In a surveillance study in Jakarta, Indonesia, 88 typhoid and 26 paratyphoid fever patients were identified by blood culture. Risk factors for transmission of typhoid fever were mainly intra... Show moreIn a surveillance study in Jakarta, Indonesia, 88 typhoid and 26 paratyphoid fever patients were identified by blood culture. Risk factors for transmission of typhoid fever were mainly intra-household factors (poor hand-washing hygiene, recent household contacts), whereas paratyphoid was mainly contracted through street food. In an additional study, street vendors observed poorer hand-washing and food-handling hygiene compared to food handlers in restaurants, and had higher bacterial loads in dishwater. Further host factor-studies in (para)typhoid patients revealed that polymorphisms in genes encoding pro-inflammatory cytokines (IFN-_, IL1A/B, IL1R1, TNFRSF1A, CASP1 and CRP) were not associated with susceptibility to typhoid fever, and might therefore at most be associated with severity of disease. An association was found of typhoid fever and a polymorphism in the PARK2/PACRG proteasome-mediated protein degradation pathway through ubiquitination, similar to infection with Mycobacterium leprae. Also an association between genotypes in the Cystic Fibrosis Transmembrane Conductance Regulator (the affected protein in Cystic Fibrosis) and susceptibility to typhoid fever was found, suggesting a decreased adherence potential of S. typhi to intestinal mucosal cells with these polymorphisms. Finally, bacterial characteristics were compared by use of AFLP and biochemical/antibiotic susceptibility profiles, showing very homogeneous S. typhi and S. paratyphi A strains circulating in the study area. Show less
Chronic kidney disease (CKD) is a progressive disease associated with increased morbidity and mortality. Different therapeutic interventions in the course of CKD are shown to be effective in... Show moreChronic kidney disease (CKD) is a progressive disease associated with increased morbidity and mortality. Different therapeutic interventions in the course of CKD are shown to be effective in slowing or preventing disease progression. This thesis focused on the progression of CKD from pre-dialysis to dialysis. The main conclusions of this thesis are: A positive first-degree family medical history of diabetes mellitus and cardiovascular disease is associated with increased mortality in the first year of pre-dialysis care, but not with decline of kidney function. Second, increased serum phosphorus levels, but not serum calcium levels, are associated with a shorter dialysis-free survival in the first two years of pre-dialysis care. Furthermore, increased phosphorus levels at start of pre-dialysis care are associated with the rate of decline of kidney function. Third, late referral to pre-dialysis care is associated with increased mortality in the first year of dialysis. Fourth, the decline of kidney function is constant in the period of one year before dialysis initiation until two to four months of dialysis therapy. After that period, the rate of decline of kidney function decreases. Finally, in contrast to common believe, in dialysis patients, cardiovascular and noncardiovascular mortality are equally increased. Show less
For part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and... Show moreFor part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and decreased with age. Also, 30-day and one-year excess mortality decreased over the years for colon and rectal cancer. After surviving the first postoperative year, the survival of surgically treated older patients aligned with their younger counterparts, except for patients with stage III disease. Part II describes the results of the analyses of the RAPIDO trial. DRTF decreased from 30% in the standard-care group to 24% in the experimental group at 3 years after randomisation, mainly due to a decrease in DM, which is probably due to better compliance preoperatively and perhaps due the earlier treatment of micrometastases in the treatment process. Although patients with DM in the experimental group had worse survival compared to patients in the standard-care group, the cumulative probability of overall survival remained comparable for both treatment groups. If the patients with a complete response can be identified during reassessment after neoadjuvant therapy, surgery may be omitted, a W&W after a cCR with an appropriate follow-up has no additional oncological risk in young patients compared to older patients (part III). This opens the door for potential organ preservation. 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
