Pulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades,... Show morePulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades, diagnosing PE is still a difficult process due to the non-specific symptoms, which can frequently overlap with symptoms of other cardiopulmonary diseases. Currently recommended diagnostic strategies for suspected acute PE consist of standardized assessment of the clinical pre-test probability (CPTP) using validated clinical decision rules (CDRs) and D-dimer testing. PE is considered safely ruled out in patients with a non-high CPTP and a normal D-dimer test. Imaging tests as computed tomography pulmonary angiography (CTPA) are required in the case of a high CPTP and/or abnormal D-dimer test to confirm the diagnosis. The first part of this thesis describes the challenges of diagnosing PE in general and in specific clinically relevant patient subgroups. Moreover, this part evaluates the diagnostic performance of non-invasive diagnostic strategies for suspected PE in specific relevant patient subgroups. The second part of this thesis focuses on venous thrombotic complications in hospitalized patients with COVID-19. Show less
The focus of this thesis is the improvement of diagnosis, early detection and treatment of CD in children. Increased knowledge, available guidelines and reliable diagnostics allow for timely... Show moreThe focus of this thesis is the improvement of diagnosis, early detection and treatment of CD in children. Increased knowledge, available guidelines and reliable diagnostics allow for timely diagnosis which can prevent complications and improve QoL, but the current healthcare approach is often unable to make the diagnosis in a timely manner. Moreover, despite timely diagnosis and effective therapy, there is a need to improve the follow up. Show less
Venous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of... Show moreVenous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of upper extremity, abdomen and cerebrum. As symptoms of VTE are nonspecific, the diagnosis of VTE is based on diagnostic tests, including clinical decision rules (CDR), D-dimer tests and imaging. Although the diagnostic management of VTE has greatly advanced in recent years with the introduction of novel CDRs and high-sensitive D-dimer tests, the diagnosis may still be challenging in certain settings. The latter is mainly caused by the indirect way of thrombus visualisation by current imaging tests, such as by showing incompressibility with compression ultrasonography (CUS) or a filling defect on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI).This thesis focuses on challenging settings for diagnosing VTE, including suspected recurrent ipsilateral DVT, upper extremity DVT, cerebral vein thrombosis and portal vein thrombosis. We studied a novel imaging technique called Magnetic Resonance Non-Contrast Thrombus Imaging (MR-NCTI) and its application in these different VTE settings. Show less
Treatment of valvular heart disease changed significantly inthe last two decades. This thesis focuses on diagnosis, patient selection and transcatheter therapies for structural heart disease.
In this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying... Show moreIn this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying it independently of the rheumatologist’s opinion. Our findings likely add knowledge to what axSpA really is. Future studies will learn us how much of these insights will translate into a better recognition of the disease in clinical practice and in better classifying them for research purposes. Since SpA is a slowly progressing disease, several years are needed to see meaningful changes in imaging abnormalities of the axial skeleton, which poses methodological challenges. We have shown that thoughtful analytical approaches, that make best use of imaging data, are helpful in better estimating progression, in unravelling its determinants and in clarify which outcomes are best to monitor disease. Efforts are made to further improve outcome measurement in axSpA, including the development of new imaging techniques, which can benefit from our proposed solutions to long-term imaging scoring. Show less
This thesis comprises immunophenotypic and molecular studies in several types of cutaneous lymphomas. These studies provide a better definition of the clinicopathologic entities and provide... Show moreThis thesis comprises immunophenotypic and molecular studies in several types of cutaneous lymphomas. These studies provide a better definition of the clinicopathologic entities and provide adjunctive diagnostic markers that may aid in diagnosis of these patients in routine diagnostics, including TOX expression in cutaneous T-cell lymphomas and MYC expression and MYC rearrangements in cutaneous B-cell lymphomas (CBCLs). Also, the results demonstrate that adverse prognostic factors in systemic lymphomas are not directly transferrable to cutaneous lymphoma patients, including TP63 rearrangements in primary cutaneous CD30+ lymphoproliferative disorders and double hit status in CBCL, underlining the importance of a separate classification system for cutaneous lymphomas. Finally, these studies may have consequences for the management and treatment of patients with cutaneous lymphomas, because of the identification of recurrent molecular alterations that could provide attractive targets for novel therapeutics, including MYD88 and CD79B mutations in patients with intravascular large B-cell lymphomas. Show less
