Background: Deep vein thrombosis (DVT) is a common multi-factorial disease with a partially understood aetiology. Although the roles of high factor (F)VIII and von Willebrand factor (VWF) levels... Show moreBackground: Deep vein thrombosis (DVT) is a common multi-factorial disease with a partially understood aetiology. Although the roles of high factor (F)VIII and von Willebrand factor (VWF) levels are recognized, that of ADAMTS13 is still unclear.Aim: To assess the association between ADAMTS13 activity levels, VWF antigen (VWF:Ag) and FVIII coagulant activity (FVIII:C) levels and DVT.Materials and methods: 365 Italian DVT patients and 292 ageand sex-matched controls were considered. Plasma ADAMTS13 activity was measured using FRETS-VWF73 assay. VWF:Ag and FVIII:C were measured using immunoassay and one-stage clotting assay (ACL TOP analyzer), respectively. Quartile analyses were performed to evaluate the individual association between ADAMTS13 activity, VWF:Ag, FVIII:C and DVT. The combined effect of high VWF levels ( 4th quartile) and low ADAMTS13 levels (< 1st quartile) was evaluated using binary variables. All models were ageand sex-adjusted. Estimated risks were reported as Odds ratio (OR) with 95% confidence intervals (CI).Results: ADAMTS13 activity was lower in DVT patients (94% vs. 98% of controls). Patients with an ADAMTS13 activity <1st quartile (86%) showed a 1.6-fold increased risk of DVT (95%CI, 1.05-2.55). The combination of low ADAMTS13 activity and high VWF:Ag levels was associated with a 15-fold increased risk (95%CI, 7.80-33.80). VWF:Ag and FVIII:C were associated to DVT with a dose-response relationship.Conclusions: ADAMTS13 activity < 86% was associated with a moderate risk of DVT. The co-presence of low ADAMTS13 activity and high VWF levels resulted in a strong synergistic effect on DVT risk. The association of VWF:Ag and FVIII:C with DVT was confirmed. Show less
Purpose The aim of this study was to evaluate whether the addition of brain CT imaging data to a model incorporating clinical risk factors improves prediction of ischemic stroke recurrence over 5... Show morePurpose The aim of this study was to evaluate whether the addition of brain CT imaging data to a model incorporating clinical risk factors improves prediction of ischemic stroke recurrence over 5 years of follow-up. Methods A total of 638 patients with ischemic stroke from three centers were selected from the Dutch acute stroke study (DUST). CT-derived candidate predictors included findings on non-contrast CT, CT perfusion, and CT angiography. Five-year follow-up data were extracted from medical records. We developed a multivariable Cox regression model containing clinical predictors and an extended model including CT-derived predictors by applying backward elimination. We calculated net reclassification improvement and integrated discrimination improvement indices. Discrimination was evaluated with the optimism-corrected c-statistic and calibration with a calibration plot. Results During 5 years of follow-up, 56 patients (9%) had a recurrence. The c-statistic of the clinical model, which contained male sex, history of hyperlipidemia, and history of stroke or transient ischemic attack, was 0.61. Compared with the clinical model, the extended model, which contained previous cerebral infarcts on non-contrast CT and Alberta Stroke Program Early CT score greater than 7 on mean transit time maps derived from CT perfusion, had higher discriminative performance (c-statistic 0.65,P= 0.01). Inclusion of these CT variables led to a significant improvement in reclassification measures, by using the net reclassification improvement and integrated discrimination improvement indices. Conclusion Data from CT imaging significantly improved the discriminatory performance and reclassification in predicting ischemic stroke recurrence beyond a model incorporating clinical risk factors only. Show less