Spondyloarthritis comprises a heterogeneous group of distinct disorders including ankylosing spondylitis, non-radiographic axial spondyloarthritis, psoriatic arthritis, arthritis related to... Show moreSpondyloarthritis comprises a heterogeneous group of distinct disorders including ankylosing spondylitis, non-radiographic axial spondyloarthritis, psoriatic arthritis, arthritis related to inflammatory bowel disease and reactive arthritis. Spondyloarthritis is the second most prevalent form of chronic inflammatory arthritis, with an estimated prevalence of about 0.5-1.5%. The studies presented in this thesis cover many aspects related to Spondyloarthritis in Colombia. The following topics were addressed. First, the analyses and performance of the different classification criteria and the factors important in the decision of the rheumatologist to order an MRI or HLA-B27 test in the diagnostic work-up of spondyloarthritis in the context of the clinical rheumatology setting. Second, a better insight was obtained with regard to the presence of comorbidities and risk factors of patients with spondyloarthritis. This included also a case control study to evaluate the relationship between periodontitis and spondyloarthritis. Third, the translation and cross-cultural adaptation to Spanish of the ASAS-HI was performed. Adittionally, the implementation of the domains and instruments of the ASAS core set in clinical trials have been evaluated. Finally, we discuss the potential unmet needs in the field of rheumatology in Colombia and we propose a research agenda for the upcoming years. Show less
The research provides insight into disease behavior in both rural and semi-urban areas in Serengeti in Tanzania. It focuses on the motives and behaviors that patients exhibit when relying on local... Show moreThe research provides insight into disease behavior in both rural and semi-urban areas in Serengeti in Tanzania. It focuses on the motives and behaviors that patients exhibit when relying on local healthcare systems, classified as traditional, transitional or modern. It describes the availability, accessibility and patterns of use of these healthcare systems, in particular how they are embedded in the local cultural heritage. It shows that behavioral patterns are dominated by psycho-social and cultural factors. In addition, background characteristics, intervening factors and situation-dependent factors that influence usage patterns are described, analyzed and explained. The analytical model based on the school of "Ethnoscience" shows where the use of these medical systems is related to the historical, cultural and economic factors that determine the daily lives of the inhabitants. The analysis of the research data provides recommendations for education and training of local middle management staff in support of integrated transcultural public health policy, as initiated by the local government of Serengeti in collaboration with the local training institutions. The findings are used as input for the intended master course in Transcultural Public Health Management in the area, and elsewhere in similar circumstances. Special attention is paid to the local medical knowledge, beliefs and practices of the target population to improve public health. Show less
We investigated the clinical and radiographic disease course of hand osteoarthritis as well as determinants of poor clinical outcome and radiographic progression over a period of six years in 289... Show moreWe investigated the clinical and radiographic disease course of hand osteoarthritis as well as determinants of poor clinical outcome and radiographic progression over a period of six years in 289 patients with hand osteoarthritis. Because these patients had osteoarthritis at multiple joints this enabled us to not only assess the association between progression of osteoarhtiritis in different hand joints groups but also between progression of hand osteoarthritis and osteoarthritis change at the knee. In addition, genetic factors in hand osteoarthritis progression were investigated as well as the influence of illness perceptions. The hand osteoarthritis subsets erosive osteoarthritis and thumb base osteoarthritis are further characterised. In the last part of the thesis the clinimetric properties of a pain score for osteoarthritis and radiographic outcome measures for hand osteoarthritis are evaluated. Show less
Worldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of... Show moreWorldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of preventive and curative strategies for cardiometabolic disease is eagerly warranted. With the studies describes in this thesis, we aimed to disentangle the interwoven physiological, environmental and genetic factors that determine cholesterol and energy metabolism to increase our understanding of their contribution to cardiometabolic disease risk. The first part of this thesis focussed on the cholesteryl ester transfer protein (CETP). The lipid transfer properties of CETP induce a proatherogenic lipoprotein profile. Therefore, CETP inhibitory molecules have been developed and tested in clinical trials for their capability to improve the lipoprotein profile and reduce CVD risk. To fully understand the role of CETP in CVD, its physiology and biological function should be fully unravelled. The focus of the second part of this thesis was on the role of energy metabolism in cardiometabolic health. Specifically, we aimed to study the association of environmental and genetic factors, which were previously described to influence brown adipose tissue (BAT) activity, with energy expenditure and disease outcomes. Show less