The distribution of muscle weakness in MG is highly heterogeneous and frequently shifts in patients. In 5% of patients MG was restricted to ocular weakness, whereas 7% of patients never had any... Show moreThe distribution of muscle weakness in MG is highly heterogeneous and frequently shifts in patients. In 5% of patients MG was restricted to ocular weakness, whereas 7% of patients never had any form of ocular weakness throughout their disease course. In 83% of MG patients at least one other extra-ocular muscle was involved at the second visit.Patients with late-onset MG and the presence of additional autoimmune diseases had more exacerbations (OR = 47) and emergency treatments (OR = 26) than early-onset MG patients without other autoimmune diseases.MG-ADL (patient questionnaire on ADL) was found to be relatively insensitive to changes in generalized weakness. This led to the absence of a significant treatment response on MG-ADL in the presence of a significant response on QMG (an objective measure of muscle weakness) in the eculizumab study. A new ADL outcome measure, MGII, was shown to have a higher sensitivity for generalized weakness than MG-ADL.RoVEMP, a novel neurophysiological test, was shown to be a specific measure for myasthenic extra-ocular muscle weakness. In addition, we found a significant correlation between magnitude of decrement and the time since the last intake of pyridostigmine, supporting that RoVEMP decrement reflects reversible neuromuscular transmission failure. Show less
This thesis about deep vein thrombosis consists of two parts. The studies described in the first part of this thesis aimed to improve the diagnostic management of deep vein thrombosis (DVT) in... Show moreThis thesis about deep vein thrombosis consists of two parts. The studies described in the first part of this thesis aimed to improve the diagnostic management of deep vein thrombosis (DVT) in general, and in diagnostic challenging circumstances specifically. First, a new diagnostic safety threshold for all future diagnostic studies in deep vein thrombosis was established, adjusted to the disease prevalence in the study population. Thereafter a new simpler clinical decision rule, as first step in the diagnostic management of DVT was designed, selecting 4 items of the Wells rule. In the following chapter’s, studies using the MRI technique: Magnetic Resonance Direct Thrombus Imaging (MRDTI) were described. This is a non-contrast enhanced MRI technique by which a thrombus can be visualized directly. This technique was applied to diagnose DVT in challenging circumstances: ipsilateral recurrent DVT, DVT in pregnant woman and upper extremity DVT. The second part of this thesis describes studies that aimed to improve the prognosis of DVT by evaluation of the persistence to prescribed therapy and predictors of the development of post thrombotic syndrome (PTS). Show less
Studies in this thesis focused on the use of MRI in patients with early inflammatory arthritis. Studies were focused on: the diagnostic value of MRI, predictive value of MRI findings for the... Show moreStudies in this thesis focused on the use of MRI in patients with early inflammatory arthritis. Studies were focused on: the diagnostic value of MRI, predictive value of MRI findings for the development of erosions, associations between age and MRI findings, the use of MRI for the development of new disease activity scores and patient reported outcomes in patients with rheumatoid arthritis. Show less
Research on the prevalence, diagnostic and prognostic value for treatment of personality pathology – i.e., both personality disorders and problematic personality characteristics – was... Show more Research on the prevalence, diagnostic and prognostic value for treatment of personality pathology – i.e., both personality disorders and problematic personality characteristics – was carried out within a mainly Dutch forensic mental health setting. Issues such as (dis)simulation and unintentional self-deception limit the utility of self-report instruments within a pre-trial setting. Personality disorders and psychopathic traits in suspected offenders in the Netherlands often lead to court rulings of enforced psychiatric treatment – an internationally unique situation. A prospective study on the predictive value of personality disorder isolated factors that can affect enforced treatment length, such as crime type and comorbidity, that can be a focus for policy makers and forensic mental health experts. Caution is advised when using self-report instruments within the forensic context, especially in the absence of response bias scales and in the case of (legal) incentives for certain outcomes. There is urgent need for international standardization of instruments and terminology and a test battery that is specifically designed for and validated within forensic populations. An increase in (detail of) digital registration of patient, treatment and risk characteristics is necessary for meaningful scientific research, a better assessment of personality and risks, fewer incidents, lower recidivism and shorter treatment. Show less
This thesis consists of a number of studies revolving around the leading research theme, i.e., the derivation of new vectorcardiographic diagnostic & prognostic information from the 12-lead... Show moreThis thesis consists of a number of studies revolving around the leading research theme, i.e., the derivation of new vectorcardiographic diagnostic & prognostic information from the 12-lead electrocardiogram (ECG). Various research questions have been addressed, but most studies use a similar data processing approach, consisting of initial mathematical synthesis of a vectorcardiogram (VCG) from a standard 12-lead ECG, followed by the measurement of general VCG characteristics like maximal QRS- and T vectors, QRS- and T integrals, the spatial QRS-T angle (SA) and the ventricular gradient (VG). Studies focus on methodological as well as on clinical issues, and are discussed in the thesis. Show less