Mutations in leucine-rich repeat kinase 2 (LRRK2) are an established cause of inherited Parkinson's disease (PD). LRRK2 is expressed in both neurons and glia in the central nervous system, but its... Show moreMutations in leucine-rich repeat kinase 2 (LRRK2) are an established cause of inherited Parkinson's disease (PD). LRRK2 is expressed in both neurons and glia in the central nervous system, but its physiological function(s) in each of these cell types is uncertain. Through sequential screens, we report a functional interaction between LRRK2 and Clathrin adaptor protein complex 2 (AP2). Analysis of LRRK2 KO tissue revealed a significant dysregulation of AP2 complex components, suggesting LRRK2 may act upstream of AP2. In line with this hypothesis, expression of LRRK2 was found to modify recruitment and phosphorylation of AP2. Furthermore, expression of LRRK2 containing the R1441C pathogenic mutation resulted in impaired clathrin-mediated endocytosis (CME). A decrease in activity-dependent synaptic vesicle endocytosis was also observed in neurons harboring an endogenous R1441C LRRK2 mutation. Alongside LRRK2, several PD-associated genes intersect with membrane-trafficking pathways. To investigate the genetic association between Clathrin-trafficking and PD, we used polygenetic risk profiling from IPDGC genome wide association studies (GWAS) datasets. Clathrin-dependent endocytosis genes were found to be associated with PD across multiple cohorts, suggesting common variants at these loci represent a cumulative risk factor for disease. Taken together, these findings suggest CME is a LRRK2-mediated, PD relevant pathway. Show less
Ebbens, M.M.; Errami, H.; Moes, D.J.A.R.; Bemt, P.M.L.A. van den; Boog, P.J.M. van der; Gombert-Handoko, K.B. 2019
Background: Medication reconciliation in transitions of care can prevent medication transfer errors (MTE). MTE can cause patient harm. Since performing medication reconciliation for every patient... Show moreBackground: Medication reconciliation in transitions of care can prevent medication transfer errors (MTE). MTE can cause patient harm. Since performing medication reconciliation for every patient is not always feasible, identification of potential risk factors of MTE could aid in targeting this intervention to the right patients.Objective: To establish the proportion of patients with one or more MTE in the outpatient nephrology setting. Secondary patient characteristics associated with MTE, type and potential harm, and medication groups were investigated.Methods: This retrospective observational cohort study was conducted in the Leiden University Medical Center, the Netherlands, between November 2017 and April 2018. The cohort involved patients in whom medication reconciliation was performed by a medical attendant using the electronic tool 'Medical Dashboard' prior to visiting the nephrologist. MTE were defined as unintended discrepancies between the medication in the hospital system and the result of the medication reconciliation. The proportion of patients with one or more MTE was calculated and the association of patient characteristics (age, sex, number of medications and kidney function (CKD-EPI)) with MTE was analyzed using multivariate logistic regression.Results: Of 380 patients, 235 patients (61.8%) had at least one MTE. On average patients used 10.3 medications. The number of medications per patient was significantly associated with MTE; OR 1.11 (95%CI 1.05-1.16). No association was found for age, sex, and kidney function.Conclusion: In ambulatory nephrology patients 61.8% had at least one MTE. Nephrology patients using a higher number of drugs are more prone to MTE. Show less
Lansu, J.; Groenewegen, J.; Coevorden, F. van; Houdt, W. van; Akkooi, A.C.J. van; H. van boven; ... ; Haas, R.L. 2019
Aims: The purpose of the study was to investigate the time dependent dynamics of wound complications and local control after preoperative radiotherapy (RT) in Extremity Soft Tissue Sarcomas (ESTS)... Show moreAims: The purpose of the study was to investigate the time dependent dynamics of wound complications and local control after preoperative radiotherapy (RT) in Extremity Soft Tissue Sarcomas (ESTS).Patients & methods: In this retrospective cohort study, all patients treated for an extremity sarcoma with pre-operative radiotherapy followed by surgery were identified from a prospectively maintained database. A wound complication (WC) was defined as any local complication of the surgical area requiring intervention, hospital readmission or significant extension of the initial admission period.Results: A total of 191 preoperatively irradiated ESTS patients were included in this study. WC was seen in 31% of the patients (n=60). WC started after a median time of 25 days from surgery, with a median duration of 76 days. Adiposity, smoking and a lower extremity or superficial tumor localization were significantly correlated with an increased WC rate. Risk factors for a duration of WC >= 120 days are early development of WC (<= 21 days after surgery) and smoking. Local control rates after 1, 3 and 5 years were 99%, 93% and 93%, respectively.Conclusion: Approximately one-third of patients selected for preoperative RT develops a WC, typically in smoking, adipose patients with superficial tumor localizations in the lower extremity. Based upon the well-established superior long-term functional outcome, maintained excellent local control rates and the temporary nature of the WC issue, preoperative RT remains our preferred treatment. Although, in patients at high risk of WC, post-operative RT might be considered. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