This thesis investigates the validity and usefulness of physician's preference-based instrumental variable analysis in clinical epidemiological studies. Chapter 2 describes a survey amongst general... Show moreThis thesis investigates the validity and usefulness of physician's preference-based instrumental variable analysis in clinical epidemiological studies. Chapter 2 describes a survey amongst general practitioners, showing substantial variation in prescribing preference and showing prescribing patterns which suggest the stochastic monotonicity assumption may be plausible for physician's preference as an instrumental variable. Chapter 3 describes an application of physician's preference-based instrumental variable analysis in a moderate-sized study, showing uninformatively wide confidence intervals which limit the usefulness of instrumental variable analysis in this setting. Chapter 4 focuses on the bias-variance trade-off of instrumental variable analysis in comparison to conventional analyses, using simulations and theoretical derivations. Chapter 5 compares instrumental variable and conventional estimates of the effect of third versus second generation oral contraceptives on occurrence of venous thromboembolism. The similarity of these estimates under different sets of assumptions suggests major confounding is unlikely. Chapter 6 contains a suggestion for an additional step for reporting of instrumental variable analyses. The focus shifts to Mendelian randomisation in the second part of the thesis. Chapter 7 reviews the methodological approaches used in Mendelian randomisation studies and the quality of reporting. Chapter 8 shows that collider-stratification bias may exist in Mendelian randomisation studies in elderly populations. Show less
The fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved... Show moreThe fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved identification of patients with an unfavourable prognosis, early in their treatment course, which may facilitate proactive approaches to improve outcomes. We discussed two conceptually distinct constructs of predictors of prognosis in order to improve the identification of patients with an unfavourable prognosis. First, the level of control of the chronic condition as a predictor could reflect to some extent the presence of a multitude of other risk factors. Second, information on early treatment response had better predictive ability for long-term outcomes and so acts as a proxy for treatment effectiveness. Treatment effectiveness depends on different aspects e.g. adequateness of initial treatment and/or drugs, the mutual trust between clinician and patient and behavioral aspects such as treatment adherence. Treatment response adds an insight that can be acted upon; guiding personalized decisions in the treatment plan. In conclusion, this thesis leads to improvement of personalized medicine and thereby could increase the efficient use of healthcare resources, with the early identification of patients at risk of an unfavourable prognosis. Show less
C. Caram-Deelder’s thesis explores the potential of secondary data – data that was generated for a different purpose than the research itself - to answer questions regarding safety and efficacy of... Show moreC. Caram-Deelder’s thesis explores the potential of secondary data – data that was generated for a different purpose than the research itself - to answer questions regarding safety and efficacy of blood products. By combining datasets of several hospitals, she demonstrated that receiving red cell transfusions from a female donor who has been pregnant is associated with increased mortality among male patients under the age of 50. Also using data from hospitals she demonstrated that old platelets shorter the time between platelets transfusions, resulting in an increased total number of transfusions on a population level. This increase is, however, unlikely to outweigh the benefit of reduced outdating and wastage. By meta-analysing studies it is shown that old platelets are inferior to fresh platelets for platelet related counts, time between transfusions and the need of additional platelet transfusions. Additionally the thesis discusses the methodological issue of the use of the terms ‘prospective’ and ‘retrospective’ in clinical observational research. These terms are still broadly used in spite of the recommendation to refrain from using them by guidelines and journals’ editorial boards. The usage of the terms was, however, not associated with the quality of the report. Show less