Distale radius fracturen komen veel voor. Bij ongeveer de helft van de distale radius fracturen komt een processus styloideus ulnae (PSU, distale ulna fractuur) voor. Een PSU fractuur is een... Show moreDistale radius fracturen komen veel voor. Bij ongeveer de helft van de distale radius fracturen komt een processus styloideus ulnae (PSU, distale ulna fractuur) voor. Een PSU fractuur is een indicator voor toegenomen instabiliteit. In een meta-analyse wordt geen verschil aangetoond in uitkomst van een distale radius fracturen met of zonder PSU fractuur. Hetzelfde geldt voor het al dan niet vastgroeien van het PSU. In ongeveer 33% van de distale radius fracturen komt distale radioulnaire (DRU) instabiliteit voor. Klinische testen en radiologische onderzoeken om dit te diagnosticeren zijn weinig betrouwbaar. Een CT-scan additioneel aan een r_ntgenfoto zorgt niet voor toename in overeenstemming over de uitslag. De overeenstemming tussen beoordelaars van CT-scans valt tegen, naast een grote normale spreiding. Wanneer DRU instabiliteit gediagnostiseerd is, zal de ossale anatomie genormaliseerd moeten worden. In dit proefschrift worden operatie-technieken beschreven die veilig en effectief zijn voor het oplossen van DRU instabiliteit. De auteur concludeert dat DRU instabiliteit een diagnostisch dilemma is. Onderzoek zal zich moeten richten op individuele normaalwaarden, zodat de diagnose makkelijker te stellen is. De aanbeveling wordt gedaan dat distale radius fracturen behandeld dienen te worden door gespecialiseerde teams zodat de complicaties beperkt blijven en indien nodig herkend en optimaal behandeld worden. Show less
Venous thromboembolism is a common disease that can lead to potential fatal complications. The diagnosis and treatment of a first venous thromboembolism has been well studied, however the... Show moreVenous thromboembolism is a common disease that can lead to potential fatal complications. The diagnosis and treatment of a first venous thromboembolism has been well studied, however the diagnostic management and therapy of recurrent venous thromboembolism still have limitations. This thesis discusses a new imaging technique for recurrent deep venous thrombosis and the duration of treatment after a recurrent venous thromboembolism. It shows that Magnetic Resonance Direct Thrombus Imaging might be a potential diagnostic tool for the diagnostic management of recurrent venous thromboembolism. Furthermore the prognosis after a first deep vein thrombosis is discussed by means of recurrence and bleeding risks. Show less
Spondyloarthritis (SpA) is a heterogeneous group of rheumatic diseases, characterized by sacroiliac-joint inflammation (sacroiliitis), peripheral and extra-articular complaints. The lack of... Show moreSpondyloarthritis (SpA) is a heterogeneous group of rheumatic diseases, characterized by sacroiliac-joint inflammation (sacroiliitis), peripheral and extra-articular complaints. The lack of diagnostic criteria makes diagnosing SpA challenging, yet, classification criteria are available. We tested the performance (sensitivity, specificity) of various classification criteria; the recently developed Assessment of SpondyloArthritis international Society (ASAS) criteria outperformed all other criteria. We investigated the discrepancies in interpretation MRIs and conventional radiographs on the presence of sacroiliitis; agreement on radiographic sacroiliitis between different readers is only moderate, but agreement regarding sacroiliitis on MRI is substantial. Rheumatologists take into account all clinical and laboratory results in addition to the imaging results in the diagnostic process. The diagnostic Berlin algorithm - in which all relevant results are taken into account __ can assist rheumatologists. We proposed a modification of this algorithm, which is accepted by ASAS and also included in the recently published guidelines for the diagnosis and treatment of SpA by the Dutch Society for Rheumatology. Besides, we performed systematic literature reviews, forming the base for the update of the ASAS management recommendations. With these results, SpA-patients can be recognized earlier, offering better treatment options and better outcomes. However, further improvements of care for SpA-patients are necessary. 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
In conclusion, the results of the present studies show how schizotypal symptoms may develop following child psychiatric psychopathology and how these symptoms unfavorably influence a persons__... Show moreIn conclusion, the results of the present studies show how schizotypal symptoms may develop following child psychiatric psychopathology and how these symptoms unfavorably influence a persons__ quality of life. It is important for clinicians to be aware of the complex dynamics of psychopathology and the higher risk for adult schizotypal symptomatology following behavioral problems and psychiatric disorders at child and adolescent age. Show less
