherlands. Considerable variation in lymph node evaluation between hospitals and pathology laboratories was revealed leading to suboptimal staging and potentially inaccurate treatment plans. Furthermore, large differences between hospitals were found in treatment according tot the guidelines. Based on the results of this thesis, it can be conclude that a part of the variation is associated with type and volume of hospitals and pathology laboratories. However, the large differences between individual hospitals suggests that these characteristics do not account for all variation. Therefore, further research is necessary to identify best practices and analyse factors which influence quality of care and outcome. Show less
In criminology, measuring recidivism is a well-known method of establishing the preventive effect of penal interventions. There are measurements of this kind dating from as early as the 19th... Show moreIn criminology, measuring recidivism is a well-known method of establishing the preventive effect of penal interventions. There are measurements of this kind dating from as early as the 19th century. Recidivism studies have been conducted in the Netherlands too, but the earliest we know of stem from the 1970s. Due to developments in public sector fund accounting methods, interest in reconviction rates is now again on the increase. The Dutch government is looking for clear indicators to gauge the success of implemented policy measures. In the area of penal law recidivism, or rather the absence thereof, is readily embraced as a valid and efficient outcome indicator. Under what circumstances do recidivism statistics provide proof of the efficacy of policy interventions? And how can this construct best be measured? In the Netherlands there is no tradition of recidivism research. The methods used in past evaluation studies vary widely, the measurements were predominantly small-scale, and most studies were conducted at a time when the penal interventions under investigation were still at a developmental stage. Recidivism research in the Netherlands has lacked a sound methodological basis and there is consequently no comprehensive view on the outcome of penal interventions – until recently, that is, since the WODC has meanwhile developed a ‘Recidivism Monitor’. This is a project in which reconviction rates of virtually all offenders who have come into contact with the Dutch judiciary are routinely computed. The development of this instrument and its applications in evaluation research form the central themes of this dissertation. Show less
The term primary cutaneous B-cell lymphomas refers to a heterogeneous group of B-cell non-Hodgkin lymphomas, that present in the skin without evidence of extracutaneous disease at the time of... Show moreThe term primary cutaneous B-cell lymphomas refers to a heterogeneous group of B-cell non-Hodgkin lymphomas, that present in the skin without evidence of extracutaneous disease at the time of diagnosis. In recent years, there has been considerable debate regarding the classification and terminology of the group of primary cutaneous B-cell lymphomas and different classification schemes were used. In the new WHO-EORTC consensus classification for cutaneous lymphomas published in 2005, three major groups of primary cutaneous B-cell lymphoma are distinguished: primary cutaneous marginal zone B-cell lymphoma and primary cutaneous follicle center lymphoma with a good prognosis, and primary cutaneous diffuse large B-cell lymphoma, leg type with an intermediate prognosis. Studies presented in this thesis focus on three aspects of these primary cutaneous B-cell lymphomas: (1) the clinical usefulness of the WHO-EORTC classification in daily practice, (2) the validity of prognostic parameters reported in previous studies and identified in patient groups classified according to previously used classification schemes and (3) optimal management for the different types of primary cutaneous B-cell lymphomas as defined in the WHO-EORTC classification. Show less
This thesis describes the outcomes of 2 year follow-up of the BeSt study (Behandel-Strategieen). This is a multicenter, randomized clinical trial comparing 4 different treatment strategies in... Show moreThis thesis describes the outcomes of 2 year follow-up of the BeSt study (Behandel-Strategieen). This is a multicenter, randomized clinical trial comparing 4 different treatment strategies in patients with recent-onset active rheumatoid arthritis: 1. sequential monotherapy, starting with methotrexate, switching to another antirheumatic drug in case of an insufficient response; 2. step-up combination therapy, also starting with methotrexate, adding other antirheumatic drugs in case of an insufficient response; 3. initial combination therapy with methotrexate, sulphasalazine and high-dose tapered prednisone; 4. initial combination therapy with methotrexate and infliximab. In all groups the goal was to achieve a disease activity score (DAS) __2.4 (low disease activity). The DAS was measured 3-monthly by a research nurse, blinded for the allocated group. The physician then adjusted therapy according to the protocol. During the 2 year follow-up, groups 3 and 4 had a more rapid clinical response, less joint damage and less treatment adjustments than groups 1 and 2. Interestingly, groups 1 and 2 did better than expected. This is probably the result of aimimg for low disease activity. Most patients prefer treatment with the newest drug. The higher costs of infliximab can largely be compensated by savings on productivity. Show less
Skin carcinomas develop at a high rate in organ-transplant recipients who are kept on immune suppressive drugs to prevent graft rejection. The present study dealt with a broad range of aspects of... Show moreSkin carcinomas develop at a high rate in organ-transplant recipients who are kept on immune suppressive drugs to prevent graft rejection. The present study dealt with a broad range of aspects of this elevated carcinoma risk, starting from the earliest oncogenic events to the ultimate therapy. Advancements on any of these aspects may be of significant benefit to the patient and his/her physician in the management of multiple and progressive skin carcinomas. The studies presented in Chapter 2 - 4 focused on the early pathogenesis of skin cancer in organ-transplant recipients to gain a better understanding of the underlying mechanism(s) of the increased skin cancer risk in these patients. We specifically focused on the role of p53 and beta-PV in early skin carcinogenesis. The clinical studies in Chapter 5 - 7 investigated the management of skin cancer in organ-transplant recipients. Show less
Congenital Human Parvovirus B19 (B19V) infection can lead to life threatening fetal complications as hydrops, fetal demise or severe fetal anaemia and thrombocytopenia. Maternal symptoms frequently... Show moreCongenital Human Parvovirus B19 (B19V) infection can lead to life threatening fetal complications as hydrops, fetal demise or severe fetal anaemia and thrombocytopenia. Maternal symptoms frequently pass unnoticed at the time of maternal infection and there was little information on the mechanism and time course of vertical transmission of B19V during gestation. Treatment consists of intrauterine fetal red blood cell and/ or platelet transfusion (IUT). The indication for treatment with IUT is set by performing fetal ultrasound screening for fetal anaemia and signs of fetal hydrops. The fetal middle cerebral artery peak systolic flow correlates well with the severity of fetal anaemia. The first two chapters of this thesis give an overview of the existing literature concerning fetal hydrops and congenital B19V infection. In the ensuing chapters we describe the course of maternal and fetal B19V infection by the B19V viral load and maternal immune response. We did not find a correlation between the fetal or maternal B19V viral load and the severity of fetal anaemia or thrombocytopenia. Thrombocytopenia is frequently encountered in congenital B19V infection, but fetal bleeding complications are not. The use of fetal platelet transfusion is therefore a matter of debate. The long- term neurodevelopment of affected fetus can be significantly delayed at a later age despite a technically correct IUT procedure. The possibility of cerebral damage due to congenital B19V infection is discussed. Parents should be counselled of these risks before the IUT procedure and long term follow -up following congenital B19V infection is advised Show less