This thesis focuses on the incidence and risk factors for nephropathy in diabetic and non-diabetic Surinamese South Asians. The Surinamese South Asians, originally descended from the North-East... Show moreThis thesis focuses on the incidence and risk factors for nephropathy in diabetic and non-diabetic Surinamese South Asians. The Surinamese South Asians, originally descended from the North-East India. Due to the former colonial bounds with the Netherlands, a relatively young South Asian migrant population settled in the Netherlands. South Asians have a high prevalence of central obesity and an eight-fold higher prevalence for type 2 diabetes mellitus. We found the following conclusions: 1.Surinamese South Asian persons have a nearly 40-fold higher risk for end-stage diabetic nephropathy in comparison to Dutch European persons. 2.There was no familial predisposition for diabetic nephropathy among South Asian families. 3.South Asian type 2 diabetic patients have a three-fold higher risk for diabetic nephropathy and faster progression of renal insufficiency in comparison to Dutch European patients. 4.Central obesity is an early and independent risk factor for increased albuminuria in normoglycemic South Asian subjects. We assume that the nearly 40-fold higher risk of end-stage diabetic nephropathy in South Asian migrants is primarily caused by central obesity which leads to: a. Early renal injury in the pre-diabetic state. b. Eight-times higher prevalence of type 2 diabetes mellitus. b. More diabetic nephropathy and faster decline in renal function. Show less
Thromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it... Show moreThromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it at the same time increases risk of bleeding. With nationwide data from Statistics Netherlands, antithrombotic therapy and relevant clinical outcomes were comprehensively examined in the patient population of atrial fibrillation, overall or among those with comorbid cancer. The results suggest the patient population was increasingly receiving anticoagulants, driven by the newly introduced medication- direct oral anticoagulant and guided by the CHA2DS2-VASc score, and meanwhile the patient population experienced fewer ischemic stroke and major bleeding. In spite of these promising changes, suboptimal medication adherence and potential underuse of anticoagulants remain directions for further improvement. Antithrombotic agent use during pregnancy was also examined in the general Dutch pregnant population, which featured a surge in antiplatelet prescriptions, and risk of preeclampsia/eclampsia decreased and several newborn outcomes improved simultaneously. Together, the studies presented in this thesis provide an overview of antithrombotic therapy in the Netherlands in recent years, providing insights for further improving this treatment and relevant patient outcomes. Show less
This thesis addresses potential threats to the validity of observational epidemiological studies. Examples of these potential sources of bias are confounding, missing data, selection bias, and... Show moreThis thesis addresses potential threats to the validity of observational epidemiological studies. Examples of these potential sources of bias are confounding, missing data, selection bias, and measurement error. Although various methods have been developed to mitigate these biases, it is often unclear which methods can be used in which empirical settings. It is also common that issues discussed in methodological studies are overlooked in clinical research. Thus, we investigated problems ofmissing data, selection bias, and measurement error occurring in several specific observational settings and discuss how to optimally handle them. Show less
The aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as... Show moreThe aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as adipokines, inflammation, HDL-cholesterol and postprandial triglyceride response, and cholesteryl ester transfer protein (CETP). We showed that hs-CRP and GlycA as measures of inflammation, adiponectin, and leptin are not associated with clinical and subclinical cardiovascular disease in the general population. However, all may be relevant markers of disease risk. Also, postprandial triglyceride excursions, genetically-determined CETP and HDL-cholesterol, while not related with subclinical atherosclerosis in the general population, may be interesting targets to pursue in women and men separately, and in subgroups of individuals at high-cardiovascular risk. Show less
Studies in this thesis were performed in a secondary care cohort of patients with hand osteoarthritis. Several factors were investigated for their association with disease status and disease... Show moreStudies in this thesis were performed in a secondary care cohort of patients with hand osteoarthritis. Several factors were investigated for their association with disease status and disease progression after two years. These factors included comorbidity, illness perceptions and MRI-defined inflammatory features such as bone marrow lesions, synovitis and joint effusion. In the MRI studies we found that these MRI-features have a clinically relevant role for their association with pain (at the same moment and after two years) and progression of radiographic damage after two years. In the second part of this thesis we evaluated the clinimetric properties of two new instruments: self-reported painful joint count and semi-automatic joint space width measurements. Show less