The objectives of this thesis are to simplify, to validate and compare diagnostic strategies in patients with clinical suspicion of acute pulmonary embolism (PE). The revised Geneva score was... Show moreThe objectives of this thesis are to simplify, to validate and compare diagnostic strategies in patients with clinical suspicion of acute pulmonary embolism (PE). The revised Geneva score was simplified and validated. Furthermore, four widely used clinical decision rules (CDRs) were directly compared in excluding PE. It was concluded that the four CDRs in combination with a D-dimer test performed similarly in the exclusion of acute PE. And we confirmed that a normal CT-scan alone can safely exclude PE in patients in whom CTPA is required to rule out VTE in these patients. We showed that the algorithm consisting of a CRD, D-dimer test and CT-scan is also effective in the management of patients with clinically suspected recurrent acute PE. In addition, the role of NT-pro-BNP has been evaluated for the risk assessment for adverse clinical outcome for patients with proven acute PE and we showed the ability to distinguish an increased risk with elevated NT-pro-BNP values for complications during the hospital stay and 30-day mortality. Finally, it is concluded that home treatment with anticoagulant seems effective and safe in patients with acute PE, when selected according to pre defined criteria. Show less
The current health care system is severely challenged by for instance rising costs, fewer new blockbuster drugs and increasing numbers of hospitalizations due to side effects. Especially in the... Show moreThe current health care system is severely challenged by for instance rising costs, fewer new blockbuster drugs and increasing numbers of hospitalizations due to side effects. Especially in the area of chronic diseases the current disease fighting strategy is failing and a more personalized medicine approach is needed. In this thesis new sub-types of rheumatoid arthritis are characterized with metabolomics analysis and symptoms patterns. The sub-types are based on diagnostic knowledge from Chinese medicine. The two sub-types of RA patients were found to have differences in apoptosis regulation of T-cells and differences in urine acylcarnitine levels. A questionnaire was designed to distinguish the two sub-types and to evaluate symptom patterns of arthritis patients. In the future the response to treatment of these sub-types of patients can be studied and specific treatment can be targeted to these sub-types. Show less
In this dissertation we present the results of our research on Helicobacter pylori infections in childhood, focusing on the prevalence, diagnosis and treatment of the infection. Our studies were... Show moreIn this dissertation we present the results of our research on Helicobacter pylori infections in childhood, focusing on the prevalence, diagnosis and treatment of the infection. Our studies were conducted in the Netherlands, Europe and Indonesia. We discuss diagnostic tests, therapeutic regimens, resistance and preventive measurements. We highlight clinical and pathophysiological aspects of the infection and describe which particular strains are prevalent and how transmission occurs. Presently, there are no established correlations between a Helicobacter pylori infection and recurrent abdominal pain, gastroesophageal reflux disease or growth retardation. We present data on the prevalence of Helicobacter pylori in young infants in the Netherlands and observe that children with at least one non-Dutch parent form a risk group. We assess risk factors in a Europe-wide study on gastroduodenal erosions and ulcers in childhood. In our study, Helicobacter pylori infection and gastrotoxic medications were relatively little implicated as etiology of that pathology. The prevalence of Helicobacter pylori infection in Indonesian young children is relatively high and points at an early acquisition of the infection. Finally, the resistance of Helicobacter pylori to clarithromycin and metronidazole was assessed for adults and children in the Netherlands. Low resistance rates were found, but the resistance in adults is increasing. We conclude that a test-and-treat regimen is justified for the Netherlands. Show less
Non-invasive imaging plays an increasingly important role in the diagnosis and risk stratification of coronary artery disease. Several techniques such as stress echocardiography and myocardial... Show moreNon-invasive imaging plays an increasingly important role in the diagnosis and risk stratification of coronary artery disease. Several techniques such as stress echocardiography and myocardial perfusion imaging have become available to assess cardiac function and myocardial perfusion. With the arrival of multi-slice computed tomography coronary angiography (CTA), non-invasive imaging of coronary anatomy has also become possible. CTA is a relatively new imaging technique; the objective of the thesis is therefore to explore the value of CTA for diagnosis and risk stratification of CAD in patients presenting with suspected and known CAD, in order to further define its role in clinical practice. The results of this thesis show that CTA provides important diagnostic information relative to existing non-invasive imaging strategies. In addition the detailed anatomic information obtained using CTA was shown to provide important prognostic information. CTA supplies complementary information to existing non-invasive imaging techniques, and has the potential to provide a more patient tailored approach to patient management. What remains to be determined is how CTA and non-invasive functional imaging should be integrated into clinical practice. Show less