Derks, M.G.M.; Bastiaannet, E.; Water, W. van de; Glas, N.A. de; Seynaeve, C.; Putter, H.; ... ; Liefers, G.J. 2018
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
Several studies during the past decade have shown that patients with venous thrombosis have an increased risk of subsequent arterial thrombosis, thus suggesting a link between the two diseases. The... Show moreSeveral studies during the past decade have shown that patients with venous thrombosis have an increased risk of subsequent arterial thrombosis, thus suggesting a link between the two diseases. The aim of this thesis was to investigate the associations of traditional cardiometabolic risk factors with risk of a first and recurrent venous thrombosis. We showed that levels of major lipids, i.e. total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, were not associated with a first venous thrombosis. In contrast, low levels of apolipoproteins B and A1 were associated with an increased risk of a first event. Regarding recurrence, tests for lipid levels, glucose levels and hematologic variables did not identify patients at an increased risk of recurrent venous thrombosis, and these tests should not be done for this indication nor influence decisions on duration of anticoagulant treatment. In this thesis, we further searched for associations between lipids and hemostatic factors, and found that levels of vitamin K-dependent factors (VKDFs), including factor IX, were associated with triglyceride levels. We hypothesized that this association could be explained by common mechanisms, regulating levels of both VKDFs and triglycerides. Show less
Secondary prevention of recurrent venous can be achieved in two ways, either by elimination of modifiable risk factors or by extending the anticoagulant treatment period in patients at high risk... Show moreSecondary prevention of recurrent venous can be achieved in two ways, either by elimination of modifiable risk factors or by extending the anticoagulant treatment period in patients at high risk of recurrence. The aim of this thesis was to identify modifiable risk factors for as well as factors that might be able to predict recurrent venous thrombotic events. This thesis reports on an increased risk of recurrences in women who continue or start using hormonal contraceptives after a first venous thrombotic event, suggesting that refraining from this modifiable risk factor decreases the risk of recurrence. Furthermore, this thesis describes several factors, male sex, unprovoked first event, levels of coagulation factor VIII and antibiotic use to be associated with recurrent venous thrombosis. These factors should eventually be taken together and used to build a prognostic model, which will be able to predict recurrences at a refined and individual level. Show less
Around 5-10% of patients with asthma do not respond adequately to inhaled steroids and long-acting bronchodilators and become difficult-to-treat; they remain symptomatic, have recurrent... Show moreAround 5-10% of patients with asthma do not respond adequately to inhaled steroids and long-acting bronchodilators and become difficult-to-treat; they remain symptomatic, have recurrent exacerbations or persistent airflow limitation. This thesis focuses on the mechanisms that may explain why these patients become difficult-to-treat and investigate biomarkers that can predict the development of specific asthma phenotypes. The different studies describe the possible role of alpha- antitrypsin in the development of persistent airflow limitation, the relationship between severity of asthma and the degree of peripheral airway inflammation and dysfunction, the clinical and inflammatory characteristics of obese patients with difficult-to-treat asthma, risk factors of lung function decline and the consistency of the eosinophilic phenotype Show less