Since a decade, Clostridium difficile infection (CDI) has increased progressively in incidence and severity of disease. Currently, CDI is considered the leading cause of nosocomial diarrhoea,... Show moreSince a decade, Clostridium difficile infection (CDI) has increased progressively in incidence and severity of disease. Currently, CDI is considered the leading cause of nosocomial diarrhoea, associated with an increased duration of hospitalization, healthcare expenses, morbidity and mortality. This thesis describes our findings with outbreak control, diagnosis, identification of specific risk factors and treatment of CDI after the discovery of the emergence of C. difficile PCR-ribotype 027 in the Netherlands. The studies illustrate the role of antibiotics in relation to persistence, severeness and spreading of CDI. Antibiotics are shown to be a primary risk factor for the development of (ribotype-specific) CDI and an essential part of the outbreak control measures (__bundle-approach__), namely antibiotic stewardship. The use of antibacterials is a risk for selection of novel endemic C. difficile strains in e.g. animals, which introduce an increasing risk of alternative zoonotic transmission routes. Except for very mild CDI, which is clearly induced by usage of specific antibiotics, antibacterial treatment is advised. This thesis reviews the comparative effectiveness of the currently available treatment modalities, thereby providing evidence-based recommendations for CDI remedies. Treatment options include: oral and non-oral antibiotics, toxin-binding resins and polymers, immunotherapy, probiotics, faecal or bacterial intestinal transplantation. Show less
Clostridium difficile infection (CDI) was discovered in 1978 as an important cause of antibiotic-associated diarrhoea. CDI became the most common healthcare-associated infection in Northern-America... Show moreClostridium difficile infection (CDI) was discovered in 1978 as an important cause of antibiotic-associated diarrhoea. CDI became the most common healthcare-associated infection in Northern-America and Europe during the antibiotic era, especially after global spread of a fluoroquinoloneresistant ribotype 027 strain in 2003. The rise of CDI urged the use of epidemiological surveillance systems to monitor disease dynamics and rapidly detect outbreaks. However, valid estimations of the infection burden of CDI in Europe were hampered by the heterogeneity and insufficiency of diagnostic algorithms for CDI, lack of standardised typing systems and incomplete surveillance methodologies. This thesis includes two studies conducted within a project named ‘the European CDI Surveillance Network’ focussing on enhancement of CDI surveillance and laboratory capacity for CDI in Europe. In the Netherlands, a sentinel surveillance system monitors the incidence of CDI in hospitals. This thesis describes (spatial) trends in the epidemiology of CDI in the Netherlands, in particular for children and the potentially zoonotic C. difficile ribotype 078. Data of a community-based case-control study was used to apply spatial scan statistics to detect CDI clustering beyond the hospital setting. Finally, this thesis provides directions for future epidemiological surveillance systems of CDI, both in the Netherlands and Europe. Show less
Assessing metabolic risk in dialysis patients, three main aspects are important: a) the pathophysiologic effects of metabolic disturbances as known from the general population are unlikely to... Show moreAssessing metabolic risk in dialysis patients, three main aspects are important: a) the pathophysiologic effects of metabolic disturbances as known from the general population are unlikely to completely reverse once patients reach dialysis. b) Specific additional problems related to chronic kidney disease, in particular protein-energy wasting, may act as “competing risk”, overshadow effects and interfere in various hormonal regulations. c) In advanced chronic kidney disease, the pattern and composition of risk is changing. The aim of this thesis is to 1) Detect specific effects of metabolic alterations in dialysis patients 2) Provide explanations for conflicting results in the literature 3) Provide a rationale for novel interventions. In this thesis, the metabolic status of dialysis patients is adressed and its consequences for the decline in residual kidney function, cardiovascular events and survival. The metabolic status includes alterations in nutritional and hormonal status, focussing on: lipid metabolism, diabetes mellitus type 2, obesity, the role of adipokines, specific effects of protein-energy wasting, and Vitamin D status with the clinical consequences. The investigations are performed in two large cohorts of dialysis patients, the 4D and NECOSAD studies (The German Diabetes and Dialysis Study and The Netherlands Cooperative Study on the Adequacy of Dialysis). Show less
